tbuckley/cabot-search huggingface dataset:
Using PSMA (prostate-specific membrane antigen) evaluation on prostate biopsies for risk stratification at time of initial diagnosis.
Authors: Marie C. Hupe, Christian Philippi, Doris Roth, Christiane Kuempers, Julika Ribbat-Idel, Finn Becker, Vincent Joerg, Stefan Duensing, Verena Lubczyk, Jutta Kirfel, Verena Sailer, Rainer Kuefer, Sven Perner, Axel Stuart Merseburger, Anne Offermann
Journal: Journal of Clinical Oncology (2019)

6 Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis for individual treatment decision is still a major clinical challenge. PSMA expression has emerged as a promising prognostic biomarker since its overexpression in radical prostatectomy specimens (RP) has been linked to disease recurrence. Aim of our study was to assess the prognostic value of PSMA on prostate biopsies (Bx) thus improving risk stratification at time of initial diagnosis. Methods: Immunohistochemistry for PSMA expression was performed on 294 Bx with corresponding RP, 621 primary tumor foci from 242 RP, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases, and 52 benign prostatic samples. Grade group, PSA, TNM-, and R-status were assessed as clinico-pathologic features. Primary endpoint was recurrence-free survival (RFS). Chi-square, ANOVA-analyses, Cox regression and log rank tests were performed for statistical analyses. Results: PSMA expression significantly associates with grade group and initial PSA level. Elevated PSMA expression on both RP and Bx significantly correlates with an increased risk of disease recurrence after curative surgery. 5-year RFS rates are 88.2%, 74.2%, 67.7%, and 26.8% for patients with no, low, medium, or high PSMA expression on Bx, respectively. Elevated PSMA level on Bx predict a 4-fold increased risk of disease recurrence independently from initial PSA and grade group on Bx. PSMA expression significantly increases during PCa progression. Conclusions: PSMA qualifies as an independent prognostic biomarker on Bx at time of initial diagnosis in addition to the established markers PSA and grade group. PSMA predicts disease recurrence following curative surgery and potentially improves the discrimination indolent vs. aggressive disease. We propose the routine assessment of PSMA expression on Bx for outcome prediction and risk stratification at time of initial diagnosis prior to treatment decision.
Edward Milne Dunbar
Authors: E G L Wilkins, A Ustianowski, F J Vilar, A Bonington
Journal: BMJ (2019)

It was said that when Edward Milne Dunbar (“Ed”) left the regional infectious diseases nit it would never be the same again. No words could be truer than these. His achievements were many in medicine, but it is his actions and what he stood for that most defined the man.

Edward Milne Dunbar trained in London, Oxford, and Manchester, and became a consultant in infectious diseases in 1980. Forever the clinician, he was one of the first to embrace the medical and social challenges of the HIV epidemic in the early 1980s and was responsible for laying the foundations for one of the most progressive HIV units in the north. Moreover, …
Predictors of future suicide attempt among adolescents with suicidal thoughts or non-suicidal self-harm: a population-based birth cohort study
Authors: Becky Mars, Jon Heron, E David Klonsky, Paul Moran, Rory C O'Connor, Kate Tilling, Paul Wilkinson, David Gunnell
Journal: The Lancet Psychiatry (2019)

