Society of Nuclear Medicine and Molecular Imaging Theranostics Center for Molecular Radiotherapy and Precision Oncology VA—A new type of peptide receptor radionuclide therapy (PRRT) has been shown to control disease in 85 percent of patients with metastatic neuroendocrine neoplasms achieving complete remission in some patients The first-in-human study utilized 177Lu-DOTA-LM3 therapy which was administered without severe adverse effects and was well tolerated by the majority of patients This research was published in the November issue of The Journal of Nuclear Medicine Neuroendocrine neoplasms are tumors that arise from diffuse neuroendocrine system cells They are most commonly found in the gastrointestinal tract Neuroendocrine neoplasms are fairly rare diseases but their incidence and prevalence have increased substantially in recent decades The majority of neuroendocrine tumors overexpress somatostatin receptors (SSTRs) which are targeted for imaging and treatment SSTR-targeted imaging using radiolabeled somatostatin agonists followed by PRRT has been remarkably successful in managing neuroendocrine tumors,” said Jingjing Zhang assistant professor in the Department of Diagnostic Radiology at the Yong Loo Lin School of Medicine at the National University of Singapore in Singapore potent SSTR antagonists—which only poorly internalize into tumor cells if at all—have surprisingly been shown to be even superior to agonists for such purposes.” To further investigate the role antagonists can play in treating neuroendocrine tumors researchers developed a study to determine the safety biodistribution and efficiency of a new type of SSTR antagonist, 177Lu-DOTA-LM3 heavily pretreated neuroendocrine neoplasms underwent PRRT with 177Lu-DOTA-LM3 Treatment-related adverse events were graded for all participants and dosimetry was performed for 11 patients 177Lu-DOTA-LM3 was administered without severe adverse effects and was well tolerated by most patients Disease control was reached in 40 out of 47 patients (85 percent) who were monitored after 177Lu-DOTA-LM3 therapy Two patients achieved complete remission by the European Organization for Research and Treatment of Cancer criteria the uptake and dosimetry of the antagonist 177Lu-DOTA-LM3 were compared with those of the commonly used SSTR agonist 177Lu-DOTATOC in patients undergoing treatment on the same dosimetry protocol. 177Lu-DOTA-LM3 demonstrated higher uptake and a longer effective half-life in tumor lesions resulting in higher tumor radiation doses than for agonist 177Lu-DOTATOC “These encouraging findings demonstrate the feasibility and superiority of SSTR antagonist 177Lu-DOTA-LM3 as compared to SSTR agonists antagonist PRRT can be performed under concurrent treatment with somatostatin analogues without the need for interrupting these medications This is especially important for patients suffering from carcinoid syndrome or even carcinoid crisis,” stated Richard P president of the academy at the International Centers for Precision Oncology (ICPO) and consultant for the Center for Advanced Radiomolecular Precision Oncology “The results are very encouraging for theranostic applications of SSTR antagonists to further improve outcomes in patients with neuroendocrine neoplasms in the future.” This study was made available online in March 2021 The authors of “First-in-human study of novel SSTR antagonist 177Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: dosimetry safety and effectiveness” include Richard P previously working at THERANOSTICS Center for Radiomolecular Precision Oncology THERANOSTICS Center for Radiomolecular Precision Oncology Visit JNM’s new website for the latest research, and follow our new Twitter and Facebook pages @JournalofNucMed Please visit the SNMMI Media Center for more information about molecular imaging and precision imaging. To schedule an interview with the researchers, please contact Rebecca Maxey at (703) 652-6772 or rmaxey@snmmi.org About JNM and the Society of Nuclear Medicine and Molecular Imaging The Journal of Nuclear Medicine (JNM) is the world’s leading nuclear medicine, molecular imaging and theranostics journal, accessed more than 11 million times each year by practitioners around the globe, providing them with the information they need to advance this rapidly expanding field. Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org JNM is published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging—precision medicine that allows diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes 10.2967/jnumed.120.258889 First-in-human study of novel SSTR antagonist 177Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: dosimetry Helmut Mäcke is a coinventor of SSTR-based antagonistic radiopeptides The patent rights are assigned to his academic institution are not responsible for the accuracy of news releases posted to EurekAlert by contributing institutions or for the use of any information through the EurekAlert system Copyright © 2025 by the American Association for the Advancement of Science (AAAS) Metrics details and SST5 are overexpressed in neuroendocrine neoplasms (NENs) but little is known about SST4 expression in NENs because of a lack of specific monoclonal antibodies We recently developed and thoroughly characterised a rabbit monoclonal anti-human SST4 antibody and showed that it is well suited for identifying SST4 expression in routine pathology samples The present study aimed to re-evaluate SST4 expression in a large set of NEN samples using this antibody we assessed SST4 expression in 722 formalin-fixed paraffin-embedded NEN samples from 274 patients by immunohistochemistry using the novel antibody 7H49L61 The immunostaining was semiquantitatively evaluated using the 12-point immunoreactivity score (IRS) and the results were correlated with clinicopathological data its expression intensity was negligible overall both cytoplasmic and membraneous staining was observed SST4 expression was somewhat higher in bronchopulmonary NEN (BP-NEN) than in gastroenteropancreatic NEN (GEP-NEN) but still very low SST4 expression positively correlated with favourable patient outcomes in BP-NEN but had a positive association with Ki-67 index or tumour grading and a negative interrelationship with overall survival in GEP-NEN SST4 expression in both BP-NEN and GEP-NEN is negligible and of no diagnostic or therapeutic relevance only cytoplasmic staining of cells was observed Given the limited and contradictory data on SST4 expression in NEN we aimed to re-evaluate SST4 expression in a large panel of BP-NEN and GEP-NEN samples using the novel antibody 7H49L61 and to correlate the expression data with clinicopathological parameters The peptide used to immunise rabbits was CQQEALQPEPGRKRIPLTRTTTF corresponding to residues 366–388 of human SST4 We evaluated 722 tumour samples from 274 patients (in detail and 1 patient with 18 samples; 396 were primary tumour samples this information was not included in the patient records) both primary and metastatic samples were available 93 (34.0%) originated from the lungs (22 TCs The localisation of 10 (3.6%) primary tumours was unknown The samples were provided by the Institute of Pathology and Cytology Bad Berka (Bad Berka Germany) and were surgically removed between 1998 and 2016 at the Department of General and Visceral Surgery Clinical data were gathered from patient records All procedures performed in this study involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments the patient information and the declaration of informed consent were approved by and permission was gained from the local ethics committee (Ethikkommission der Landesärztekammer Thüringen) for this retrospective analysis Informed consent for the use of tissue samples for scientific purposes was obtained from all individual participants included in the study when entering the Theranostic Research Center and the Department of General and Visceral Surgery The neuroendocrine tumours evaluated in the present investigation were obtained from 141 men (51.5% of cases) and 123 women (44.9%) The overall mean age of the patients at diagnosis was 58.5 years (median: 59.7 years Forty-seven of the (corresponding) primary tumours (17.1%) were classified as T1; 46 (16.8%) as T2; 58 (21.2%) as T3; and 24 (8.8%) as T4 the extent of the primary tumour was not reported lymph node metastases were present in 123 cases (44.9%) Distant metastases were disclosed for 114 patients (41.6%) whereas 89 patients (32.5%) had no distant metastases at diagnosis the presence of distant metastases was not reported 19 of 171 patients (11.1%) with GEP-NEN had Union for International Cancer Control stage I disease and 102 patients (59.6%) had stage IV disease The disease stage was not determined for the 93 BP-NEN patients and the 10 patients with unknown tumour origin and 75 (27.4%) displayed grade 3 histology Tumour grading was not reported for five (1.8%) patients tumours for which hormone-related symptoms such as gastrointestinal ulcers flushes or hypoglycaemia were reported in the patient files tumours for which the relevant symptoms were denied in the patient anamnesis For 128 tumours this information was not included in the patient files The median overall follow-up time was 53.3 months Representative staining patterns obtained in bronchopulmonary (A–C) and gastroenteropancreatic neuroendocrine neoplasms (D–F) using the antibody against somatostatin receptor 4 (SST4) 7H49L61 The percentage of positive tumour cells classified in five categories (no positive cells [0] and > 80% positive cells [4]) was multiplied by the staining intensity classified in four categories (no staining [0] IRS values ranging from 0 to 12 were obtained Only tumour samples with an IRS ≥ 3 were considered SST4-positive Because the data were not normally distributed (according to a Kolmogorov–Smirnov test) and Spearman’s rank correlation were performed p values ≤ 0.05 were considered significant Somatostatin receptor 4 (SST4) expression in bronchopulmonary and gastroenteropancreatic neuroendocrine neoplasms by tumour entity and site of origin of the primary tumour (A) Numbers of tumours positive (immunoreactivity score [IRS] ≥ 3) or negative (IRS < 3) for SST4 (B) Box plots of SST4 expression levels of the tumours circles indicate mild outliers (1.5–3 interquartile range [IQR] from the nearest quartile) and asterisks indicate extreme outliers (> 3 IQR from the nearest quartile) large-cell neuroendocrine carcinoma of the lung; SCLC Tumours deriving from the ileum (median IRS: 0.50; mean IRS: 1.00) showed significantly lower SST4 expression than did those originating from the stomach (median IRS: 2.25; mean IRS: 3.55; Mann–Whitney test: p < 0.001) from the duodenum/jejunum (median IRS: 1.25; mean IRS: 2.42; Mann–Whitney test: p < 0.045) from the rectum (median IRS: 3.00; mean IRS: 2.69; Mann–Whitney test: p < 0.001) or from the pancreas (median IRS: 3.00; mean IRS: 3.17; Mann–Whitney test: p < 0.001) tumours originating from the appendix (median IRS: 0.00; mean IRS: 1.03) displayed significantly lower IRS values than did those deriving from the stomach (Mann–Whitney test: p = 0.046) or from the pancreas (Mann–Whitney test: p = 0.029) we analysed correlations between SST4 expression and clinical data separately for the two tumour types Overall survival of patients with (A) bronchopulmonary neuroendocrine neoplasm (BP-NEN) or (B) gastroenteropancreatic neoplasm (GEP-NEN) by somatostatin receptor 4 (SST4) expression of their tumours The median immunoreactivity scores (IRSs) for all BP-NEN tumours of 3.0 and for all GEP-NEN tumours of 1.5 were set as the cut-off values for discrimination between high or low SST4 expression (A) Log-rank test: p = 0.021; Breslow test: p = 0.007 (B) Log-rank test: p = 0.530; Breslow test: p = 0.245 but unlike the earlier immunohistochemical studies our investigation demonstrated for the first time cytoplasmic as well as membraneous staining of tumour cells the overall median IRS across tumours was only 2.0 below the threshold set for receptor positivity SST4 expression seems to be negligible in NEN overall There were some differences in SST4 positivity rates and SST4 expression levels between BP-NEN and GEP-NEN and also between GEP-NEN tumours with different sites of origin the highest median IRS observed across all NEN entities and sites of origin was noted in AC and amounted to only 3.7 All data generated during this study are included in this published article. The amino acid sequence of the receptor against which the antibody was raised is publicly available through the Uniprot database (https://www.uniprot.org/uniprotkb/P31391/entry) Gastroenteropancreatic neuroendocrine neoplasm Large-cell neuroendocrine carcinoma of the lung One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumours in 35,825 cases in the United States Exploring the rising incidence of neuroendocrine tumors: A population-based analysis of epidemiology and survival outcomes in patients with neuroendocrine tumors in the United States Gastroenteropancreatic neuroendocrine tumors Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumours in the United States The new WHO classification of gastrointestinal neuroendocrine tumors and immunohistochemical expression of somatostatin receptor 2 and 5 Overview of the 2022 WHO classification of neuroendocrine neoplasms Classification of neuroendocrine neoplasms: Lights and shadows Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors Somatostatin receptors 2 and 5 are the major somatostatin receptors in insulinomas: An in vivo and in vitro study Somatostatin receptor subtypes in human non-functioning neuroendocrine tumors and effects of somatostatin analogue SOM230 on cell proliferation in cell line NCI-H727 Somatostatin receptor subtypes 2 and 5 are associated with better survival in well-differentiated endocrine carcinomas Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours Somatostatin and dopamine receptor profile of gastroenteropancreatic neuroendocrine tumors: An immunohistochemical study Expression of somatostatin receptor (SSTR) subtypes (SSTR-1 4 and 5) in neuroendocrine tumors using real-time RT-PCR method and immunohistochemistry Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin Correlation of somatostatin receptor 1–5 expression [18F]F-FDG PET/CT and clinical outcome in a prospective cohort of pancreatic neuroendocrine neoplasms Somatostatin receptor 2-targeting compounds Concomitant expression of several peptide receptors in neuroendocrine tumours: Molecular basis for in vivo multireceptor tumour targeting Differential expression of somatostatin receptors 1–5 in neuroendocrine carcinoma of the lung Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: New diagnostic The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): Current strategies in diagnosis and treatment Conclusions of an expert meeting February 2011 in Weimar Diagnosis and treatment of bronchopulmonary tumours: State of the art Neuroendocrine tumors of the lung: Current challenges and advances in the diagnosis and management of well-differentiated disease Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas—predominance of receptor subtype 4 Monoclonal antibodies against the human somatostatin receptor subtypes 1–5: Development and immunohistochemical application in neuroendocrine tumours Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors Prognostic value of somatostatin receptor subtypes in pancreatic neuroendocrine tumours International union of basic and clinical pharmacology Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors Immunohistochemical expression of somatostatin receptor subtypes in a panel of neuroendocrine neoplasias Reassessment of SST4 somatostatin receptor expression using SST4-eGFP knockin mice and the novel rabbit monoclonal anti-human SST4 antibody 7H49L61 CXCR4 chemokine and endothelin A receptor expression in a large set of paragangliomas Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue Prognostic value of PD-L1 expression in bronchopulmonary neuroendocrine tumours Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients Pancreatic neuroendocrine tumors (PNETs): Incidence prognosis and recent trend toward improved survival Comparison of functional and nonfunctional neuroendocrine tumors in the pancreas and peripancreatic region Evaluation of outcomes following surgery for locally advanced pancreatic neuroendocrine tumors Assessment of G protein-coupled oestrogen receptor expression in normal and neoplastic human tissues using a novel rabbit monoclonal antibody Download references Open Access funding enabled and organized by Projekt DEAL This research did not receive any specific grant from any funding agency in the public Department of General and Visceral Surgery Laboratory of Pathology and Cytology Bad Berka Conceptualization: A.L.; Methodology: A.L.; Investigation: B.E. A.L.; Writing—original draft preparation: A.L.; Writing—review and editing: B.E. Daniel Kaemmerer received support for travelling to meetings by the companies IPSEN and PFIZER Stefan Schulz is the founder and scientific advisor of 7TM Antibodies GmbH and declares no competing non-financial interests but competing financial interests All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-022-19014-w Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research EG caught up with Robag Wruhme to learn more about the release of his new ‘Speicher 123’ EP on Kompakt This is a linchpin for the urban high life congratulations on the release of your ‘Speicher 123’ EG: What can your fans expect to find on ‘Speicher 123’ Is there a particular concept running through this one The ‘Speicher’ series want more oriented dance material A playground where I feel very comfortable I’m not one of those who only produce one sound and one mood