tbuckley/cabot-search huggingface dataset:
Assessment of circulating tumor cell number as a transitional surrogate endpoint for survival in phase II trials for metastatic castration-resistant prostate cancer.
Authors: Howard I. Scher, Robert Thomas Mccormack, Arturo Molina, Matthew Raymond Smith, Robert Dreicer, Fred Saad, Ronald De Wit, Karim Fizazi, Dana T. Aftab, Ana Limon, Martin Fleisher, Johann S. De Bono, Gary J. Kelloff, Glenn Heller
Journal: Journal of Clinical Oncology (2019)

143 Background: Short-term measures of response that reflect clinical benefit are a critical unmet need for clinical trials for mCRPC. Using data from 5 randomized mCRPC trials, we showed that a response endpoint (RE) based on a change in CTC number using the FDA cleared CellSearch® (Menarini) platform from any, (≥ 1, CTC any) to 0 (CTC0) per 7.5 ml of blood was associated strongly with overall survival (OS). Here we explored whether different CTC and PSA REs could serve as “transitional surrogates” defined as a biomarker validated in phase 2 but not in phase 3 trials for overall survival (OS), using the baseline and week 13 prostate-specific antigen (PSA) level and CTC counts. Methods: Four 13-week REs were studied: (i) PSA50 (≥ 50% PSA decline from baseline), (ii) CTC0 (≥ 1 CTC/7.5 ml of blood at baseline and 0 CTCs at week 13), (iii) both PSA50 and CTC0, and (iv) either PSA50 or CTC0. The relative effectiveness of these REs as transitional surrogates for OS was evaluated at the patient level by discrimination, the separation between responder and non-responder survival curves, and at the trial level using explained variation, the accuracy in predicting k-month survival in a trial with the response proportion. Results: A total of 6081 pts were enrolled of whom 5660 (93%) survived until week 13 and among these patients 3080 (54%) had a baseline CTC count ≥ 1 and baseline PSA ≥ 5 ng/ml. At the patient level, separation between responder and non-responder survival curves over time was greater using CTC0 than PSA50 (average difference in survival probability 0.35 vs. 0.29, respectively). At the trial level, explained variation in survival over time was also greater for CTC0 than PSA50 (average R-squared 0.67 vs. 0.58, respectively). CTC/PSA combination REs did not improve on CTC0 at either level. Conclusions: The CTC0 RE provides stronger discrimination than PSA50 at the patient level and greater observed explained variation at the trial level. The results suggest that for the individual patient, a decrease in CTCs to zero at week 13 is a stronger indicator of longer term OS than the more widely used PSA50 and serves as a reasonably likely surrogate for OS in clinical trials.
Observation for clinical stage (CS) IS germ-cell tumors in patients treated at the National Cancer Institute in Mexico.
Authors: Nora Sobrevilla-Moreno, Miguel A. Alvarez, Jose Luis Aguilar, Rodrigo Espinosa-Fernandez, Jorge Martinez-Cedillo, Yolanda Miranda-Ponce, Alejandro Escalona-Ledesma, Miguel Jimenez, Angel Herrera Gomez
Journal: Journal of Clinical Oncology (2015)

e15546 Background: Testicular germ-cell tumor (TGCT) is the most frequent solid neoplasm in young adults. Current guidelines recommend that CS IS patients should be treated with cisplatin-based chemotherapy (CT). Long-term adverse events such as infertility and cardiovascular disease are well known. Methods: We retrospectively reviewed the clinical charts from patients with TGCT treated in our institution from january 2000 to december 2012. CS IS patients were identified, treatment type and patterns of recurrence were registered. Prognostic factors were analyzed. Results: 25 patients with CS IS were identified, all had non-seminoma histology. Most frequent histologies were yolc sac (YS) 80%, teratoma 72%, carcinoembryonic 60%, immature teratoma 28%, seminoma 28%. All patients had S1 disease after orchiectomy, mean AFP levels were 81.5 (2.3-515 ng/ml), HCGB 5.6 (0-90 mIU/ml) and LDH 166 (SD44.7 IU/L). 