BackgroundSuicidal thoughts and non-suicidal self-harm are common in adolescents and are strongly associated with suicide attempts. We aimed to identify predictors of future suicide attempts in these high-risk groups.MethodsParticipants were from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort study in the UK. The sample included 456 adolescents who reported suicidal thoughts and 569 who reported non-suicidal self-harm at 16 years of age. Logistic regression analyses were used to explore associations between a wide range of prospectively recorded risk factors and future suicide attempts, assessed at the age of 21 years.Findings38 (12%) of 310 participants with suicidal thoughts and 46 (12%) of 380 participants who had engaged in non-suicidal self-harm reported having attempted suicide for the first time by the follow-up at 21 years of age. Among participants with suicidal thoughts, the strongest predictors of transition to attempts were non-suicidal self-harm (odds ratio [OR] 2·78, 95% CI 1·35–5·74; p=0·0059), cannabis use (2·61, 1·11–6·14; p=0·029), other illicit drug use (2·47, 1·02–5·96; p=0·045), exposure to self-harm (family 2·03, 0·93–4·44, p=0·076; friend 1·85, 0·93–3·69, p=0·081), and higher levels of the personality type intellect/openness (1·62, 1·06–2·46; p=0·025). Among participants with non-suicidal self-harm at baseline, the strongest predictors were cannabis use (OR 2·14, 95% CI 1·04–4·41; p=0·038), other illicit drug use (2·17, 1·10–4·27; p=0·025), sleep problems (waking in the night 1·91, 0·95–3·84, p=0·069; insufficient sleep 1·97, 1·02–3·81, p=0·043), and lower levels of the personality type extraversion (0·71, 0·49–1·03; p=0·068).InterpretationMost adolescents who think about suicide or engage in non-suicidal self-harm will not make an attempt on their life. Many commonly cited risk factors were not associated with transition to suicide attempt among these high-risk groups. Our findings suggest that asking about substance use, non-suicidal self-harm, sleep, personality traits, and exposure to self-harm could inform risk assessments, and might help clinicians to identify which adolescents are at greatest risk of attempting suicide in the future.FundingAmerican Foundation for Suicide Prevention, National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust, and the University of Bristol.
Validation of plasma miR-371a-3p expression in patients with metastatic and early stage germ cell tumor.
Authors: Lucia Nappi, Marisa Thi, Amy Lum, David Huntsman, Bernhard J. Eigl, Kim N. Chi, Christopher Martin, Brock O Neil, Benjamin Louis Maughan, Alan So, Peter C. Black, Martin Gleave, Alexander William Wyatt, Jean-Michel Lavoie, Daniel Khalaf, Siamak Daneshmand, Robert James Hamilton, Ricardo Romao Nazario Leao, Craig R. Nichols, Christian K. Kollmannsberger
Journal: Journal of Clinical Oncology (2019)

526 Background: Identification of relapsing/residual viable germ cell malignancy (GCM) is often challenging in patients with CSI on surveillance or with residual post-chemotherapy disease. The presence of a biomarker for GCM would overcome the uncertainty of the current methods and improve the quality of care of those patients. Methods: A 2-cohorts pilot study involving patients with clearcut evidence of GCM (clinical stage IS, metastatic and GCM prior orchiectomy) for the development cohort and patients with CSI with or without signs of tumor relapse and patients with metastatic GCM post-chemotherapy for the validation cohort. Blood samples collected in Streck tubes were obtained prior to chemotherapy for the development cohort and post-orchiectomy, at the time of suspicious relapse or post-chemotherapy in the validation cohort. Plasma miR-371a-3p (miR371) was analyzed by RT-PCR. Positive predictive value (PPV), sensitivity, specificity, negative predictive values (NPV) and AUC of the ROC for miR371 and standard diagnostic tools (CT scan, AFP, BHCG and LDH) were calculated correlating qualitative miR371 expression to the presence of viable GCM. Results: 132 patients were enrolled into the development (33 pts) and validation (99 pts) cohorts. Within the development cohort 31/33 pts were miR371 positive, 2/33 pts were negative. 31 true positives were found among the 31 miR371 positive patients for a PPV of 100% (31/31). Two true negatives were found among the 2 patients who had no miR371 expression identified (teratoma, lymphoma). The validation cohort was chosen to evaluate the methodology among patients with predicted lower volumes or no clinically apparent disease. 13/99 patients within the validation cohort were miR371 positive and all 13 had subsequent confirmation of viable GCM. For the overall study of 132 pts, PPV was 100% (46/46), NPV 98%, sensitivity 96% and specificity 100%, the AUC of the ROC was 0.96. Conclusions: Detectable circulating miR-371a-3p levels predict viable GCM and may represent a strategy for biological rather than radiographic assessment for surveillance of early stage and for post-treatment patients. Larger studies to validate these and like results have been planned.
Cell-cycle fate-monitoring to identify individual chemosensitive and chemoresistant cancer cells in heterogeneous cancer populations.
Authors: Robert M. Hoffman, Shuya Yano, Michael Bouvet, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Shinji Miwa
Journal: Journal of Clinical Oncology (2015)