I am happy to be able to express myself in different directions EG: In which ways would you say your sound has evolved since the release of your first EP for Kompakt you always gain new knowledge about the matter and the demands grow with it I’ve become more serious and critical That’s good on an intellectual level but it sometimes annoys me because I miss the youthful lightness “You always gain new knowledge about the matter and the demands grow with it I’ve become more serious and critical” EG: What does your studio look like at the moment Have you recently picked up any new soft or hardware you’d personally recommend and little can often be more than a thousand buttons and sunk money which in the end only collects useless dust EG: How do you keep entertained when not in the studio or music that have caught your attention lately I’m reading ‘Herkunft’ by Saša Stanišić The problem with series is that I get addicted to it too quickly and it eats up my time completely Surely not everyone that really “listens to themselves” is going to make it in the industry people are very fortunate to have been in the right place at the right time this would mean that ANYONE could be a big act who indulges in these attributes as “all others being regarded as losers” EG: What are your thoughts on the current state of the scene What would you like to see more and less of where “community” has no social component This is a monkey circus where whoever sits highest in the tree and opens their mouth gets the best spot “This is a monkey circus where whoever sits highest in the tree and opens their mouth gets the best spot” Robag Wruhme: Art is the tool to recognize and perceive oneself That’s why art is interpreted so differently because people are configured in such detail the cellation of art is always an expression of a rich society What particular milestones are you looking forwards to now Robag Wruhme: I’m working on the next album and this one will go down in history the three are getting a sister who will get to the point again Robag Wruhme’s ‘Speicher 123’ EP is out now via Kompakt. Purchase your copy here Follow Robag Wruhme: SoundCloud | Instagram | Facebook | Spotify Metrics details Little is known about the expression of the orphan G protein-coupled receptor GPR19 at the protein level After verification of the antibody specificity using GPR19-expressing cell lines and a GPR19-specific siRNA the antibody was used for immunohistochemical staining of a variety of formalin-fixed paraffin-embedded normal and neoplastic human tissue samples GPR19 expression was detected in a distinct cell population within the cortex and in endocrine cells of the bronchial tract Among the 30 different tumour entities investigated strong GPR19 expression was found in adenocarcinomas typical and atypical carcinoids of the lung the receptor was also present in large cell neuroendocrine carcinomas of the lung and a subpopulation of pancreatic neuroendocrine neoplasms a negative correlation with the expression of the proliferation marker Ki-67 and a positive interrelationship with patient survival was observed our results indicate that in adenocarcinomas and neuroendocrine tumours of the lung GPR19 may serve as a suitable diagnostic or therapeutic target While there is data on GPR19 mRNA expression there appears to be no information on the expression of GPR19 at the protein level in normal and neoplastic tissues or cancer cell lines in collaboration with Thermo Fisher Scientific (Waltham USA) we developed a rabbit polyclonal antibody targeting the carboxyl-terminus of human GPR19 The antibody specificity was first tested using the SCLC cell line OH-1 We then determined the expression profile for GPR19 for normal human tissues and a wide range of human tumours using a large panel of formalin-fixed normal and neoplastic human tissue samples These experiments revealed a strong GPR19 expression almost exclusively in lung tumours we expanded the number of lung tumour samples examined and finally evaluated GPR19 expression in a broad panel of different lung tumour entities The expression results were then correlated with clinical data Verification of the specificity of the anti-GPR19 antibody by immunocytochemistry analyses (A) OH-1 cells or (D) NCI-h82 cells expressing GPR19 endogenously were fixed and stained with the anti-GPR19 antibody followed by an Alexa Fluor 488-conjugated anti-rabbit secondary antibody E) For analysis of the specificity of the antibody GPR19 expression was silenced in OH-1 cells or NCI-h82 cells using a GPR19-specific siRNA the anti-GPR19 antibody was preincubated for 2 h with 10 µg/ml of the peptide used for immunisations of the rabbits 4′,6-diamidino-2-phenylindole (DAPI) staining of DNA Verification of the specificity of the anti-GPR19 antibody by Western blot analyses Left lane: Western blot analysis of membrane preparations of OH-1 cells that endogenously express GPR19 (“control”) Middle lane: Western blot analysis of membrane preparations of OH-1 cells after transfection with siRNA targeting GPR19 (“+ siRNA”) the antibody was preincubated for 2 h with 10 µg/ml of the immunising peptide (“+ peptide”) Ladder indicates migration of protein molecular weight markers (kDa) All results are representative of three independent experiments Immunohistochemical detection of GPR19 localisation in normal human tissues. Immunohistochemical staining (red-brown colour) and counterstaining with haematoxylin. Scale bar, 30 µm (A,B,E), 50 µm (C,D,F). Inset in (C) adsorption control, in which the anti-GPR19 antibody was preincubated for 2 h with the peptide used to immunise the rabbits (+ peptide). Arrows in (C,D,F), endocrine cells; asterisk in (E), intestinal ganglion. Immunohistochemical detection of GPR19 localisation in human tumour entities Immunohistochemical staining (red-brown colour) and counterstaining with haematoxylin Insets in (A–F) represent adsorption controls in which the anti-GPR19 antibody was preincubated for 2 h with the peptide used to immunise the rabbits (+ peptide) as well as in endocrine cells of the prostate and in syncytiotrophoblasts of the placenta Faint staining was noted occasionally in the hepatocytes of the liver no immunostaining was observed in the thyroid gland Double-labelling immunohistochemical analysis of GPR19 expression and the expression of chromogranin A (CgA) in human duodenum and colon tissue Labelling of GPR19 was visualised using Cy3-conjugated goat anti-rabbit antibody (red) Labelling of CgA was visualised using Alexa Fluor 488-conjugated donkey anti-mouse antibody (green) Overlapping expression is represented by orange/yellow colour Blue colour represents 4′,6-diamidino-2-phenylindole (DAPI)-stained DNA GPR19 expression pattern in different lung tumour entities. Immunohistochemical staining (red-brown colour) and counterstaining with haematoxylin. Scale bar, 50 µm (A–F). Expression profile of GPR19 in different lung tumour entities (A) Percentage of GPR19-positive cases within the different lung tumour entities Tumours were only considered positive with Immunoreactivity Score (IRS) values ≥ 3 (B) GPR19 expression levels (IRS values) in the different lung tumour entities large cell neuroendocrine carcinomas of the lung Overall survival of patients with GPR19-positive (IRS ≥ 3) or -negative lung tumours the small vertical ticks mark individual patients whose survival times have been “right censored” because they were still alive at the end of the observation period GPR19 knockdown with a GPR19-specific siRNA again led to a strong redction of the immunosignal the immunosignals obtained in the immunocytochemistry and Western blot analyses as well as in the GPR19-positive tissue samples were completely abolished by preadsorption of the antibody with its immunising peptide when comparing the novel anti-GPR19 antibody with another commercially available polyclonal antibody directed against an amino acid sequence in the third extracellular loop of GPR19 a more distinct immunosignal and less non-specific background staining were observed indicating a higher sensitivity and specificity of this antibody the C-terminal end of GPR19 represents a better epitope for generating an antibody than the third extracellular loop This discrepancy may be due to species differences or to a lack of translation of GPR19 mRNA into protein in these organs at least medium–high receptor expression in a large number of individual tumours is necessary; this requirement was not met by most of the tumour entities we investigated due to its high expression rate in adenocarcinomas and neuroendocrine tumours of the lung with at the same time only very low occurrence in healthy organs so that only minor side effects are to be expected GPR19 clearly represents an interesting diagnostic or therapeutic target that should be investigated further A rabbit polyclonal antibody was produced against the carboxyl-terminus of human GPR19 in collaboration with and obtained from Thermo Fisher Scientific (Waltham The peptide used for immunisations of the rabbits was Cys-REAKEKKLAWPINSNPPNTFV corresponding to residues 395–415 of human GPR19 the antibody also detects rat and mouse GPR19 Endogenous GPR19-expressing OH-1 or NCI-h82 cells (DSMZ Germany) grown on coverslips overnight were either left untreated or treated with chemically synthesised double-stranded GPR19 small interfering RNA (siRNA) duplexes (Santa Cruz Biotechnology according to the manufacturer’s instructions A scrambled siRNA was used as the negative control (Santa Cruz Biotechnology The cells were fixed with 4% paraformaldehyde and 0.2% picric acid in phosphate buffer (pH 6.9) for 20 min at room temperature and incubated with the novel anti-GPR19 antibody (1:100 dilution) overnight at 4 °C followed by incubation with Alexa Fluor 488-conjugated secondary antibody (Invitrogen USA; 1:5,000 dilution) for 2 h at room temperature Samples were mounted using Fluoromount G (Invitrogen USA) and analysed using a Zeiss LSM 510 META laser-scanning confocal microscope (Carl Zeiss the anti-GPR19 antibody was either omitted or adsorbed for 2 h at room temperature with 10 µg/ml of the peptide used for rabbit immunisations the protein content of the samples was determined using the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific USA) according to manufacturer’s instructions and the samples (20 µg of protein per lane) were subjected to 7.5% sodium dodecyl sulphate–polyacrylamide gel electrophoresis and immunoblotted onto polyvinylidene fluoride membranes Blots were incubated with the novel anti-GPR19 antibody (1:100 dilution) overnight at 4 °C then incubated with peroxidase-conjugated secondary anti-rabbit antibody (1:5000 dilution; Santa Cruz Biotechnology) for 2 h at room temperature and visualised by enhanced chemiluminescence (Amersham the anti-GPR19 antibody was preincubated for 2 h at room temperature with 10 µg/ml of the immunising peptide For the initial evaluation of GPR19 expression in different human tumour entities, 304 archived formalin-fixed, paraffin-embedded tumour samples from 304 patients (Table 1; lung tumours originally 10 samples each from ADC and SCLC) were obtained from the Department of Pathology of the Ernst-Moritz-Arndt-University (Greifswald Germany) and the Laboratory of Pathology and Cytology Bad Berka (Bad Berka Many of the tumour specimens contained adjacent non-neoplastic tissue tumour-free human tissue samples from the cortex and testicles (n = 5–10 each) were obtained from the Department of Pathology of the Ernst-Moritz-Arndt-University (Greifswald The local ethics committee (Ethikkommission der Landesärztekammer Thüringen) granted permission for this retrospective analysis Informed consent for the use of tissue samples for scientific purposes was obtained from all study participants when they entered the Theranostic Research Center sections were dewaxed and rehydrated via a graded ethanol series during which endogenous peroxidases were blocked by an additional incubation of the slides in 0.3% H2O2 in methanol for 45 min Samples were then microwaved in 10 mM citric acid (pH 6.0) for 16 min at 600 W and incubated with the anti-GPR19 antibody (1:100 dilution) overnight at 4 °C followed by incubation with biotinylated anti-rabbit IgG and peroxidase-conjugated avidin (Vector ABC “Elite” kit; Vector Laboratories The binding of the primary antibody was visualised using 3-amino-9-ethylcarbazole in acetate buffer (BioGenex Sections were counterstained with Mayer’s haematoxylin and mounted in Vectamount™ mounting medium (Vector Laboratories the novel anti-GPR19 antibody was either omitted or adsorbed for 2 h at room temperature with 10 µg/ml of the peptide used for rabbit immunisations a subset of serial sections was additionally incubated with a rabbit polyclonal anti-GPR19 antibody directed against an amino acid sequence in the third extracellular domain of GPR19 (Thermo Fisher Scientific For double-labelling fluorescence immunohistochemistry sections were incubated overnight at 4 °C with the rabbit anti-GPR19 antibody (1:100 dilution) together with a mouse monoclonal anti-chromogranin A (CgA) antibody (1:50 dilution; DAKO The sections were then washed and incubated for 2.5 h in darkness at room temperature with Cy3-conjugated goat anti-rabbit secondary antibody and Alexa Fluor 488-conjugated donkey anti-mouse antibody (1:1000 dilution; Dianova with DAPI; Thermo Fisher Scientific) and evaluated using an LSM 510 META laser scanning confocal microscope (Carl Zeiss The percentage of positive tumour cells in each of five categories (no positive cells 4) was multiplied by the staining intensity quantified in four categories (no staining When a patient had more than one tumour tissue sample the arithmetic mean was calculated from the IRS values of the different slides belonging to the same patient Only tumours with an average IRS ≥ 3 were considered to be GPR19-positive All immunohistochemically stained samples were evaluated by two independent final decisions were achieved by consensus Because the Kolmogorov–Smirnov test showed that the data were not normally distributed the Kaplan–Meier method with a log-rank test was used We have generated and characterised a novel rabbit anti-human GPR19 antibody that is well-suited for visualising human GPR19 expression in formalin-fixed This antibody provided for the first time a broad profile of GPR19 protein expression in a wide variety of normal and neoplastic human tissues GPR19 was expressed mainly by neuronal and neuroendocrine structures and cells GPR19 was predominantly expressed in adenocarcinomas of the lung and lung tumours with a neuroendocrine background in other neuroendocrine tumour entities such as medullary thyroid carcinomas In adenocarcinomas and neuroendocrine tumours of the lung GPR19 may serve as a suitable diagnostic or therapeutic target All data generated during this study are included in this published article. The amino acid sequence of the receptor against which the antibody was raised is publicly available through the Uniprot database (https://www.uniprot.org/uniprotkb/Q15760/entry) Large cell neuroendocrine carcinoma of the lung G-Protein coupled receptors: Structure and function in drug discovery G protein-coupled receptors: Structure- and function-based drug discovery Orphan G protein-coupled receptors (GPCRs): Biological functions and potential drug targets Advancements in therapeutically targeting orphan GPCRs A novel gene codes for a putative G protein-coupled receptor with an abundant expression in brain The G protein-coupled receptor repertoires of human and mouse The orphan G-protein-coupled receptor GPR19 is expressed predominantly in neuronal cells during mouse embryogenesis Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock Adropin as a fat-burning hormone with multiple functions: Review of a decade of research The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis Comparative expression study of the endo–G protein coupled receptor (GPCR) repertoire in human glioblastoma cancer stem-like cells U87-MG cells and non malignant cells of neural origin unveils new potential therapeutic targets Expression of G protein-coupled receptor 19 in human lung cancer cells is triggered by entry into S-phase and supports G2–M cell-cycle progression G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells Adropin acts in brain to inhibit water drinking: Potential interaction with the orphan G protein-coupled receptor Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice Adropin: A hepatokine modulator of vascular function and cardiac fuel metabolism Identification of signal transduction pathways used by orphan G protein-coupled receptors Somatostatin receptor subtypes in human pheochromocytoma: Subcellular expression pattern and functional relevance for octreotide scintigraphy Download references These authors contributed equally: Lorena Gerlach and Anna-Sophia Liselott Beyer Download citation DOI: https://doi.org/10.1038/s41598-023-46395-3 THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging PHILADELPHIA - Research presented at the 2018 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) demonstrates for the first time the benefit of providing earlier lutetium-177 (177Lu) prostate-specific membrane antigen (PSMA) radioligand therapy to patients with metastatic prostate cancer this therapy has only been used in patients with end-stage disease The study included 224 patients with metastatic prostate cancer who were restaged following diagnosis with gallium-68 (68Ga)-PSMA positron emission tomography/computed tomography (PET/CT)--the diagnostic partner of 177Lu-PSMA radioligand therapy (PRLT); the two form a theranostic nuclear medicine pairing Theranostics refers to the combination of a predictive biomarker identified through diagnostic imaging using radiolabeled