24% patients received BEPx3 CT, 76% were observed. Mean time from surgery to CT was 61.7 (SD 41.1) days (d). Mean time from orchiectomy to negative tumor markers (TM) for patients in observation was 46d (SD2.8). Relapse free survival (RFS) was 11.23m (IC95%9.1-13.1). A shorter RFS (8.7m (IC95%5.6-11.8) was identified in the observation group compared to patients treated with CT (18.9m (IC95%14.1-23.7), p = .029). Other factors related to shorter RFS were seminoma and YS tumor histology (p = .068 and p = .057, respectively). 36% patients relapsed, 33.3% in the CT group, 36.8% in the observation group (NS). 55.6% patients with YS tumors relapsed (44% for patients without YS tumor, p = 0.07). 8 paients received CT (CISCA 12.5%, BEPx3 87.5%). One patient died due to non disease related causes before treatment. Complete response (CR) was achieved in 66.7% of patients. 2 patients had a second relapse. 76% of patients are alive and continue follow-up. Median overall survival has not been reached. Conclusions: Observation for CS IS patients may be feasible. Although RFS is shorter, overall survival is not modified. No prognostic factors for relapse were statistically significant, YS tumor histology and longer time from orchiectomy to negative TM may be related to increased risk for relapse. Further study is warranted.
Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts
Authors: A. Capasso, J. Lang, T. M. Pitts, K. R. Jordan, C. H. Lieu, S. L. Davis, J. R. Diamond, S. Kopetz, J. Barbee, J. Peterson, B. M. Freed, B. W. Yacob, S. M. Bagby, W. A. Messersmith, J. E. Slansky, R. Pelanda, S. G. Eckhardt
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX). <h3>Methods</h3> BALB/c-Rag2<sup>null</sup>Il2rγ<sup>null</sup>SIRPα<sup>NOD</sup> (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm<sup>3</sup>. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment. <h3>Results</h3> Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor. <h3>Conclusion</h3> Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.
Identification of bone involvement in patients with prostate cancer recurrence using <sup>18</sup>F-fluciclovine PET/CT and impact on subsequent management.
Authors: Michael S Kipper, Paul Dato
Journal: Journal of Clinical Oncology (2019)

248 Background: Bone is the most frequent site of metastasis in prostate cancer. Accurate localization of recurrence following primary treatment can help optimize salvage therapy. Positron emission tomography (PET) tracer, 18 F-fluciclovine, is approved in Europe and the US for men with rising prostate specific antigen (PSA) after prior treatment. LOCATE was a prospective trial to study the impact of 18 F-fluciclovine PET/computed tomography (PET/CT) on management of men with prostate cancer recurrence and negative standard imaging after curative intent treatment. Here, we explore changes in management (CIM) in men with 18 F-fluciclovine-avid bone lesions. Methods: 18 F-Fluciclovine PET/CT was performed and interpreted according to standard practice at 15 US centers. Eligible men (≥ 18 y; prior curative intent treatment of prostate cancer; recurrence based on rising PSA; negative/equivocal findings on standard bone and pelvic imaging) had their treatment plans recorded pre- and post-scan. Results: A total of 213 men (median pre-scan PSA, 1.0 ng/mL) were enrolled. Overall, 18 F-fluciclovine detected lesions in 122 (57%) and 126 (59%) had CIM post-scan. 18 F-Fluciclovine-avid bone lesions were found in 23 (11%) men. Prior to the fluciclovine scan, 21 (91%) had a 99m Tc-MDP scan (20 negative, 1 equivocal results), 1 (4%) had an unspecified bone scan (negative result) and 1 (4%) did not receive a bone-specific scan. Of the 23 men with positive scans, 15 (65%) had post-scan CIM: ADT added to planned radiotherapy (RT; 4, 27%); ADT replaced with targeted treatment of fluciclovine-positive extrapelvic bony areas (4, 27%); RT modified to target fluciclovine-positive areas (4, 27%); modified ADT regime (2, 13%); and watchful waiting in favor of RT (1, 7%). The majority of men with no post-scan CIM were prescribed ADT (6/8, 75%). Conclusions: Despite negative standard bone imaging, 18 F-fluciclovine localized recurrence of prostate cancer to bone in 11% of patients; the majority of whom had a management change as a result, frequently in order to target fluciclovine-positive sites. Further study to investigate the clinical outcomes of such changes is warranted. Clinical trial information: NCT02680041.