e13514 Background: Essentially every population of cancer cells in a tumor or in culture is heterogeneous, especially with regard to chemosensitivity and resistance. Methods: In the present study, the fluorescent ubiquitination-based cell cycle indicator (FUCCI) imaging system was used to determine cell cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5 μM) or cisplatinum (CDDP) (5 μM) for 3 h. Cell cycle progression and apoptotic changes were monitored by time-lapse FUCCI imaging for 72 h. Results: Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell-cycle arrest in S/G2/M in most of the cells. However, a subpopulation of the cells could escape the block and undergo mitosis and subsequently underwent apoptosis while the cells arrested in S/G2/M survived. Conclusions: Chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G2/M arrest by FUCCI imaging which can be used to screen for novel agents that kill cell-cycle-arrested cells.
Impact of single day multidisciplinary clinics on the lead time from diagnosis to initiation of treatment in head and neck cancers.
Authors: Raju K. Vaddepally, Vijay Damarla, Bonita Singal, Jeanne Winn, Jerome D. Winegarden, Samir Narayan, Jan A. Akervall
Journal: Journal of Clinical Oncology (2015)

e17523 Background: We evaluated the impact of single day multidisciplinary clinics (MDC) on the lead time from diagnosis to treatment in head and neck cancers compared with patients prior to the implementation of MDC. We also made a unique attempt to show the relationship of demographic factors to the lead time. Methods: We retrospectively analyzed clinical and demographical variables of 310 patient’s records collected from head and neck cancer tumor registry at St.Joseph Mercy Hospital, Ann Arbor, from 2007 to 2013. We had 170 cases in the MDC period compared to 140 prior to the MDC. Results: We excluded 60 cases from analysis because of missing information, no date of biopsy in 5, no documentation of first treatment date in 42 and tumor was resected on the same day of biopsy in 22 cases. This left 129 cases (76%) in the MDC and 112 cases (80%) in the Pre-MDC group. Mean age was 63 in both the groups. Frequencies of other demographic factors include males (76% vs 79%), Caucasians (91% vs 88%), married (66% vs 62%) and Medicare insurance (57% vs 50%), median distance from clinic (miles) 22 vs 17, in the MDC vs Pre-MDC groups respectively. Most of the cancers were squamous cell carcinomas (88% vs 83%), however, we had more stage 4 disease in MDC (56%) vs (41%) Pre-MDC group. The median number of days from biopsy to definitive treatment in the MDC was 35 vs 33.5 in Pre-MDC group. To compare the two groups, controlling for demographic variables and an interaction between stage and site, we fit a generalized linear regression model. There was no difference in the time from biopsy to definitive treatment in the two groups, p = 0.14. The time to definitive treatment was 1.13 (95% CI: 0.96 to 1.32) times longer, for the MDC group. There was no association between stage 1|2 vs 3|4, p = 0.30. Marital status was the only variable statistically significantly related to lead time (p = 0.04). Time to definitive treatment was 0.83 (95% CI: 0.70 to 0.99) times long, for married vs unmarried patients. Conclusions: There was no significant difference in lead time with single day MDC compared to patients Pre-MDC in Head & Neck cancer patients. Interestingly, marital status was associated with decrease in lead time in married compared to unmarried patients.
Concurrence of prostatic adenocarcinoma and lymphoma: Clinical and pathological characteristics–Single institutional experience.
Authors: Jasreman Dhillon, Julio M. Pow-Sang, Michael Adam Poch, Ling Zhang
Journal: Journal of Clinical Oncology (2015)