ligands (which lock onto the specific cancer cell receptor/biomarker) with precise therapy targeted on the now-identified cancer cells while healthy cells are unharmed--minimizing side effects and improving quality of life for patients The patients were grouped according to previous therapies chemotherapy and external beam radiation therapy Serum prostate specific antigen (PSA) levels were monitored before and after therapy with 177Lu PRLT Study results showed a reduction in PSA level in 70 percent of the patients treated with 177Lu PRLT and 54 percent had their PSA decline by more than 50 percent The median overall survival in all patients was 27 months First-line PRLT was associated with the longest survival (all 18 patients alive at 55 months) Patients previously treated with chemotherapy had a significantly shorter survival (median of 19 months) Survival was also shorter in patients with previous radium-223 (223Ra) treatment (17 months) prior surgical or radiation treatment of the primary tumor had no significant effect on overall survival Patients demonstrating a PSA decline of more than 50 percent after at least two PRLT cycles Additional treatment with newer antiandrogen agents Abiraterone or Enzalutamide in combination with 177Lu PRLT also prolonged survival "Our study demonstrates a potential survival benefit and superior response after early initiation of 177Lu-PSMA radioligand therapy," explains Harshad R of the THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging Zentralklinik Bad Berka in Bad Berka Germany "PRLT was safe with no or minimal side effects likely to have a significant impact on patients' lives--maintaining their quality of life for longer." "This approach of precision oncology uses the concept of theranostics--i.e. 177Lu-PRLT patients were selected and followed-up with 68Ga-PSMA PET/CT using the same ligand for molecular imaging and molecular radiotherapy." "These findings will help to determine the right place of 177Lu-PSMA radioligand therapy in the treatment of metastatic prostate cancer--for example before chemotherapy--and serve as a starting point for a prospective randomized controlled clinical trial." Abstract 529: "Early initiation of Lu-177 PSMA radioligand therapy prolongs overall survival in metastatic prostate cancer," Harshad R Link to Abstract The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging vital elements of precision medicine that allow diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes Metrics details Low anterior resection (LAR) and abdominoperineal resection (APR) are the two main surgical procedures after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer APR is associated with poorer prognosis; however existing data do not consider intensified CRT (5-Fluorouracil (5-FU)/Oxaliplatin + radiation) protocols Clinicopathological data of patients treated with APR and LAR from the CAO/ARO/AIO-04 trial were analysed in terms of prognostic parameters and quality of life (QoL) Based on higher response rate after intensified CRT APR after preoperative CRT was associated with a significantly worse overall survival (p = 0.0056) disease-free survival (p < 0.0001) and local recurrence rate (p = 0.0047) Clinicopathological data including clinical T stage (p < 0.000001) postoperative lymph node (LN) positivity (p = 0.013) and number of positive LN (p = 0.0049) significantly differed between procedures and showed higher values in APR patients The quality of total mesorectal excision (TME) was significantly better (p < 0.0001) and complete resection rates were higher (p = 0.0022) in LAR compared to APR patients Subgroup analyses showed worse LR rates in APR patients after standard CRT (5-FU mono and radiation) but not after intensified CRT role functioning (p = 0.019) and physical functioning (p = 0.001) had a slightly poorer outcome in APR patients The poorer prognosis of patients undergoing APR for locally advanced rectal cancer may be explained by clinicopathological characteristics Intensified CRT may compensate for the higher risk of LR after APR in patients with worse TME quality QoL in APR patients was comparable to LAR patients these trials date back to the beginning of preoperative CRT/ SCRT in rectal cancer the Swedish Rectal Cancer Trial considered a resection margin of 5 cm below the tumour as essential and resulted in a higher rate of APR for tumours localized in the mid-rectum a distance of 2 cm or even less between the tumour and aboral resection margin is recommended we assessed the impact of surgical technique (APR vs LAR) on clinical outcome and quality of life (QoL) physical functioning (PF2) and chemotherapy side effects (CT) were compared between patients with LAR and APR Differenced in QoL data were considered as small (< 10) the 5-year follow-up data are underrepresented due to the termination of follow-up as soon as the last patient was enrolled Due to the explorative nature of the analysis the p-values were not adjusted for multiple testing and are only descriptive Part of the data have been presented at the “Deutsche Chirurgenkongress” 2022 in Leipzig Data were available in n = 1173 patients treated within the CAO/ARO/AIO-04 trial. APR was performed in n = 303 patients, ISR in n = 61 and LAR in n = 809 patients. DFS and OS (Fig. 1) were significantly worse after APR than after LAR (p = 0.0002 and p = 0.0051, respectively). No difference was found between patients treated with LAR and ISR. Overall survival of patients according to type of surgery(left) Disease-free survival of patients according to type of surgery (right) Local recurrence rate according to surgical procedure in patients treated with standard CRT (left) Local recurrence rate of patients treated with intensified CRT (right) Patients with incomplete QoL data sets after grouping into APR and LAR* were excluded In both groups baseline values for the functioning categories (role social and physical) as well as for global health score decreased during treatment Values for chemotherapeutic side effects showed worse outcome after baseline Due to the time point “after treatment” that implicated the assessment after CRT surgery and adjuvant therapy the decrease of the functioning scales and the increase for chemotherapy side effects is well explained All values at least partially recovered over time In the APR group, no relevant improvement was found after 12 months. In terms of “chemotherapy side” effects the data differed significantly between both groups after postoperative chemotherapy (p = 0.047) and during follow-up after 12 months (p = 0.002) (Table 3) we examined the impact of surgical technique on the clinical outcomes and QoL on n = 1173 patients with rectal cancer treated within the randomized phase III CAO/ARO/AIO-04 trial comparing preoperative 5-FU-mono CRT (standard CRT) and 5-FU/Oxaliplatin-based CRT (intensified CRT) We found that APR was associated significantly with worse LR and distant metastasis rates than LAR the prognosis of patients undergoing ISR was similar to that of those undergoing LAR Although the number of ISR patients was rather low (n = 61) the results suggest that isolated tumour localization may not play a pivotal role in prognosis who reported a higher incidence of involved CRM and worse clinical outcomes after APR than after LAR Analyzing the relevance of TME quality in each subgroup oncological relevance was only found for LR in LAR* patients This finding may potentially be affected by the difference of preoperative strategies with respect to the surgical method a potential bias of poorer TME quality in APR patients affected by removal of the specimen rather than the surgical resection itself might also be of relevance and oncological outcomes in patients with medium TME quality were comparable to those of good TME quality This result is different from those seen in patients who underwent primary surgery who showed clear differences between medium and good TME quality Together with the data from this trial (APR ISR and LAR) showing that TME quality led to significant prognostic differences only in patients with standard CRT these results might indicate that intensification of preoperative treatment compensates for poorer TME quality these data were retrieved from surgeries intended to achieve the highest TME quality and high TME quality should remain a top priority of surgeons Absence of significant correlations may also be attributed to smaller sample sizes in subgroups It is important to acknowledge that resection status is still a relevant parameter they also identified a worse outcome of PF2 in patients after APR This difference was suggested to be due to older patients in the APR group This reason does not hold true in our dataset as patient age was comparable the reduced ability to perform basic and instrumental activities of daily living may be attributed to the type of surgery These results might display the physical difference after two different resection techniques As the results in the role function increase after time it is unclear whether this is a true effect just a result of a small sample size or impacted by increasing age of the patients We would like to acknowledge the limitations of the present study The CAO/ARO/AIO-04 trial was not designed to analyse the difference between APR and LAR* this is a subgroup analysis and therefore should be interpreted with a high degree of caution Lack of significance may be explained by the small sample sizes Patients with locally advanced rectal cancer undergoing APR after preoperative CRT have poorer oncological outcomes than patients who undergo LAR* which might be explained by the significantly advanced tumour stages of the patients receiving APR Intensified preoperative treatment narrows outcome results of both groups TME quality was not a prognostic factor in patients receiving intensified CRT in the CAO/ARO/AIO-04 trial The completeness of resection (R0) remains a relevant parameter even after intensified CRT and should therefore be attempted to improve oncological outcomes Although most QoL parameter do not differ between patients with APR and LAR All included data is available from the corresponding author on reasonable request Abdominoperineal resection for rectal cancer in the twenty-first century: Indications Abdominoperineal excision following preoperative radiotherapy for rectal cancer: unfavorable prognosis even with negative circumferential resection margin The abdominoperineal resection itself is associated with an adverse outcome: the European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer Improved survival with preoperative radiotherapy in resectable rectal cancer Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer Preoperative versus postoperative chemoradiotherapy for rectal cancer Chemotherapy with preoperative radiotherapy in rectal cancer Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs conventionally fractionated radiochemotherapy Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): Final results of the multicentre Tumor regression grading after preoperative chemoradiotherapy as a prognostic factor and individual-level surrogate for disease-free survival in rectal cancer Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial Pathological features of rectal cancer after preoperative radiochemotherapy Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy Prognostic implications of the distribution of lymph node metastases in rectal cancer after neoadjuvant chemoradiotherapy Poorer oncologic outcome of good responders to PCRT with remnant lymph nodes defies the oncologic paradox in patients with rectal cancer Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma Results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 phase 3 trials College of American Pathologists Consensus Statement 1999 Association of plane of total mesorectal excision with prognosis of rectal cancer: Secondary analysis of the CAO/ARO/AIO-04 phase 3 randomized clinical trial Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control The long-term influence of hospital and surgeon volume on local control and survival in the randomized German Rectal Cancer Trial CAO/ARO/AIO-94 Quality of life in restorative versus non-restorative resections for rectal cancer: Systematic review The impact of radiotherapy on quality of life for cancer patients: A longitudinal study Effect of neoadjuvant therapy and rectal surgery on health-related quality of life in patients with rectal cancer during the first 2 years after diagnosis Quality of life of patients after low anterior and abdominoperineal resection for rectal cancer–A matched-pair analysis Download references A list of authors and their affiliations appears at the end of the paper Internistische Gemeinschaftspraxis Friedberg Schwerpunktpraxis Für Hämatologie Und Onkologie Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil Medizinisches Versorgungszentrum Für Onkologie Hämatologisch-Onkologische Schwerpunktpraxis Strahlentherapie Singen & Friedrichshafen Gemeinschaftspraxis Für Hämatologie Und Internistische Onkologie Praxis Für Hämatologie Und Internistische Onkologie Gemeinschaftspraxis Für Strahlentherapie Und Radioonkologie Gemeinschaftspraxis Für Hämatologie Und Onkologie Gemeinschaftspraxis Muhr Am See/Weißenburg Onkologisch-Internistische Schwerpunktpraxis Internistische Gemeinschaftspraxis Schloßmühlendamm Gemeinschaftspraxis Für Radioonkologie Und Strahlentherapie the interpretation of the data and drafted the manuscript.T.B performed all statistical analysis of the presented data.M.E. contributed in acquisition and interpretation of the data and critically revising the manuscript.R.K contributed in interpretation of the QoL data and revised the manuscript critically for important intellectual content.M.G. were responsible for accurate data acquisition at their respective department They contributed in data interpretation and revised the manuscript critically for important intellectual content.All authors reviewed the manuscript The authors declare no competing interests The study was approved by the local ethic committee All patients were enrolled with the understanding and appropriate informed consent A signed informed consent from each patient is provided Below is the link to the electronic supplementary material Download citation DOI: https://doi.org/10.1038/s41598-024-83105-z Metrics details are known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is considered to be present mainly in highly proliferative and advanced tumors comprehensive data are still lacking on potential differences in SST or CXCR4 expression pattern in GEP-NEN in dependence on the place of origin comprising both primary tumors (PT) and metastases (MTS) originating from different parts of the gastrointestinal tract or the pancreas were evaluated for SST and CXCR4 expression by means of immunohistochemistry using monoclonal antibodies SST2A was present in 85% of PT with a high intensity of expression PT displayed higher SST2A and chromogranin A (CgA) expression levels than MTS In both PT and MTS lower SST2A and CgA expression levels were found in tumors originating from the appendix or colon Tumors derived from appendix or colon were associated with significantly worse patient outcomes Positive correlations were noted between SST2A and CgA as well as between CXCR4 and Ki-67 expression levels SST2A and CgA negativity of the tumors was significantly associated with poor patient outcomes SST2A was the most prominent receptor expressed in the GEP-NEN samples investigated expression levels varied considerably depending on the location of the primary tumor are well known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) where they serve as the molecular basis for SST-based diagnostics and treatment modalities From 5 tumors (3%) localization of the primary was unknown The samples were provided by the Institute of Pathology and Cytology Bad Berka and had been surgically removed between 1999 and 2014 at the Department of General and Visceral Surgery The clinical data were gathered from the patient records In 82 of the 165 patients an SST-based PET/CT had been performed The PET/CT scans were processed with Siemens e.soft Nuclear Medicine Workstation automatic region of interest was drawn on the individual tumor lesions and SUVmax values were calculated To avoid major influence of partial volume effect on lesion SUVmax region of interest was drawn only on lesions greater than 1.5 cm in size Permission was gained from the local ethics committee (Ethikkommission der Landesärztekammer Thüringen) for this retrospective analysis All data were recorded and analyzed anonymously SST and CXCR4 expression pattern in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) Depicted are typical examples of staining patterns for SST2A counterstaining with hematoxylin; scale bar: 500 µm (A–D) Insets in E–H: for adsorption controls the anti-SST antibodies and the anti-CXCR4 antibody were incubated with 10 µg/ml of the peptide used for immunizations (+Peptide) The percentage of positive tumor cells quantified in five gradations (no positive cells (0) >80% positive cells (4)) was multiplied by the staining intensity quantified in four gradations (no staining (0) Tumor samples with average IRS values ≥3 were considered positive With the antibodies against the SSTs and the CXCR4 distinct immunostaining of the plasma membrane but also of the cytoplasm of the tumor cells was seen which reflects receptor internalization due to agonist stimulation the percentage of positive nuclei was determined All immunohistochemical stainings were evaluated by two independent blinded investigators (RM the IBM SPSS statistics program version 22.0.0.0 was used Because the data were not normally distributed (Kolmogorov-Smirnov test) the Kaplan-Meier method with