Anti‐C1q autoantibodies are frequently detected in patients with systemic sclerosis associated with pulmonary fibrosis
Authors: C. Liaskos, S. Rentouli, T. Simopoulou, A. Gkoutzourelas, G.L. Norman, A. Brotis, I. Alexiou, C. Katsiari, D.P. Bogdanos, L.I. Sakkas
Journal: British Journal of Dermatology (2019)

Anti‐C1q autoantibodies (autoAbs) are associated with systemic lupus erythematosus (SLE), but their presence in other rheumatic diseases has not been adequately investigated. We aimed to assess anti‐C1q autoAbs and circulating immune complexes (CICs) in systemic sclerosis (SSc). In total 124 patients with SSc were studied; 106 were female and the median age was 59·4 years (range 25–81·4). Overall 75 (60·5%) had limited cutaneous SSc and 49 (39·5%) had diffuse cutaneous SSc. Also included were 25 patients with Sjögren syndrome (SjS), 29 with rheumatoid arthritis (RA), 38 with SLE and 53 healthy controls. Enzyme‐linked immunosorbent assays with high‐ and low‐salt buffers were used to measure anti‐C1q antibodies and CICs. The former allows only anti‐C1q antibody binding to C1q and the latter also allows IgG Fc to bind to C1q. Anti‐C1q antibodies were present in 20 of 124 (16·1%) patients with SSc: five had high levels (> 80 RU mL−1) and 10 (50%) had moderate levels (40–80 RU mL−1). Anti‐C1q antibodies were also present in one of 25 (4%) patients with SjS, one of 29 (3%) with RA (P < 0·05 for both) and three of 53 (6%) healthy controls (P < 0·01). Anti‐C1q antibodies were detected in 13 of 38 (34%) patients with SLEs. Anti‐C1q antibodies were more frequent in male than female patients with SSc (P = 0·005); this association remained after multivariate regression analysis. Anti‐C1q antibody level was the most important factor in predicting the presence of pulmonary fibrosis, and the second most important in predicting pulmonary arterial hypertension. Fourteen patients with SSc (11·3%) had CICs. Anti‐C1q autoAbs were frequently detected in patients with SSc, and their high levels predict the co‐occurrence of pulmonary fibrosis or pulmonary arterial hypertension.
A phase II, dose finding, placebo-controlled, study of zuclomiphene citrate to amerliorate the frequency and severity of hot flashes caused by androgen deprivation in men with advanced prostate cancer.
Authors: Robert H. Getzenberg, Domingo Rodriguez, Michael L Hancock, Harry Fisch, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2019)

TPS338 Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT not only lowers testosterone, but also decreases estrogen levels which can cause significant side effects including hot flashes, loss of bone and bone fractures, and decreases in libido. Up to 80% of the men on ADT report hot flashes and 30-40% of men have moderate to severe hot flashes. Concern over hot flashes make patients less likely to begin ADT and can lead to early discontinuation of ADT. While the off-label use of potent steroidal estrogens has demonstrated efficacy, the appropriate dose as well as dosing route or schedule of these potent estrogens, has not been established. Furthermore, the potential for safety issues with potent steroidal estrogens remains a significant limitation to their clinical utility. Zuclomiphene citrate, is novel weak nonsteroidal estrogenic agent that should ameliorate hot flashes caused by ADT, and as one of the isomers of clomiphene, has a 50 year safety history of being well tolerated in men. Methods: The Phase 2, placebo controlled, dose finding clinical trial (V72203) evaluating zuclomiphene citrate (VERU-944) capsules, oral daily dosing, for the treatment of moderate to severe hot flashes in men with prostate cancer on ADT is in progress. Men are randomized to daily doses of placebo or zuclomiphene 10mg, 50mg or 100mg. V72203 is enrolling approximately 36 men per arm in 10 sites in the United States. The primary efficacy endpoint is the mean change in frequency of moderate and/or severe hot flashes from baseline to week 4 and maintained until week 12. Secondary endpoints include changes from baseline in bone turnover markers, free and total testosterone, SHBG, PSA, and safety. Hot flashes are being measured in real time utilizing an electronic data capture device (ePRO) provided to each subject. We anticipate completion of enrollment by the end of 2018 with study results by second quarter of 2019. Clinical trial information: NCT03646162.