e16101 Background: Prostatic adenocarcinoma (PA) is the most common cancer in men. Majority of non-Hodgkin lymphoma (NHL) and PA occur in the elderly, age > 65 years. Per latest SEER data incidence of PA and NHL account for 147.8 per 100,000 men and 19.7 per 100,000 men and women per year. It is expected to have a relatively high concurrence of the two neoplasms. However, lymphoma involving the prostate is rare (Bostwick et al, 1998) and many cases could be under investigated. The clinical and pathological nature of lymphoma coexisting with PA is likely under reported. Methods: Data of patients with both NHL/Hodgkin’s lymphoma and PA was retrieved from our institutional files after obtaining IRB approval. Data was reviewed and diagnoses confirmed. Results: Approximately 3500 prostatic biopsies and radical prostatectomies were performed from 2001 – 2013. 34 patients (0.9%) had both PA and lymphoma (median age 69 yrs). Of these, 7 patients had concurrently diagnosed PA and lymphoma (5 in LNs, 1 in prostate and 1 in pharynx) including 2 cases (prostatectomy and a lymph node) of composite tumor (PA+mantle cell and PA+SLL). No further lymphoma work-up was available in prostatic tissue in the remaining cases. Lymphoma was discovered incidentally in 9 of 34 cases (SLL/CLL = 6, MCL = 1, FL = 1, PCM = 1) in patients with PA. On follow up 3 of 34 cases (1 FL, 1 SLL/CLL, and 1 MCL) progressed to DLBCL and 1 CLL transformed into histiocytic sarcoma. Of 16 patients with complete follow up, 7 patients died of disease (5 of lymphoma and 2 of PA). The patients dying of PA had M1 disease and Gleason score of 7(3+4) and 8 (4+4). The median overall survival (OS) of the 7 patients was 51 months after diagnosis of lymphoma whereas, 5 year survival is reported to be 100% for PA alone without distant spread. Conclusions: Lymphoma is rarely diagnosed in prostatic tissue or lymph nodes sampled to rule out metastatic PA. Exploration of atypical lymphoid cells at these sites is warranted to avoid a tunnel vision as some subtypes of lymphoma can be more aggressive than low grade PA. Large scale, multi-center study is necessary to have better understanding of the concurrent neoplasms.
WIRE AND MAGNET SEPTOTOME, A NEW METHOD FOR ENDOSCOPIC LEAK-FREE SECTION OF SEPTA IN THE GI TRACT: PRELIMINARY RESULT OF A PILOT ANIMAL STUDY
Authors: F Huberland, C Sandersen, O Bastin, N Cauche, C Delattre, R Rio-Tinto, A Delchambre, J Devière, D Blero
Journal: Endoscopy (2019)

Treatment of symptomatic mid- or distal- esophageal diverticulum is challenging. The rationale of the endoscopic treatment is its marsupialisation into the esophagus and/or treatment of underlying motility disorders. Section of the septum carries the risk of bleeding and perforation, the latter being potentially prevented by the use of magnets or sutures endoscopically performed at the bottom of the diverticulum.
Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer
Authors: Bo Gong, Kazuma Kiyotani, Seiji Sakata, Seiji Nagano, Shun Kumehara, Satoko Baba, Benjamin Besse, Noriko Yanagitani, Luc Friboulet, Makoto Nishio, Kengo Takeuchi, Hiroshi Kawamoto, Naoya Fujita, Ryohei Katayama
Journal: The Journal of Experimental Medicine (2019)

Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non–small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti–PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1–resistant NSCLC patients. These secreted PD-L1 variants worked as “decoys” of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti–PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.
Malignant pheochromocytoma: A comprehensive genomic profiling study.
Authors: Gennady Bratslavsky, Andrea Necchi, Oleg Shapiro, Joseph Jacob, Laurie M. Gay, Brian Michael Alexander, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Thi Nho, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Siraj Mahamed Ali, Jon Chung, Venkataprasanth P. Reddy, Vincent A. Miller, Alexa Betzig Schrock, Nick Liu, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