a log-rank test was used P values ≤ 0.05 were considered statistically significant In cases where one patient had more than one tumor slide an arithmetic mean was calculated from the IRS values of all the slides of this patient primary tumor and metastasis/es taken together (per patient analysis) Only when primary tumors and metastases were compared arithmetic means were calculated for the primary tumor samples and metastasis/es sample(s) separately All data of the individual patients including gender, age, localisation of the primary tumor, type and derivation of the samples investigated as well as prior therapies are depicted in the Supplementary Table 6 Overall, SST2A was by far the most prominently expressed receptor in the GEP-NEN samples investigated (Fig. 2A,B), followed by SST5, CXCR4, SST3, SST1 and SST4. Expression profiles of different somatostatin receptor (SST) subtypes and CXCR4 chemokine receptor in primary tumors and metastases of gastroenteropancreatic neuroendocrine neoplasms (A) Percentage of positive cases for different SSTs and CXCR4 Tumors were only considered positive at IRS values ≥3 (B) Box plots of somatostatin receptor (SST) and CXCR4 expression levels (IRS values) Outliers are defined as follows: circles: mild outliers; data that fall between 1.5 and 3 times above the upper quartile or below the lower quartile; asterisks: extreme outliers; data that fall more than 3 times above the upper quartile or below the lower quartile To evaluate the extent of intratumor heterogeneity in receptor expression the mean standard deviation (SD) of the IRS values of the SSTs and of the CXCR4 was calculated from the respective SDs of the individual patients for all samples (primary tumors plus metastases taken together) as well as for the primary tumors (PT) and metastases (MTS) separately showing again the highest variation for the SST2A but also a similar variation in PT and MTS: Mean SD: SST1: all samples: 1.00 when correlating the IRS values of the SSTs the Ki-67 levels and the SUVmax values of the SST-PET/CT between PT and MTS of the individual patients significant interrelationships were found for the SST2A (rsp = 0.627; p < 0.001) p < 0.001) and the SUVmax values of the SST-PET/CTs (rsp = 0.371 CXCR4 (A) and Ki-67 (B) expression levels in primary tumors and metastases of gastroenteropancreatic neuroendocrine neoplasms of different origin Kruskal-Wallis test: (A) p < 0.001 (primary tumors); p = 0.042 (metastases) With all other parameters investigated no relevant differences between the different tumor entities were seen Between the Ki-67 index and SST1, SST5 and CXCR4 expression levels positive correlations were observed, but negative correlations between the Ki-67 index and the SST2A and CgA score values (Table 1) When considering the DOTA-TOC-PET/CT scans separately a significant interrelationship was seen for SST2A only (rs = 0.450 SST5 and CXCR4 as well as Ki-67 expression intensities significantly correlated with tumor grading (SST5: τ = 0.178 whereas a negative correlation was noted between SST2A and CgA expression intensities and tumor grading (SST2A: τ = −0.281 exhibited a positive association with tumor stage and size (tumor stage: τ = 0.351 Presence or absence of lymph node or distant MTS had no influence on SST CXCR4 or CgA expression intensities and also no effect on SUVmax values of the PET/CT scans No interrelationship was seen between CgA serum values and CgA expression in the tumor samples (r = 0.039 There was also no correlation between serum CgA levels and SST or CXCR4 expression in the tumors patients showed significantly higher serum CgA levels (Mann-Whitney test: p < 0.001) a reduced Karnofsky index (Mann-Whitney test: p = 0.017) and lower overall survival times (Mann-Whitney test: p = 0.001) between serum CgA levels and the Karnofsky performance index a negative association was observed (rs = −0.325 significantly higher CXCR4 expression rates and a tendency towards a higher Ki-67 index were seen in non-functional tumors as compared to functional tumors (Mann-Whitney test: CXCR4: p = 0.019; Ki-67: p = 0.103) were significantly lower in patients with non-functional tumors (Mann-Whitney test: p = 0.006) was significantly more often associated with distant metastases (distant metastases were present in 81% of the cases in functional tumors and in 56% of the cases in non-functional tumors; χ2 test: p = 0.002) All other parameters did not significantly differ between functional and non-functional tumors Overall survival of GEP-NEN patients with either no SST2A expression or with SST2A positivity of the tumor (A) or with either no chromogranin A (CgA) expression or with CgA positivity of the tumor (B) Mean survival (years ± SD): patients with SST2A-positive tumors: 5.37 ± 4.73; patients with SST2A-negative tumors: 2.37 ± 1.83; patients with CgA-positive tumors: 4.90 ± 4.51; patients with CgA-negative tumors: 2.08 ± 1.92 differences in receptor expression could be demonstrated depending on the derivation of the tumor sample Tumors originating from appendix or colon showed lower SST2A and CgA but higher CXCR4 and Ki-67 expression levels as compared to those from other provenances patients with tumors derived from appendix or colon showed the worst outcome These relationships are further substantiated by the fact that in the present study a positive correlation was detected between patient outcome and SST2A or CgA expression but a negative association with Ki-67 expression Due to the overall low expression rates of SST5 further studies with a significantly higher number of cases are obviously needed functionality of the tumors had no influence on SST expression but there was a significantly lower CgA expression in non-functional as compared to functional tumors significantly higher CXCR4 and Ki-67 expression levels in non-functional than in functional tumors could be shown pointing to a somewhat higher malignancy of non-functional tumors SST2A was the most prominently expressed receptor in the GEP-NEN samples investigated SST2A-based functional imaging and (if surgery is not possible) SST2A-based therapies (pharmacotherapy with somatostatin analogs PRRT) should be first choice in metastasized tumor stage there was substantial variation in expression levels between individual patients Expression levels varied considerably depending on the location of the primary tumor with distinctly lower values in NEN originating from appendix and colon as compared to tumors from other intestinal origins We also observed significantly lower expression levels in MTS than in PT SST2A expression declined depending on the malignancy of the tumor and there was a distinct association between SST2A expression and patient outcome Since CXCR4 presence was inversely correlated with 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neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumors Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution The value of serum chromogranin A as a predictor of tumor burden and nomogram-based survival in well – moderate non-functional pancreatic neuroendocrine tumors with liver metastases Correlation of histopathological expression of somatostatin receptor 2 with standardised uptake values in 68Ga-DOTATOC PET/CT 68Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas: strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2 Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOTATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC SUV of [68Ga]DOTATOC-PET/CT predicts response probability of PRRT in neuroendocrine tumors Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly Prognosis and long-term survival after operation in patients with pancreatic and peripancreatic neuroendocrine tumors of a single center Download references Rebekka Mai and Daniel Kaemmerer contributed equally Institute of Pathology and Cytology Bad Berka Center for Molecular Radiotherapy and Molecular Imaging Conceived and designed the experiments: D.K. Each of the authors has approved the manuscript and acknowledges that he or she participated sufficiently in the work to take public responsibility for its content Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-019-39607-2 Metrics details Almost all people with spinal cord injury/disease (SCI/D) suffer from neurogenic bowel dysfunction (NBD) with a considerable impact on quality of life The Association of the Scientific Medical Societies in Germany (AWMF e.V.) guideline for NBD in SCI/D aims to provide practice-oriented support for the care of patients with NBD resulting from congenital or aquired SCI/D The guideline describes the diagnosis and bowel management of NBD in people with SCI/D treatment processes in acute medical care and rehabilitation as well as for lifelong aftercare are presented The present guideline was developed under the leadership of the German-speaking Medical Society for Paraplegiology in a multiprofessional interdisciplinary guideline team To exceed the level of expert recommendations consensus was reached within the framework of a structured nominal group process in defined steps under neutral moderation considering the criteria of the German guideline development instrument (DELBI) Individual bowel management must be developed on the basis of an adequate diagnosis and considering the different lesion types Due to the multifactorial influenceability of the intestine and the individual neurological deficit Various and complex bowel management programmes are the basis of the treatment of NBD Guidelines can only be successful in so far as they are applied in everyday life the selection and application of the measures described must always take into consideration the individual situation of the person concerned and the correct application is always a prerequisite for success spinal cord injury/disease (SCI/D) is associated with neurogenic bowel dysfunction (NBD) the effects of NBD can lead to serious health consequences Shame and fear due to a lack of bowel control can lead to social isolation crucial to recognise and analyse the neurological deficits in bowel function caused by SCI/D and the multifactorial influence on this system Despite the many activities of our professional society on this topic specialised further training courses to become a “neurogenic bowel expert” and in-house training courses the practical implementation in everyday clinical practice falls far short of our expectations Feedback from the interprofessional teams of the paraplegic centres points to a deficit of practically oriented guidelines with clear recommendations for action nursing staff in the paraplegic centres in particular accompany the adjustment to a regulated and continent bowel management it was necessary to create a comprehensible German-language practical instruction manual Neither guideline provides an explanation of guideline development or evidence-based graduations of recommendations we saw the need for the development of a guideline based on a structured consensus process and adapted to the German conditions The aim of the guideline is to compile the current state of knowledge on the definition and diagnosis of NBD as well as on bowel management to ensure the competent treatment of patients with NBD to prevent complications and thus positively influence the quality of life of those affected This guideline aims to provide practice-oriented support for the care of patients with NBD We have summarised the individual implementation of all the findings regarding anamnesis and bowel function diagnostics in the context of bowel management Bowel management refers to the entire range of activities that help a person with SCI/D achieve regular planned and time-limited bowel evacuation with sufficient stool volume and adequate stool consistency; to maintain health and well-being; and to avoid complications and unplanned defecations Bowel management is a process that includes assessment individual planning and implementation of interventions considering individual influencing factors Successful bowel management always requires multiprofessional cooperation between different occupational groups (interdisciplinary teams) The present guideline was developed under the leadership of the German-speaking Medical Society for Paraplegiology e.V (Deutschsprachige Medizinische Gesellschaft für Paraplegiologie e.V health care and nursing as well as nursing science and dieticians/medical nutritionists worked together in a multiprofessional interdisciplinary guideline team (the “Bowel Dysfunction Guideline Group” – BDGG) A systematic literature search was conducted in the databases PubMed The search terms were neurogenic bowel dysfunction neurogenic bowel and meningomyelocele/spina bifida The analysis of this literature search served as the basis for this guideline We proved the grey literature for SCIRE project and existing guidelines (MASCIP The BDGG identified relevant areas of focus and met several times to develop draft recommendations Each recommendation was discussed under relevant clinical considerations to facilitate the application of the knowledge the recommendations developed by the BDGG were discussed in a face-to-face meeting and the final recommendations were voted on separately the draft guideline were submitted to the representatives (mandates holders) of the professional societies of the Association of the Scientific Medical Societies (AWMF) involved in the guideline for voting in their boards as a first external review These had the opportunity to assess and comment on the draft in this development phase the present guideline is not only an expert opinion the consensus process and prior to submission and publication of the now consented guideline at the AWMF the second external review was conducted by all members of the DMGP The members had 4 weeks to comment on the guideline The pathophysiological features of NBD are disturbed sensory function and motility and limited-to-absent reflex control of bowel voiding and continence Changes in gastrointestinal functions after SCI/D depend on clinical appearance at the level of the lesion the completeness of the injury and the time since the onset of SCI/D Of crucial clinical importance are the changes in the motility of the upper and lower gastrointestinal tract whether the ability to empty the rectum is maintained and whether the anal closure mechanism is functioning the changes in the gastrointestinal tract after SCI/D can be divided into three phases with the phases merging smoothly into one another Definitions of typical changes in neurogenic bowel dysfunction such as faecal incontinence, constipation, transit constipation or outflow obstruction can be found in Supplementary Material 1 A detailed description of the typical phasic sequence of neurogenic bowel dysfunction can be found in Supplementary Material 2 (see Fig. 1). Leading clinical symptoms of neurogenic bowel dysfunction in people with SCI/D triggering defecation through digital stimulation Stool observation using the Bristol stool scale (Supplementary File 3) Assessment of the abdomen with palpation and auscultation including pelvic floor assessment to evaluate the skin condition and identify proctological diseases fissures/anal tags/perianal thromboses/deformities Anal reflex and bulbocavernosus reflex testing Recommendation 1: The medical history and the assessment of anal sphincter tone should be the essential aspects of the initial diagnosis Level of evidence: expert consensus (100%) Advanced diagnostics for neurogenic bowel dysfunction (including stool protocol proctoscopy and colonoscopy as well as other imaging procedures) are carried out according to the clinical The overall goal of bowel management is to achieve secondary continence with regular and sufficient bowel emptying within an individually acceptable time frame and at the right time according to the patient’s agenda Recommendation 2: The bowel voiding rhythm the voiding technique and the use of laxatives and aids should be determined for the establishment of bowel management defecation time and subjective patient satisfaction should be assessed for the evaluation of bowel management these symptoms also apply in principle; however these lesions show variable expression with partially preserved sensitivity and motor function the possible use of conservative interventions and their combinations with increasing invasiveness after spinal shock has subsided is presented simplified and differentiated according to lesion type Therapy pyramid for neurogenic bowel dysfunction (modified from [10]) Recommendation 4: The algorithm should provide the basis for the development of initial bowel management The adjustment of bowel management should be oriented towards success (continence and voiding rhythm) and should be determined on an individual basis bowel evacuation should be planned after a meal (gastrocolic response) Recommendation 6: An rectum check should be performed after defecation to verify complete evacuation Recommendation 7: A change in bowel management should only be made after sufficient observation (3-5 evacuations/week) (exception: acute interventions) In addition to nutritional management [11] rectal emptying techniques and physical measures constitute the conservative part of bowel management sufficient fluid intake (1500–2000 ml/day) and intake of dietary fibre (up to 30 g/day soluble and insoluble) should be the basis of the dietary recommendations The following measures are presented without ranking Correct execution according to professional instructions is obligatory Disposable gloves are necessary for all rectal procedures It is advisable to empty the bladder before emptying the bowels The procedures are to be performed by the patient or a caregiver Increasing abdominal pressure by using still innervated abdominal muscles (change in sitting position (bending the upper body forward pressing the arms or legs into the abdomen digital palpation of the rectal ampulla to determine the filling status before and after emptying Dilating the anal canal to release the sphincter spasm or to trigger the voiding reflex stimulation of bowel evacuation by applying external stimuli for reflex evacuation Digital evacuation of the rectal ampulla with the finger by the patient or caregiver high enema) Instillation of water at body temperature or ready- made enema solution for retrograde irrigation of the rectum and the left colon Administration of micro enemas/enemas (ready-made solutions) The enema provides a chemical and/or physical stimulus that causes peristalsis to be stimulated and the stool in the rectum to be softened Digital stimulation by circular movement above the anal sphincter with a gloved finger for approx wait 5–10 min to see if the reflex for defecation can be triggered Recommendation 9: The use of rectal evacuation techniques must be carried out correctly according to the individual and the paralysis-specific situation Evacuation techniques designed to trigger reflex evacuation are only useful for the upper lesion type whereas digital evacuation is useful for both lesion types Apart from the sitting position for defecation any form of movement can have a positive effect on stool transport The following physical measures can be used in a targeted and supportive manner Caution - Risk of burns due to reduced sensitivity Since neurogenic rectal dysfunction is often at the forefront of SCI/D, attention must first be paid to regular rectal emptying, which can be initiated with rectal laxatives. Depending on intestinal motility and stool consistency, oral laxatives can also be used (see Table 2) Recommendation 10: Level 1 and 2 oral laxatives should be used to modulate stool and support bowel function. Level 3 oral laxatives should only be used for short periods in people with SCI/D and neurogenic bowel dysfunction (see Fig. 3). In tetraplegics at risk of autonomic dysreflexia the injection should be given while monitoring blood pressure; incontinence after too high a dose should be avoided Recommendation 11: Botulinum toxin-A can be used for outlet constipation due to a spastic anal sphincter (off-label) the influence on the quality of life should be examined in addition to clinical parameters Recommendation 12: After conservative therapeutic measures have been exhausted sacral neuromodulation (SNM) can be considered for select patients with neurological incomplete SCI/D Recommendation 13: A Malone stoma may be considered as an alternative form of treatment for constipation or to achieve secondary continence for faecal incontinence Recommendation 14: Deafferentation should be a treatment option for refractory autonomic dysreflexia in the context of bowel management Recommendation 15: If deafferentation is indicated the use of sacral anterior root stimulation to improve bowel evacuation should be considered As a definitive solution in these cases, the colon should be drained to conduct terminal colostomy [23] A double colostomy is also suitable as a temporary solution for decubitus and faecal incontinence (minor surgical intervention and easier relocation) Recommendation 16: A definitive colostomy should be considered if all conservative measures have failed and constipation or faecal incontinence is refractory A terminal colostomy is then to be created Autonomic dysreflexia (in spinal cord injury above T6) the primary goal is to eliminate constipation In addition to colonic massage and antiflatulents anal stretching to remove the air in the rectum may be helpful Recommendation 18: If there is a known risk of AD precipitating triggers should be avoided as much as possible during bowel management patients report bleeding in connection with bowel evacuation Bleeding is often caused by injuries to the rectal mucosa or the haemorrhoidal cushions caused by manipulation during evacuation or irrigation Injuries can be avoided by using sufficient lubricant Recommendation 19: In cases of repeated bleeding such as tumours or inflammatory bowel diseases A special situation exists with the so-called “faecal impaction” Repeated incomplete bowel movements lead to a progressive build-up of stool masses in the colon up to the development of a coprolite (faecal stone) These stool masses are processed again by the microbiome of the colon This results in a fermentation process that leads to liquefaction of the stool in the aboral region and simultaneously increases the gas pressure above the stool column the coprolite triggers the recto-anal inhibitory reflex (RAIR) which relaxes the sphincter ani internus muscle Either liquid or foul-smelling stools are excreted and/or there is an explosive discharge if sufficient pressure has built up this is mistakenly interpreted as banal diarrhoea and possibly treated with loperamide (slows down bowel movement) Detection of a coprolite is performed by digital palpation sonography or radiology (empty abdominal radiograph) a contrast enema will confirm the diagnosis CT is usually unnecessary (except to rule out a causative stenosing tumour) difficulty with faecal evacuation and faecal incontinence The consequences of neurogenic bowel dysfunction (as well as neurogenic bladder dysfunction) often have a greater impact on the quality of life of those affected than the restrictions on mobility It is therefore extremely important to provide the best possible support and recommendations for comprehensive care to the affected persons themselves and also to their caregivers from the various professions Only 20 randomised trials of generally poor quality were identified and it was found that it is generally not possible to make recommendations based on this evidence At the time of the development of this guideline there were no guidelines worldwide with a higher level of evidence than expert recommendations The multidisciplinary development group of the present guideline with experts from different disciplines felt the need to raise the evidence level of the recommendations and therefore developed concrete recommendations at consensus level in a structured process the recommendations of the two aforementioned guidelines correspond to the recommendations of the German guideline presented The expert group defines the goals of bowel management following SCI/D as follows: self-management leading to regular and predictable bowel emptying at a socially acceptable time and place using minimal physical and pharmacological interventions to achieve complete bowel emptying within an acceptable time frame autonomic dysreflexia (which can be life threatening) and other complications The lack of application of the GRADE methodology to assess the quality of the available evidence and the strength of the derived recommendations is certainly a limitation of the present German guideline According to the rules of the German Guideline Society the validity of a guideline is limited to 5 years Then an update of the content must be prepared an improvement of the methodology of guideline development (e.g. evaluation of systematic reviews and meta-analyses according to the PRISMA statement application of the GRADE approach for recommendations) is intended The guideline was developed by a multiprofessional interdisciplinary team at a consensus level with predominantly a small amount of evidence due to a lack of meaningful studies Various and complex bowel management programmes are the basis of the treatment of neurogenic bowel dysfunction more than one procedure is required to develop an effective bowel routine fairly high-fibre diet and sufficient fluid intake are important components of bowel management rectal emptying techniques and emptying aids as well as physical measures constitute the conservative part of bowel management Rectal or oral laxatives are often used to support these conservative approaches Surgical interventions such as sacral neuromodulation deafferentations with anterior root stimulation Malone stoma and colostomy are the final therapeutic options if conservative treatment is not sufficiently effective the overall aim of bowel management is to reduce bowel-related complications and to improve the quality of life of those affected Neurogene Darmfunktionsstörung bei Querschnittlähmung The data described in the article are available from corresponding author on reasonable request Evaluating guidelines: a review of key quality criteria The digital rectal examination scoring system (DRESS) International spinal cord injury bowel function basic data set (Version 2.0) International bowel function extended spinal cord injury data set International standards for neurological classification of spinal cord injury (revised 2011) Consensus review of best practice of transanal irrigation in adults Dietary management of neurogenic bowel in adults with spinal cord injury: an integrative review of literature Anorectal biofeedback for neurogenic bowel dysfunction in incomplete spinal cord injury Effects of abdominal massage in management of constipation–a randomized controlled trial Application of a heat- and steam-generating sheet increases peripheral blood flow and induces parasympathetic predominance Botulinum toxin therapy: its use for neurological disorders of the autonomic nervous system Sacral nerve stimulation as an option for the treatment of faecal incontinence in patients suffering from cauda equina syndrome Clinical outcome of sacral neuromodulation in incomplete spinal cord-injured patients suffering from neurogenic bowel dysfunctions Sacral neuromodulation for neurogenic bladder and bowel dysfunction with multiple symptoms secondary to spinal cord disease Antegrade continence enema procedure: impact on quality of life in patients with spinal cord injury Sacral anterior root stimulation improves bowel function in subjects with spinal cord injury Effect of sacral anterior root stimulator on bowel dysfunction in patients with spinal cord injury Effect of stoma formation on bowel care and quality of life in patients with spinal cord injury The impact of stoma for bowel management after spinal cord injury “Imola-Montecatone” subtotal colectomy to improve bowel management in spinal cord injury patients Abdominal Pain: A Comparison between Neurogenic Bowel Dysfunction and Chronic Idiopathic Constipation Lifestyle intervention for adults with spinal cord injury: results of the USC-RLANRC Pressure Ulcer Prevention Study The severity of bowel dysfunction in patients with neurogenic bladder Plain abdominal radiograph as an evaluation method of bowel dysfunction in patients with spinal cord injury Outcomes of bowel program in spinal cord injury patients with neurogenic bowel dysfunction Clinical evaluation and management of neurogenic bowel after spinal cord injury Constipation and other chronic gastrointestinal problems in spinal cord injury patients Management of the patient with chronic spinal cord injury Curcumin and fennel essential oil improve symptoms and quality of life in patients with irritable bowel syndrome Meteorismus – Ursachen und gezielte Therapieansätze Prediction of severe neurogenic bowel dysfunction in persons with spinal cord injury Neurogenic bowel management after spinal cord injury: a systematic review of the evidence Autonomic dysreflexia during bowel evacuation procedures and bladder filling in subjects with spinal cord injury Topical anesthesia blunts the pressor response induced by bowel manipulation in subjects with cervical spinal cord injury SCIRE Project: Neurogenic bowel dysfunction and management. https://scireproject.com/evidence/rehabilitation-evidence/bowel-dysfunction-and-management/ last assessed Jan Coggrave M, Norton C, Cody JD. Management of faecal incontinence and constipation in adults with central neurological diseases. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD002115. https://doi.org/10.1002/14651858.CD002115.pub5 Treatments in neurogenic bowel dysfunctions: evidence reviews and clinical recommendations in adults GRADE: an emerging consensus on rating quality of evidence and strength of recommendations Download references Department of Paraplegiology and Neuro-Urology Counseling Center for Nutrition and Digestion of Paraplegics All authors read and approved the manuscript Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41393-022-00786-x Current Bladder Dysfunction Reports (2023) Credit: LuGenIum Consortium for Independent Research & Wren Laboratories - Malignant neuroendocrine tumors (NETs) are relatively rare and associated with poor long-term survival According to research presented at the 2016 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) an investigative blood test could predict how patients will respond to peptide receptor radionuclide therapy (PRRT) before they commit to a course of treatment Cancerous NETs can develop in a variety of places where hormone signaling occurs between nerve cells and organs of the endocrine system but the most common origins of these tumors are in the gastrointestinal tract These cancers sneak up on oncologists due to their rarity and the fact that symptoms such as flushing diarrhea and sweating are often regarded as unrelated to disease and part of normal life events Most cases are not caught until these tumors have already spread to other organs making them difficult to treat with conventional means A targeted treatment established in the early 2000s called peptide receptor radionuclide therapy (PRRT) zeros in on active peptide receptors that are over-expressed on the surface of NETs The injected drug binds specifically to these receptors and knocks out tumors by irradiating them with a powerful dose of short-range radioactive material while sparing healthy tissues nearby PRRT has helped many patients and is associated with lower systemic side effects researchers are working to predict patient response prior to the start of treatment with molecular imaging A visualization of NET receptor activity informs clinicians of the potential path of PRRT in the body prior to therapy including somatostatin receptor imaging (SRI) since NET tumors commonly express somatostatin receptor activity; but not all do researchers are investigating a genetic blood test called a NETest which measures the specific NET genes circulating in the blood that appear to define and predict responsiveness to PRRT "This research shows that the molecular information obtained from a simple blood draw can be easily integrated with radiological and molecular imaging to provide a more accurate assessment of tumor behavior and response to therapy," said Lisa Bodei of the European Institute of Oncology Division of Nuclear Medicine in Milan and a member of the Molecular Imaging and Therapy Service at Memorial Sloan Kettering Cancer Center in New York researchers evaluated a total of 72 NETs being treated with PRRT by using a potent radionuclide agent called Lu-177 DOTATATE over the course of 33 months a bioassay that tracks a common protein in NETs called chromogranin A Researchers performed statistical analyses and developed a predictive response index of select NETest genes as a predictor of PRRT success and categorized patients' response to treatment as either responsive or non-responsive Results showed that PRRT led to a 68 percent rate of overall disease control with median progression-free survival not achieved at the end of follow-up Researchers were able to determine that 73 percent of low-grade tumors responded to treatment while only half of high-grade tumors responded SRI and chromogranin were not able to predict PRRT effectiveness The NETest exceeded SRI evaluation and predicted both therapy response and non-response The predictive response index of select NETest genes associated with metabolism signaling and grading was found to be more than 90 percent accurate a patient would be able to know if PRRT would be an effective cancer therapy for them," said Bodei further blood tests could be used to monitor the progress of treatment rather than relying on statistics that are not specific to them as individuals." Scientific Paper 43: "A Blood-Based Multi-Transcript Test - the NETest - Predicts and Defines the Efficacy of Peptide Radio Receptor Therapy in Neuroendocrine Tumors," L Istituto Scientifico Romagnolo per lo Studio e la Theranostics Center for Molecular Radiotherapy and Imaging About the Society of Nuclear Medicine and Molecular Imaging The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to raising public awareness about nuclear medicine and molecular imaging a vital element of today's medical practice that adds an additional dimension to diagnosis changing the way common and devastating diseases are understood and treated and helping provide patients with the best health care possible Metrics details Structured patient feedback survey evaluating real-world home care use and satisfaction with the intermittent colonic exoperistalsis (ICE) treatment device MOWOOT in spinal cord-injured (SCI) individuals with chronic constipation SCI individuals with chronic constipation were invited to use MOWOOT 10–20 min daily and answer a questionnaire about their bowel situation before treatment (feedback 1 F1) and after ≥10 months of use (feedback 2 concomitant use of laxatives and evacuation aids and satisfaction with bowel function and management Eleven participants used the device for a mean (SD) of 13.27 (4.03) months mean time per evacuation decreased by 24.5 min (p = 0.0076) and the number of failed attempts to evacuate/week by 1.05 (p = 0.0354) with a tendency toward increased bowel movements and softer stool consistency Participants experienced decreased difficulty/strain (p = 0.0055) without significant changes in the use of laxatives and