Abstract P074: Epidemiology of Diabetes Phenotypes and Association with Cardiovascular Risk in the National Health and Nutrition Examination Survey (NHANES)
Authors: Michael Bancks, Ramon Casanova, Edward Gregg, Alain Bertoni
Journal: Circulation (2019)

Introduction: A recent study among Scandinavian adults identified novel unique diabetes phenotypes using data on traditional diabetes characteristics. Our objective was to assess whether unique diabetes phenotypes are present in a multi-ethnic US sample and, if so, are differentially associated with cardiovascular disease (CVD) risk factors. Methods: We included 4300 NHANES participants (age ≥20 years) from exams 2003-04 to 2013-14 identified as having diabetes by any of the following: self-report of previous diabetes diagnosis, self-report of diabetes medication use, fasting glucose ≥126 mg/dL (≥8 hours fasting), random glucose ≥200 mg/dl, and glycated hemoglobin (HbA1c) ≥6.5%. We used an iterative data-driven method ( k- means clustering) to partition the sex-stratified sample into unique groups based on data for each of the following: self-reported age of diabetes diagnosis, body mass index (BMI), waist circumference, HbA1c, and years of insulin use. We estimated the association between diabetes subgroup with traditional CVD risk factors, accounting for demographics and NHANES sampling methods. Results: We identified four unique subgroups of diabetes phenotypes related to age (AR), insulin use (IU), severe obesity (SOR), and severe hyperglycemia (SHG). Of the 4300 diabetes cases, 51.3% were AR, 5.9% were IU, 30.3% were SOR, and 12.5% were SHG (Table). We observed differences in subgroup prevalence by race/ethnicity. Compared to the AR phenotype, all groups had higher HbA1c and BMI, the IU and SOR groups had greater blood pressure and cholesterol medication use, and the IU group had worse profiles for renal, eye, and neuropathy complications. Conclusion: Our findings corroborate that diabetes is a heterogeneous disease with unique subgroups and, a novel aspect of our work, differentially distributed across race/ethnicity. Our findings challenge whether diabetes prevention and treatment strategies should be reconsidered to phenotype-specific in order to reduce diabetes incidence, morbidity, and mortality.
Novel Recurrent Germline JAK2 G571S Variant in Childhood Acute B-Lymphoblastic Leukemia: A Double Hit One Pathway Scenario
Authors: Franziska Auer, Minhui Lin, Karin Nebral, Christoph G. W. Gertzen, Oskar A. Haas, Michaela Kuhlen, Holger Gohlke, Shai Izraeli, Jan Trka, Jianda Hu, Arndt Borkhardt, Julia Hauer
Journal: Blood (2018)
SPINK1 expression and outcomes postprostatectomy in race-specific cohorts.