508 Background: Malignant pheochromocytomas (MP) are a rare form of endocrine malignancy which can occur in familial and sporadic clinical settings. We performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 181,782 consecutive clinical cases, 43 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. IHC for PD-L1 expression was performed on a subset of patients (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. There were 33 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site. The primary tumor was used for sequencing in 13 (30%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (70%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (26%), TP53 (21%), SDHB (11%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 7 (16%) of cases involving SDHB (4 cases) and BRCA1, MEN1, and MSH2 (1 case each). The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: MP represent a rare form of endocrine cancer that feature a variety of genomic alterations. Although the GA/tumor is relatively low for MP, CGP can reveal important potential targets for therapy in the metastatic setting including RET, NF1 and FGFR1. MAP do not reveal strong potential for immunotherapy with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies. Based on this data, further study of CGP as a method of developing precision therapies for MP appears warranted.
Abstract P300: Cluster Analysis of Discrepancies Between Self-Reported and Investigator-Assessed Biomeasures of Cardiovascular Disease Risk
Authors: Sohye Lee, Ruth Lindquist
Journal: Circulation (2019)

Introduction: Hypertension and obesity are major cardiovascular disease (CVD) risk factors that affect huge numbers of Americans. Although hypertension and obesity are largely preventable and manageable, national statistics evidence that these CVD risks are not effectively managed. Patterns of personal under-estimates of individual risk, i.e., discrepancies between one’s perceived health (self-reported biomeasures) relative to actual health (investigator-assessed biomeasures) may contribute to delays in seeking care that could result in CVD risk detection and management. Hypothesis: We hypothesized that personal patterns of awareness reflecting a higher degree of self-reported underestimation of biomeasures of CVD risk would reveal personal profiles of greater CVD risk. Methods: Adults, aged 18 and over were recruited at a large community event. Self-reported systolic and diastolic blood pressure (SBP, DBP; mmHg), weight (lb.) were collected before objective investigator-obtained assessments of SBP, DBP, and weight. K-means (non-hierarchical) cluster analysis was used to divide data into clusters. The z-score of mean differences between self-reported and measured SBP, DBP, and weight were included in the cluster analysis. ANOVA was used to examine differences in variables among clusters. Results: A total of 61 subjects were eligible and included in the cluster analysis. The mean age of the sample was 55.2 yrs (range 21 to 73; SD: 12.9) and mostly female (63.9%). Mean SBP, DBP, and weight were 133.8, 77.6, and 176.8, respectively. Three clusters from k-means cluster analysis were identified. Cluster 1 (n=22) had moderate discrepancies, with mean differences in SBP, DBP, weight of 14.0, 3.2, -0.5, respectively. Cluster 2 (n=17) had low discrepancies, with mean differences in SBP, DBP, weight: 3.0, -2.6, 7.1, respectively. Cluster 3 (n=22) showed high discrepancies, with mean differences in SBP, DBP, weight of 27.2, 10.5, 4.5, respectively. There were significant mean differences between Cluster 2 (low discrepancies) and Cluster 3 (high discrepancies) in investigator-obtained SBP and DBP (p&lt;0.01, p&lt;0.05, respectively). Conclusions: A wide range of accuracy in personal awareness of biomeasures of risk was uncovered with patterns of discrepancy ranging from low to high; those having a pattern of greatest inaccuracy had significantly higher SBP and DBP (key risk factors for CVD) than those with least inaccuracy. These data highlight the importance of regular objective screening of biomeasures and suggests that relying on personal awareness or self-report of biomeasures is ineffective. The greater discrepancy between self-perceived and investigator-assessed numbers was associated with greater blood pressure-related CVD risks underscoring the potential benefit of arming individuals with information to “know their numbers.”