evacuation aids Satisfaction with bowel function and management improved (p = 0.0095) and more participants reported being very satisfied/satisfied (p = 0.0300) Long-term in-home ICE treatment improved bowel function and chronic constipation symptoms in SCI individuals providing clinical benefits to this population it is essential to implement a management plan to improve the symptoms of bowel dysfunction Despite the clinical benefits of ICE device treatment and the advantages of its autonomous use studies focused on SCI individuals are missing assessing the feasibility of management strategies that promote individuals’ autonomy in the home setting is important to obtain valuable real-world data The aim of this structured patient feedback survey was to assess the long-term effectiveness and tolerability as well as the satisfaction with the ICE device in a home setting in SCI individuals diagnosed with chronic constipation No additional selection criteria were considered and therefore participants mainly had neurogenic bowel dysfunction (NBD)-related chronic constipation which may be combined with other causes of chronic constipation including side effects of medications and complications due to SCI concomitant dysfunctions Those who accepted were provided with a MOWOOT device and were asked to give a voluntary 4 M Medical GmbH supplied the ICE device free of charge to the participants as a supplement to their current treatment Participants were instructed to perform the ICE treatment for 10–20 min daily they were free to adapt the supportive medication (e.g. laxatives or suppositories) or device settings (massage duration and level) at any time and they were also asked to maintain their usual lifestyle and diet habits following a moderately active lifestyle and a healthy diet including fiber and enough fluid intake is the first step in bowel management and all participants with chronic constipation are supposed to do it Participant feedback was collected using a self-administered questionnaire designed to collect data at baseline (F1) and after at least ten months of ICE device use (F2) It was sent to all participants simultaneously the period of device use evaluated was different for each participant This structured participant feedback was anonymous it followed all confidentiality requirements for personal data protection in compliance with European legislation (Supplementary materials) Image of the MOWOOT-II device with the pneumatic console and the exoperistaltic belt The inner side of the exoperistaltic belt is shown below (A) Diagram depicting the inflating-deflating sequence of the four pneumatic active elements (B) which was designed for the purpose of this study included a series of items to report demographic data (i.e. age and sex) and feedback regarding device use including bowel function management and symptoms A detailed description of the variables collected and transformation into categorical variables are provided as Supplementary methods All analyses were performed using the intention–to-treat (ITT) population to investigate the effects of time of ICE device use participants were categorized according to time under treatment (i.e. total period of device use) as <12 months and ≥12 months Quantitative variables were described as the mean and standard deviation (SD) Paired measures were analyzed using the Student’s t-test and the Chi-squared/Fisher’s exact test; comparisons between groups were performed using the two-way ANOVA The statistical analysis is further described in the Supplementary methods Statistical significance was set at a two-tailed p-value < 0.0500 Data processing and analyses were performed using GraphPad Prism software Four participants used the device for <12 months and seven used it for ≥12 months Changes in diet and fluid intake between groups lacked statistical significance ( < 12 months vs three out of the seven participants with ≥12 months of device use reported changes in lifestyle consisting of a higher fiber intake (n = 1) a fluid intake of 1.5 L−2 L per day (n = 1) The rest of participants reported no major changes There was no difference between participants followed up for <12 months and ≥12 months (two-way ANOVA p = 0.5532 for min/day and p = 0.5299 for adherence) Table 2 summarizes the variables associated with bowel function at F1 and F2 Participants reported decreased “time per evacuation” decreased number of “failed attempts to evacuate” and decreased number of “incomplete movements” and a concomitant increase in the number of “bowel movements” indicating improved bowel function after treatment Differences in “time per evacuation” and “failed attempts to evacuate/week” before and after months of treatment reached statistical significance Subgroup analyses according to time under treatment showed a similar trend especially in the subgroup of participants using the ICE device ≥12 months changes seemed more prominent than in the subgroup of participants who used the ICE device for <12 months although without statistically significant differences Most symptoms of discomfort associated with chronic constipation were significantly reduced after treatment (Table 3) The strain to evacuate was reduced in 70.0% of participants abdominal pain was reduced in 60.0% of participants and bloating was reduced in 72.7% of participants Abdominal cramps ameliorated in 72.7% of participants while spasms improved in 60.0% of participants discomfort symptoms ameliorated in 56.1% of participants of which four were under treatment for >12 months reported suppression of chronic constipation symptoms while using MOWOOT which were reported at F1 with the maximum score (6 reported as “Absent.” Another participant-reported suppression of abdominal pain one reported suppression of cramps and spasms and the third participant (under treatment for <12 months) reported vertigo Analyses according to the time under treatment showed similar overall trends with significant changes in participants under treatment for ≥12 months for bloating and spasms but not for those under treatment for <12 months and rectal bleeding were not statistically significant in any of the groups whereas discomfort symptoms analyzed collectively significantly changed overall and in the two groups these results showed increased improvement in participants with ≥12 months vs Regarding the use of laxatives and evacuation aids, three out of 11 participants reduced the use of laxatives, suppositories, or enemas (Table 3) although the difference before and after treatment did not reach statistical significance None of the participants reported any serious adverse events Only one (9.1%) participant reported a sporadic episode of abdominal pain with spontaneous remission that did not require treatment interruption Ratings were similar in the subgroups of participants according to time under treatment This structured patient feedback survey evaluated the effectiveness and satisfaction of the long-term in-home use of the ICE MOWOOT device in SCI individuals with chronic constipation Participants reported a significant decrease in evacuation time and failed attempts to evacuate per week along with an increased number of bowel movements after 10–24 months of ICE treatment Discomfort symptoms of constipation were significantly reduced and stool consistency softened with treatment despite the overall unchanged use of laxatives and evacuation aids Participants’ satisfaction with bowel function and management after device use increased and they rated its tolerability Almost all participants were very satisfied/satisfied with the ICE device Even though assessing QoL was beyond the scope of this survey the clinical benefits and reported satisfaction after ICE device use likely improved the QoL of SCI individuals although to a greater extent in the long-term ( ≥ 12 months) group indicating overall increased benefits in participants who used the ICE device longer discomfort symptoms decreased in both groups but participants who used the ICE device for ≥12 months reported significantly decreased bloating changes lacked statistical significance across subgroups and variables the differences observed in both groups were likely clinically significant in terms of positive impact on QoL supporting the long-term use of the ICE device prolonged use of the ICE device may provide greater improvement in bowel function and chronic constipation symptoms further supporting the inclusion of the ICE device in the bowel routine of SCI individuals Manual massage requires a therapist for its daily application which is unfeasible and expensive for patients on the healthcare system cheaper alternative to manual abdominal massage it may even be more effective owing to the regularity of treatments daily time of device use exceeded the recommended length yielding mean adherence rates >100% regardless of the total period of use suggest that the ICE device will be effective to treat chronic constipation in the home setting regardless of the patient profile in terms of the underlying chronic constipation etiology long-term in-home ICE treatment improved bowel function and symptoms of chronic constipation in individuals with SCI Due to the feasibility of its use in the home setting and participant-reported excellent adherence the ICE device may be a good option to treat chronic constipation Integrating the ICE device use to the bowel management routine may positively impact SCI individuals’ health likely contributing to improving their QoL as well The datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request Hou S, Rabchevsky AG. Autonomic consequences of spinal cord injury. In: Comprehensive physiology [Internet]. Wiley; 2014. p. 1419–53. Available from: https://onlinelibrary.wiley.com/doi/10.1002/cphy.c130045 Colorectal motility and defecation after spinal cord injury in humans Bowel dysfunction in spinal cord injury: current perspectives Qi Z, Middleton JW, Malcolm A. Bowel dysfunction in spinal cord injury. Curr Gastroenterol Rep. [Internet]. 2018;20. Available from: https://pubmed.ncbi.nlm.nih.gov/30159690/ Guideline for the management of neurogenic bowel dysfunction in spinal cord injury/disease Appropriate use of laxatives in the older person Levels of satisfaction with current chronic constipation treatment options in Europe - an internet survey Stercoral perforation of the rectosigmoid colon due to chronic constipation: a case report Global audit on bowel perforations related to transanal irrigation Mechanism of abdominal massage for difficult defecation in a patient with myelopathy (HAM/TSP) [7] Abdominal massage for the alleviation of constipation symptoms in people with multiple sclerosis: a randomized controlled feasibility study The use of abdominal massage to treat chronic constipation Safety and efficacy of intermittent colonic exoperistalsis device to treat chronic constipation: a prospective multicentric clinical trial American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol [Internet]. 2005;100:s1–4. https://pubmed.ncbi.nlm.nih.gov/16008640/ Phenomenological study of neurogenic bowel from the perspective of individuals living with spinal cord injury Relationship between neurogenic bowel dysfunction severity and functional status and quality of life in individuals with spinal cord injury The effect of abdominal massage on constipation and quality of life Effect of abdominal massage on constipation and quality of life in older adults: a randomized controlled trial Bauchmassage als Intervention bei Menschen mit Querschnittlähmung-eine Pilotstudie The effect of abdominal massage on bowel function in patients with spinal cord injury Review of the efficacy and safety of transanal irrigation for neurogenic bowel dysfunction controlled trial of transanal irrigation versus conservative bowel management in spinal cord-injured patients Neurogenic bowel management using transanal irrigation by persons with spinal cord injury An open prospective study on the efficacy of Navina Smart an electronic system for transanal irrigation Long-term outcome and safety of transanal irrigation for constipation and fecal incontinence Long-term outcome and safety of transanal colonic irrigation for neurogenic bowel dysfunction Download references Heiko Lienhard for contributing to the recruitment of participants at Werner Wicker Kliniken Bad Wildungen and specially Maria Pérez Sánchez and Sara Cervantes for providing medical writing support during the preparation of the manuscript We thank Ralf Müller and Markus Wilhelms for critically reviewing the final manuscript version Neurologische Fachkliniken Beelitz-Heilstätten Peter Koßmehl & Jeannette Obereisenbuchner drafted and reviewed the manuscript and approved the final version critically revised the manuscript for important intellectual content IH-F is a co-founder and employee of usMIMA S.L Ethical approval was not required for this survey as it collected anonymous participant data on the use of a marketed CE-certified medical device class IIa in a questionnaire/survey format Download citation DOI: https://doi.org/10.1038/s41394-023-00597-z According to the organizers of Germany's Party.San Open Air festival, which is scheduled to take place August 9-12 in Bad Berka, Florida death metal veterans DEICIDEhave canceled their previously announced summer European tour "for reasons which are beyond of our control." The organizers add "We are very sorry about this decision and need to go on without the band Polish kings of satanic death metal BEHEMOTH will headline on Saturday We thank Nergal and crew for the great help and the quick conversions of [their] schedules BEHEMOTH are the ineffable kings of satanic death metal and they will without doubt rule the festival We hope you are happy as we are about this unexpected booking!“ DEICIDE recently completed the North American headlining "March Of Death 2012" trek sold 2,200 copies in the United States in its first week of release It was produced by Mark Lewis (THE BLACK DAHLIA MURDER CHIMAIRA) at Audiohammer Studios in Sanford DEICIDE last year completed the "God Is Dead – To Hell With God Tour" with support from BELPHEGOR DEICIDE's "Conviction" video was directed by David Brodsky and Tim Kellen (Brodsky also handled editing duties while Kellen animated the video) and produced by MyGoodEye LLC The clip tells the story of frontman Glen Benton and his pursuit of Jesus the German photographer set out to convey the truth about how people really lived in the communist GDR – depicting her fellow citizens with a ‘timeless coolness’ the German photographer set out to convey the truth about how people really lived in the communist GDR – depicting her fellow citizens with a ‘timeless coolness’ - A recent study reported in the May issue of the Journal of Nuclear Medicine demonstrates that Ga-68 DOTATATE PET/CT scans are superior to In-111 pentetreotide scans the current imaging standard in the United States for detecting neuroendocrine tumors (NETS) and could significantly impact treatment management NETS occur mostly in the respiratory and digestive tracts and are usually slow-growing It's therefore critical to delineate the extent of disease accurately for proper management While the incidence of NETS is relatively low with 2.5-5 cases per 100,000 in the United States data from the National Cancer Institute show a five-fold increase worldwide from 1973 to 2004 although they comprise less than two percent of gastrointestinal cancers they are more prevalent than stomach and pancreatic cancers combined corresponding author for the study and professor of clinical radiology and radiological sciences at Vanderbilt University School of Medicine "Our purpose was to evaluate the safety and efficacy of Ga-68 DOTATATE PET/CT compared to In-111 pentetreotide imaging for diagnosis staging and re-staging of pulmonary and gastroenteropancreatic neuroendocrine tumors." With concerns for patient safety detailed toxicity data were also collected The two imaging methods were performed in 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic (GEP) NETs The study found that Ga-68 DOTATATE PET/CT combined with CT and/or liver MRI changed care in 28 of 78 (36 percent) patients Ga-68 DOTATATE PET/CT correctly identified three patients for peptide receptor radiotherapy who had been incorrectly classified by In-111 pentetreotide lower radiation exposure and improved accuracy the study makes a strong case for the use of Ga-68 DOTATATE imaging over the current standard While Ga-68 DOTATATE PET/CT is in widespread use outside of the United States Food and Drug Administration (FDA) has not yet approved its use for the diagnosis our investigation will provide sufficient evidence on the safety and efficacy of Ga-68 DOTATATE to the U.S then patients throughout the United States could soon have access to a higher-quality scan allowing better patient management decisions while also lowering radiation exposure and shortening examination time." Such approval would also open up the possibility of reimbursement for the scans by third-party payers of the Veterans Affairs Hospital (VA Tennessee Valley Healthcare System) Support for this study was provided by the U.S Department of Veterans Affairs Merit Review: I01BX007080 Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network and local institutional and philanthropic gifts Please visit the SNMMI Media Center to view the PDF of the study, including images, and more information about molecular imaging and personalized medicine. To schedule an interview with the researchers, please contact Laurie Callahan at (703) 652-6773 or lcallahan@snmmi.org. Current and past issues of the Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org 10.2967/jnumed.115.163865 But plenty of MLB teams are after the conclusion of the 2019 season Washington's championship