Authors: Farzana A Faisal, Harsimar B Kaur, Jeffrey J. Tosoian, Scott A. Tomlins, Edward M. Schaeffer, Tamara L. Lotan
Journal: Journal of Clinical Oncology (2019)

23 Background: The SPINK1 molecular subtype has been shown to be more common in African American (AA) men with prostatic adenocarcinoma (PCa) than European Americans (EA). Other studies have suggested that SPINK1 expression is associated with more aggressive disease. However, there have been limited studies examining clinical outcomes by SPINK1 status in racially diverse cohorts. Methods: The objective was to determine the associations between SPINK1 subtype, race, and clinical and pathologic outcomes after radical prostatectomy (RP). A total of 186 AA and 206 EA men who underwent RP at Johns Hopkins were matched according to pathologic Gleason grade. We examined SPINK1 status by immunohistochemistry on tissue microarrays using a genetically validated assay. ERG and PTEN were assessed previously using validated immunohistochemistry assays. SPINK1 prevalence was compared between races. Logistic regression and Cox proportional hazard analyses assessed the association of SPINK1 status with pathologic and oncologic outcomes in race-specific multivariate models. Results: SPINK1-positive subtype was present in 25% (45/186) of AA and 15% (30/206) of EA men (p = 0.013). SPINK1 expression was generally mutually exclusive with ERG expression and PTEN loss in both racial cohorts. There were no differences in pathologic grade group (GG), pathologic stage, biochemical recurrence (BCR)-free survival, or metastasis-free survival between SPINK1-positive and SPINK1-negative tumors in the overall cohort or by race. In multivariable analyses, SPINK1 expression was not associated with BCR (AA: HR 0.99, 95% CI 0.56-1.75, p = 0.976; EA: HR 0.88, 95% CI 0.43-1.77, p = 0.720) or metastasis (AA: HR 0.79, 95% CI 0.25-2.49, p = 0.691; EA: HR 1.55, 95% CI 0.58-4.11, p = 0.381) in either the AA or the EA cohort. Conclusions: SPINK1-positive subtype is more prevalent in AA than EA men with PCa. While previous studies showed that SPINK1 may be associated with more aggressive PCa, we found that SPINK1 protein expression was not associated with worse pathologic or oncologic outcomes including BCR and metastasis after RP in either AA men or EA men.
RISK FACTOR PROFILES AND OUTCOMES OF VERY YOUNG ADULTS WITH MYOCARDIAL INFARCTION: RESULTS FROM THE YOUNG-MI REGISTRY
Authors: Junjie Yang, Biery David, Avinainder Singh, Sanjay Divakaran, Ersilia M. DeFilippis, Bradley Collins, Jon Hainer, Marcelo Di Carli, Ron Blankstein
Journal: Journal of the American College of Cardiology (2019)
Analysis of the National Cancer Data Base (NCDB) on impact and trend of neoadjuvant chemotherapy in upper urinary tract urothelial cancer.
Authors: Rashad Khan, Danning Huang, Alina Basnet
Journal: Journal of Clinical Oncology (2019)

408 Background: Five year cancer specific survival rate is between 12- 70% for pT2 and higher UUTUC tumors. Adjuvant platinum based therapies have proven to improve Overall survival (OS) in observational series. Compromised renal function after surgery, delayed recovery from surgery pose challenge for adjuvant chemotherapy (AC). Thus, neoadjuvant chemotherapy (NAC) is an appealing option. However, there is only limited evidence on the role of NAC in UUTUC. Methods: We conducted a retrospective study of UUTUC (stage I- III) who underwent complete or partial nephroureterectomy with peri-operative chemotherapy. We then compared OS outcome among NAC vs AC groups. OS was calculated using Kaplan Meier analysis. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 50539 UUTUC patients reported in NCDB (2004-2016), 20121 met our inclusion criteria. 360 patients received NAC, 2617 received AC and 17144 received only surgery. Patients who received NAC were more likely to be younger, treated at academic centers, have Medicare and private insurance, have clinical T3 and higher tumor, have lower Charlson-Deyo Score (CDCC) score and undergo complete nephroureterctomy. One, three and five year OS among NAC and AC is depicted in table 1. With 150 months (m) follow up, median OS was 73.89 m for NAC and 54.14 m for AC group. A log rank test with p value=0.3437 shows no significant difference in survival rates of the two groups. Though consistent upward trend is observed in the use of NAC from 2004 to 2015, significantly higher percentages of patients still undergo only surgery without perioperative chemotherapy. Conclusions: Numerically higher mOS in NAC group was not statistically significant different from AC group. Use of perioperative chemotherapy appears to be much lower in UUTUC. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration of chemotherapy, and provider/patient selection bias. Overall survival among two groups. [Table: see text]