caused one baseball team to rocket up this list, while another one cracked the top 25 for the first time since this list was originally released in September 2018. And with the NFL season winding down, the Buffalo Bills are primed to take a fall in the next update but their "lofty" position will change soon Teams 26-123 are at the bottom of the article (Full explanation of the formula can be found in the box below.) This is what happens when the Kings actually make the playoffs, something that hasn't happened since 2006. Wally Skalij/Los Angeles Times via Getty Images1. Sacramento Kings 28.55 pointsSports Misery Index FormulaThe five primary factors in the Fan Misery Index formula: Championships: The more (and more recently) you win championships if your most recent championship was 25-plus years ago it's almost as if you've never won at all.2 Playoff berths: How are you going to win a championship if you don't make the playoffs It's bad enough to not hoist the big trophy at the end of the year but not even putting yourself in the postseason is cause for a venting session or 10 We won't tolerate too much bellyaching from teams that are always in the postseason.3 but what's the point if you don't do anything once you're there Seeing your team go one-and-done in the postseason is quite painful -- almost as bad as not going in the first place Heartbreaks: It's one thing to lose -- it's another to get your heart ripped out of your chest "Temple of Doom" style losing at the last second or simply losing a title game some winning teams scored high in this metric because you're going to have more "bad beats" the more you play at the final table.5 Rival comparison: Having your team stink and break your heart is bad enough but having the fans of the teams you hate celebrating championships and playoff wins is salt in the wound.Misery bonus: Teams that have gone 25-plus years without winning a championship are assigned a "bonus." The longer a team goes without a title the bigger that bonus.Note that this formula takes into account the recency factor: Winning a championship in the past five years does not allow you to be miserable nor does anyone care about some heartbreak that happened 30-40 years ago (cough Stuff that happened last season is factored more than stuff that happened two to five years ago which means more than stuff six to 10 years ago which means more than stuff 11 to 20 years ago The Kings actually have a bit of positive mojo for once as their young roster hung around the playoff race for a while last season and they have a good shot to break their playoff drought in this campaign Sacramento remains atop a list that it has little interest in topping Name a trigger for misery and a Kings fan can relate even if you ignore the fact that the franchise hasn't won a championship since moving to Sacramento in 1985 The Kings haven't made the playoffs since 2006 (the longest drought in the NBA) and haven't won a playoff series since 2004 meaning that a teenage sports fan can't remember seeing the franchise triumph in anything important But it gets worse. In the fleeting moment in which the Kings were really good, they lost to the Lakers in the 2002 Western Conference Finals after some controversial officiating in Game 6 (the name Tim Donaghy ring a bell?) and an overtime loss at home in Game 7 Kings fans have had to watch Lakers fans celebrate five championships since 2000 and had to stomach watching Warriors fans celebrate their recent three-championship dynasty putting the Bills in the runner-up spot for the first time There are plenty of reasons for Buffalo fans to be miserable -- only one playoff appearance since 1999 having had to watch the rival Patriots win six Super Bowls and get to four others since that last playoff win losing four straight Super Bowls in the early 1990s You get the point -- the Bills Mafia hasn't had much to cheer about besides tailgate antics outside of New Era Field the Bills are set to make the playoffs for the second time in 20 seasons That will drop them in the next batch of rankings And if they can muster that elusive playoff win at least relative to normal Padres expectations as San Diego finished with a losing record for the ninth season in a row and in last place in the NL West for the third time in four years The Padres have now missed the playoffs for the 13th season in a row and haven't won a playoff series since 1998 when they were swept in the World Series by the Yankees So how did the Padres move down in misery? One reason was that they watched the rival Dodgers lose in the divisional series (better than watching them advance to the World Series). The second was getting to enjoy Fernando Tatis Jr. before he got injured. A full season out of Tatis, and improvement from Manny Machado could have the Padres in business next season San Diego remains near the top of the list The old familiar feeling of regret and disappointment returned in tsunami-like wave for Browns fans as rare optimism turned into the standard amount of sadness which should almost certainly vault Cleveland back to No The first memory of the Panthers in the NHL was their fans throwing thousands of plastic rats onto the ice in 1996 as the third-year franchise made an unlikely run to the Stanley Cup Final Problem is that the first memory is the only positive one and the only season the team won a playoff series you're used to seeing the Panthers lose over and over In a season in which many of the most miserable NHL franchises had positive achievements the Panthers have not only not won a playoff series they've only made it to the playoffs four times in the following 22 seasons the cross-state Lightning have a Stanley Cup and are a perennial playoff contender but imagine how much better it'd be if the local hockey team wasn't so miserable With free-agent signings such as Le'Veon Bell and C.J. Mosley and a promising young quarterback in Sam Darnold it would have been reasonable for Jets fans to expect their team to take a step up But any Jets fan who was expecting such a move should have known better as this year was another awful one for New York Darnold contracted mononucleosis early and then saw ghosts later in the year helping doom the Jets to a ninth consecutive year without making the playoffs It's been over a half-century since the Jets made it to the Super Bowl and won it behind Joe Namath's guarantee The only guarantees right now for Jets fans are dysfunction misery and jealousy of the rival Patriots and former Jets coach (for a day) Bill Belichick Turns out hiring a losing coach wasn't the way to advance the franchise's fortunes The Dolphins weren't afraid of hitting bottom this year as they went into full tank mode in an attempt to change the mojo and direction of the franchise While that made for some ugly and terrible football this season you can't blame Miami for venturing outside the box as its track the past two decades has been one of despair and sullenness The 20 seasons post-Dan Marino have been awful in South Beach as the Dolphins have only made the playoffs four times -- including only once in the past 11 -- and haven't won a playoff game since 2000 While the success of the Patriots hasn't helped being unable to come close to replacing the production of Marino is the primary reason the Dolphins have gone from a consistent playoff team in the 20th century to a trainwreck in the 21st Having to endure 223 losses the past two seasons is more than enough misery for a fan base to endure Having their two primary division rivals (the Yankees and Red Sox) combine for nine World Series titles since the Orioles' last title in 1983 hasn't been easy for Baltimore fans to stomach But neither of those are why the O's have jumped into the top 10 The Nationals' unlikely run to a World Series title was a bushel of salt in the already-opened wounds of Baltimore fans as the one set of bragging rights that Orioles fans still had went up in smoke with all of the Nats' clutch plays down the stretch and into October With a rebuild that's still far away from bearing fruit and many more losses to come the Orioles could be very high on this list for a long while Brett Hull might have been in the crease illegally but Sabres fans would probably take losing Game 6 of the Stanley Cup Final over what has happened since Buffalo has been toward the bottom of the NHL for much of the 20 years since that Cup loss as the Sabres haven't made the playoffs since the 2011 season (the longest streak in the league) and haven't won a playoff series since 2007 Sabres fans hope players like Jack Eichel can lead them back to respectability Last season showed some promise early before Buffalo ran out of juice and finished toward the bottom again Sabres fans not only have had to watch their team flounder but they've also had to watch the nearby Penguins win three Stanley Cups since 2009 Can Eichel be the spark that eventually reverses that bothersome trend One playoff win in 62 seasons has Lions fans re-evaluating their priorities. Rey Del Rio/Getty Images10. Detroit Lions This ranking seems appropriate for the Lions who are the only NFL team that's played in every year of the Super Bowl era that's never been in the big game as the Lions haven't won an NFL championship since 1957 a playoff game since 1991 or a division title since 1993 Detroit has missed the playoffs four of the past five seasons and has made the postseason only three times since 1999 This season saw the Lions fall way short of the postseason yet again Lions fans have gotten to watch some entertaining top-level players on their losing teams (Barry Sanders those players prematurely retired in their primes instead of continuing to be part of the Lions After only seeing one playoff win in 62 seasons die-hard Detroit fans are tempted to do the same The Reds fell slightly in this installment but things aren't exactly rosy for Cincinnati The Reds haven't won a World Series since 1990 haven't won a playoff series since 1995 and have now missed the postseason six years in a row Watching highlights of the Big Red Machine on VHS doesn't exactly make things better rebuilding and having their hearts broken on the rare occasions when they contend as the Cardinals have won two World Series since 2006 and are fresh off a division title while the Indians have been a postseason regular The league's oldest franchise isn't exactly killing it though there has been some incremental improvement lately Cincinnati has been aggressive in free agency and trades recently and might be in line for a standings jump The Suns used to be on the entertaining side of bad as they've had star players such as Charles Barkley as the Suns missed the playoffs for a ninth straight season and are one Kings playoff berth away from having the top misery spot in the NBA The Suns were by the far the worst team in the West last year and lost 58 or more games for the fourth consecutive season though they've shown some upward signs thus far this season Phoenix used to be a frequent playoff participant But even good Suns teams have been firewalled by slightly better teams with the Bulls and Rockets blocking them in the 1990s and the Spurs and Lakers killing good Suns runs in the 2000s Watching the rival Lakers and Warriors combine for eight championships since 2000 has also been depressing Things are slowly getting better for the White Sox as they improved their AL Central position and have built an intriguing combination of young players and free agents But it's still not enough to move the ChiSox off this list even considering their relatively recent World Series title in 2005 and lack of a misery bonus The White Sox have had an extremely hard time making the playoffs in their history Despite being around for the entirety of the World Series era the Pale Hose have only made the playoffs nine times in 116 seasons and have missed the postseason 11 years in a row And don't get a White Sox fan started about the Cubs' 2016 drought-busting championship as the one thing that could always make a South Sider smile (the Cubbies' 108 years without a title) was taken from them in cruel fashion there were only two franchises that had never played in a World Series the Mariners also own the longest playoff drought in professional sports That 2001 season wasn't exactly fulfilling either as Seattle tied a major league record with 116 regular-season wins before being tripped up one step short of the perpetually elusive World Series Mariners fans have had great players to watch in the past such as Ken Griffey Jr. but that doesn't exactly make things better for the franchise especially because Seattle is in the midst of yet another rebuilding project After making a big splash by moving from out of the Top 25 to No But that certainly doesn't mean that things are going well in Gotham Madison Square Garden isn't close to the excitement level of the Knicks' last title in 1973 -- or even where it was when the Knicks were contenders in the 1990s It seemed like a pretty simple proposition -- rallying for a second consecutive playoff appearance (something that only happened one other time in the franchise's 50 seasons in Milwaukee) would be enough to drop the Brewers off this list completely unleashing Washington on a mythical run to its first-ever championship Being that close to eliminating a team that eventually won the World Series was another in a long line of punches to the stomach and kept the Brewers on this list The Rangers debuted on this list in September and moved up after another unsuccessful season in which they not only finished below .500 but had to watch the cross-state rival Astros make another long playoff run Imagine how bad they'd feel if Houston won its second World Series title in the past three years But even removing the Astros from the equation Texas has made the playoffs only eight times since arriving in the Metroplex in 1972 and has missed the postseason the past three years And making the playoffs has been a painful proposition for Rangers fans as Texas lost back-to-back World Series in 2010 and 2011 (despite being one strike away from a title in 2011) and was subject to Jose Bautista bat-flips in 2015 at least there's a new stadium that will prevent fans from melting in the oppressive Texas summer heat The Redskins were once one of the NFL's marquee franchises as they won three Super Bowls between 1982 and 1991 and played in a fourth But if you're a fan in your early 30s or younger and you probably hate Daniel Snyder with a passion Since Joe Gibbs retired as coach after the 1992 season the Redskins have only made the playoffs five times And even though Washington has dropped a couple spots since the last update it seems nowhere close to making the postseason and getting off this list after another clunker this season It's not just a matter of rarely making the playoffs The Redskins have only won two playoff games since Gibbs left with one of those coming when Gibbs briefly returned to coaching They haven't won a playoff game since 2005 and haven't advanced past the divisional round since their 1991 title Kevin Garnett was a Timberwolves icon, but he had to go to Boston to win an NBA title. David Sherman/NBAE via Getty Images19. Minnesota Timberwolves The T-Wolves have fallen slightly since making their debut in September but there are plenty of reasons for their fans to be glum Minnesota has missed the playoffs in 14 of the past 15 seasons and hasn't won a playoff series since making it to the Western Conference finals in 2004 The first rendition of the Hornets wasn't a world-beater as Charlotte never got out of the second round from 1988 to 2002 despite having players such as Larry Johnson and Alonzo Mourning But those four second-round defeats would seem like gold to the contemporary Hornets fan as the Charlotte franchise has mostly seen misery since it was rebooted as the Bobcats in 2004 and renamed the Hornets in 2014 Not even having arguably the greatest basketball player of all time as their principal owner has been enough to get the Hornets on track, as Michael Jordan has only seen the team make the playoffs three times in 15 seasons. With star player Kemba Walker now in Boston there isn't much hope for a sudden resurgence who joined the NBA the same year as the Hornets win three titles since 2006 is also a sore spot for Charlotte fans It's official: Bears fans can't have nice things. After riding a dominating Khalil Mack-led defense to an NFC North title last year the Bears were upset in the playoffs after a missed field goal then stubbed their toe this season and will miss the playoffs yet again their never-ending search for a franchise QB might start up again The Angels are the newbie in this installment, which is hard to believe on first glance because they have Mike Trout who recently won his third MVP in the past four seasons But the help the Halos have provided Trout has been disgraceful as they've become an also-ran at the same time the cross-freeway rival Dodgers have rolled off seven NL West titles in a row Just imagine how bad it'd be for Angels fans if the Dodgers won the World Series That said, the days of Rally Monkeys and thunder sticks seem far away, even with the Anthony Rendon signing. The Angels have missed the playoffs five seasons in a row and nine out of the past 10. In that time, the Angels haven't won a playoff game, much less a playoff series. While watching Trout (and Shohei Ohtani) provides entertainment value the lack of positive results in Orange County is distressing The Bucs' 2002 title is the only thing keeping them from being higher on the list Most of their 44 seasons have been terrible making this one seem almost decent by comparison The franchise started by losing 26 consecutive games and hasn't gotten much better since as the Buccaneers haven't qualified for the playoffs since 2007 (the second-longest streak in the NFL behind the Browns) and have only made it twice since winning Super Bowl XXXVII The Raiders actually made a step up this season staying in the playoff race for a while thanks to a young roster filled with several exciting young talents and a bevy of future draft picks the Raiders are set to leave Oakland for Las Vegas as soon as they start showing signs of blossoming A lack of proper talent evaluation is one big reason the Pirates have been mostly awful since losing Barry Bonds in free agency after the 1992 season Pittsburgh set a major league record with 20 consecutive losing seasons after that and has only won one playoff series in the 40 years since the "We Are Family" team defeated the Orioles in the 1979 World Series And it doesn't look like a second win is coming anytime soon We mentioned the Rays in the Pirates' writeup Tampa used an array of young talent and cutting-edge management to make the playoffs for the first time in six seasons the Rays won the wild card and took the AL champion Astros to the brink in the division series While fan support is an issue (which is why they've considered a timeshare with Montreal) youthful players and a franchise that could be off this top 25 for good A list of teams 26-123 in the Misery Index Please enable JS and disable any ad blocker See the list below and start planning your excursion “Welcome to student life: sleep like a Bauhausler” The iconic Bauhaus Dessau Foundation Complex is the natural starting point for an adventure in BauhausLand. Visitors now have the chance to stay in the Prellerhaus, one of Germany’s first student dormitories. Built in 1926, the Prellerhaus provides an authentic student experience, with special rooms themed after famous Bauhaus alumni. Haus des Volkes, Probstzella. Image Courtesy of goBauhaus“Off the beaten track” In Probstzella, travellers will find the Haus des Volkes, Thuringia’s largest Bauhaus complex. Originally built for workers in 1927, the community center was designed by Alfred Arndt and includes a hotel, restaurant, bowling alley, cinema, and saunas. Weimar. Image Courtesy of goBauhaus“The Steiner Connection” Philosopher Rudolf Steiner influenced the thinking of some Bauhaus teachers, like Wassily Kandinsky, and today you can stay in Steiner’s former home in Weimar. Located fittingly on Bauhasstrasse, the house is now a hotel, Villa Hentzel, and dates from the 18th century. Bauhaus University. Image Courtesy of goBauhaus“The ‘Goethe didn’t stay here’ Design Apartments” Also located in Weimar is a more modern option. Designed and decorated by Bauhaus University graduates, these contemporary vacation rentals show a 21st century take on Bauhaus principles. Weimar. Image Courtesy of goBauhaus“On your bike” From Weimar, you can bike part of the Feininger Cycle Trail, named for Bauhaus artist Lyonel Feininger, to arrive in Bad Berka. Relax in this spa town at Velo Inn, a B&B catering to cyclists and hikers, and channel Marcel Breuer, who was inspired by bicycle steel tubing to create his iconic furniture. In Magdeburg you can compare historic Bauhaus architecture with modern avant-garde design by staying in the Grüne Zitadelle (Green Citadel), Austrian architect Friedensreich Hundertwasser’s last project You'll now receive updates based on what you follow Personalize your stream and start following your favorite authors If you have done all of this and still can't find the email Canadian death metallers KATAKLYSM have decided to "immortalize" the character that was featured on the cover of their most recent album and have him re-appear as the main character — dubbed "The Heartbeast" — on their next offering Commented KATAKLYSM vocalist Maurizio Iacono: "We had so [much] killer feedback on the artwork but especially on the character that we decided to keep him as the band's fifth band member.. kinda like IRON MAIDEN did with 'Eddie.' We have the perfect concept for the next album art.. KATAKLYSM filmed its performance last summer at the Party.San Open Air festival in Bad Berka titled "Live in Deutschland (The Devastation Begins)" The set will feature the whole show filled with an explosive setlist a 30-minute documentary covering the band's 15-year history and a bonus live CD A February 20 North American release via Nuclear Blast is expected Nuclear Blast Records will re-release KATAKLYSM's latest album in North America to coincide with the band's upcoming U.S The album will be reissued on February 6 with new packaging and will contain the "The End of Serenity: Live in Strassbourg" DVD which was filmed during the "Serenity in Fire" campaign in France The CD will also contain all of the band's video clips and will be limited to 5,000 copies KATAKLYSM is currently on the road with SWORN ENEMY as part of the "Trendkiller Tour" The world’s leading publication for data science Note: If you are interested in the details beyond this post, the Berka Dataset, all the code, and notebooks can be found on my GitHub Page This post is just a hands-on practice building a loan default prediction model. If you are interested in this topic and want to see some more in-depth work that I accomplished for a client, using optimization to turn their loss into profit using such loan default prediction models, please see my other article here: Loan Default Prediction for Profit Maximization it is always an interesting and challenging problem to predict how likely a client is going to default the loan when they only have a handful of information the data science teams in the banks build predictive models using machine learning The datasets used by them are most likely to be proprietary and are usually collected internally through their daily businesses there are not many real-world datasets that we can use if we want to work on such financial projects The Berka Dataset, or the PKDD’99 Financial Dataset, is a collection of real anonymized financial information from a Czech bank, used for PKDD’99 Discovery Challenge. The dataset can be accessed from my GitHub page This is an optional step since the raw files contain only delimiter-separated values so it can be directly imported into data frames using pandas Here I wrote SQL queries to import the raw data files into MySQL database for simple and fast data manipulations (eg join and aggregation functions) on the data Above is a code snippet showing how to create the bank database and import the Account table There should not be any troubles in the first two steps if you are familiar with MySQL and the database systems. For the "Load data" step, you need to make sure that you have enabled the LOCAL_INFILE in MySQL. Detailed instruction can be found from this thread By repeating step 2 and step 3 on each table all the data can be imported into the database Again, if you choose to import the data directly into Python using Pandas, this step is optional. But if you have created the database and become familiar with the dataset through some SQL data manipulations, the next step is to transfer the prepared tables into Python and perform data analysis there. One way is to use the MySQL Connector for Python to execute SQL queries in Python and make Pandas DataFrames using the results After modifying the database info such as host execute the query and convert it into Pandas DataFrame: and good for experimentation purposes compared to directly import the files into Pandas DataFrames Unlike other ML projects where we are only given with acsv file (1 table) this dataset is quite complicated and there is a lot of useful information hidden between the connections of tables so this is another reason why I want to introduce the way of loading data into the database first Now the data is in MySQL server and we have connected it Python so that we can smoothly access the data in data frames The next steps are to extract features from the table Since predicting the loan default is a binary classification problem we first need to know how many instances in each class By looking at the status variable in the Loan table According to the definitions from the dataset description we can make them into binary classes: good (A or C) and bad (B or D) There are 606 loans that fall into the "good" class and 76 of them are in the "bad" class we can look into the variables and plot the histograms to see if they correspond to different distributions The loan amount shown below is a good example to see the difference between the two classes it still shows an interesting pattern that loans with a higher amount tend to default they don’t have to be the existing variables provided in the tables we can always be creative and come up with some out-of-the-box solutions on creating our own features when joining the Loan table and the Account table we can get both the date of loan issuance and the date of account creation We may wonder if the time gap between creating the account and applying for the loan plays a role so a simple subtraction would give us a new variable consists of days between the two such activities on the same account where a clear trend can be seen that people who apply for the loan right after creating the bank account tend to default By repeating the process of experimenting with existing features and created features I finally prepared a table that consists of 18 feature columns and 1 label column After the features are extracted and put into a big table it is necessary to transform the data so that they can be fed into the machine learning model in an organic way Our dataset is pretty clean and there is any missing value so we can skip the imputation and directly jumpy into scaling for the numerical values The are several options of scalers from scikit-learn I used MinMaxScaler to rescale the numerical values between 0 and 1 the typical strategy of dealing with categorical variables is to use OneHotEncoder to transform the features into binary 0 and 1 values The code below is a representation of the feature transformation steps: The first thing in training a machine learning model is to split the train and test sets It is tricky in our dataset because it is not balanced: there are almost 10 times more good loans than bad loans A stratified split is a good option here because it preserves the ratio between classes in both train and test sets There are many good machine learning models for binary classification tasks the Random Forest model is used in this project for its decent performance and quick-prototyping capability An initial RandomForrestClassifier model is fit and three distinct measures are used to represent the model performance: Accuracy It is noticeable that Accuracy is not sufficient for this unbalanced dataset If we finetune the model purely by accuracy then it would favor toward predicting the loan as "good loan" F1 score is the harmonic mean between precision and recall and ROC AUC is the area under the ROC curve These two are better metrics for evaluating the model performance for unbalanced data The code below shows how to apply 5-fold stratified cross-validation on the training set It is clearly seen that the accuracy is high but the F1 score is very low because of low recall There is room for the model to be finetuned and strive for better performance By assigning different values to the hyperparameters of theRandomForestClassifier such as n_estimators max_depth min_samples_split and min_samples_leaf it will iterate through the combinations of hyperparameters and output the one with the best performance on the score that we are interested in Refitting the model with the best parameters we can take a look at the model performance one the whole train set and the test set: The performance on the train set is great: more than 2/3 of the bad loans and all of the good loans are correctly classified and all of the three performance measures are above 0.84 the result is not quite satisfying: most of the bad loans are labeled as "good" and the F1 score is only 0.267 There is evidence that overfitting is involved so more effort should be put into such iterative processes in order to get better model performance we can now rank the features based on their importance The top 5 features that have the most prediction powers are: we have already seen the unusual behaviors that could be related to the loan default such as the loan amount and days between account creation and loan application In this post, I introduced the whole pipeline of an end-to-end machine learning model in a Banking application I described the Berka dataset and the relationships between each table Steps and codes were demonstrated on how to import the dataset into MySQL database and then connect to Python and convert processed records into Pandas DataFrame Features were extracted and transformed into an array ready for feeding into machine learning models I fit a Random Forest model using the data and generated the list of top 5 features that play roles in predicting loan default This machine learning pipeline is just a gentle touch of the one application that could be used with the Berka dataset It could go deeper since there is more useful information hidden in the intricate relationship among tables; it could also go wider since it can be extended to other applications such as credit card and client’s transaction behaviors But if just focusing on this loan default prediction there could be three directions to dive further in the future: Again, This post is just a hands-on practice building a loan default prediction model from scratch. If you are interested in this topic and want to see some more in-depth work that I accomplished for a client, using optimization to turn their loss into profit using such loan default prediction models, please see my other article here: Loan Default Prediction for Profit Maximization Thank you for reading! If you like this article, please follow my channel and/or become my referred member today (really appreciate it 🙏 ). I will keep writing to share my ideas and projects about Data Science Feel free to contact me if you have any questions Join Medium with my referral link – Zhou (Joe) Xu I am a data scientist at Sanofi. I embrace technology and learn new skills every day. You are welcome to reach me from Medium Blog, LinkedIn, or GitHub My opinions are my own and not the views of my employer Step-by-step code guide to building a Convolutional Neural Network A beginner’s guide to forecast reconciliation Here’s how to use Autoencoders to detect signals with anomalies in a few lines of… Solving the resource constrained project scheduling problem (RCPSP) with D-Wave’s hybrid constrained quadratic model (CQM) An illustrated guide on essential machine learning concepts Derivation and practical examples of this powerful concept The world’s leading publication for data science Vocalist Chris Barnes of Florida death metallers SIX FEET UNDER has issued the following update: "To the loyal fans of SIX FEET UNDER, our longtime friends and bandmates Terry Butler (bass) and Greg Gall (drums) have decided to move on and depart from SIX FEET UNDER [as first reported by BLABBERMOUTH.NET yesterday] Steve Swanson (guitar) and myself are grateful for all the fun times we've shared together through the years and wish them the best of luck in their musical endeavors Steve and myself are very excited about the future of SIX FEET UNDER and I have been working hard on writing the new SIX FEET UNDER material for the past four months with a new writing partner "I will make this guarantee and promise to all the fans of SIX FEET UNDER: the new lineup will be a death metal force to be dealt with with the long-awaited addition of a brutal-as-fuck drummer and riffs that will rip your face off "Thank you all for your continued support and devotion Butler released the following statement to BLABBERMOUTH.NET regarding his departure from SIX FEET UNDER: "I would just like to put it out there that Greg Gall [drums] and I have parted ways with SIX FEET UNDER I have been helping OBITUARY out on bass over the past year and now will be officially joining them as a permanent band member I have had the pleasure of meeting a lot of our dedicated fans and have made many friends along the way "I wish nothing but the best for Chris Barnes [vocals] and Steve Swanson [guitar] in their future with SIX FEET UNDER." Live In Germany" DVD will be released on January 31 in Europe (three days earlier in Germany) and February 1 in North America via Metal Blade Records The set consists footage of the band's August 8 2009 performance at the Party.San Open Air festival in Bad Berka The gig was filmed by Roax Films with nine cameras and recorded in 5.1 Surround Sound picture size 16:9 — best entertainment guaranteed The "Victim Of The Paranoid" performance from the DVD can be viewed below the initial European pressing includes the digipak version of the latest SIX FEET UNDER covers album The DVD is being released on mid-price and the bonus CD does not cost a penny extra This release and the attached price strategy is a big thank you from Barnes and his gang to all their loyal fans a view of the Alps or the Baltic … we choose affordable B&Bs and apartments in GermanyThis article is more than 8 years oldVintage caravans Ignore the unprepossessing name of the Schittlerhaus This family-run apartment hotel is at the foot of the Allgäu Alps in the south-west and its panoramic setting is complemented by seven classy apartments and one smaller guest room The local peaks are great for both summer hiking and winter sports Apartments for two from €52 room-only, plus €10 a night for each extra guest, schittlerhaus.de This article was amended on 30 August 2016 to replace the photograph of the Hopper Hotel Et Cetera The entry originally showed a picture of another hotel not featured in this article.