tbuckley/cabot-search huggingface dataset:
Chronotherapeutic regimen with liposomal cisplatin for systemic treatment of primary liver cancer.
Authors: Levan Tavartkiladze, Alexandre Tavartkiladze, Teimuraz Sordia, Ani Gvajaia
Journal: Journal of Clinical Oncology (2019)

e15678 Background: Primary liver cancer (HCC) treatment is one of the priority issues of clinical oncology due to inefficiency and quantitative lack of medicines. The goal of our research was to perform treatment of Primary Liver Cancer, based on chronobiological mechanisms, assessment of treatment efficiency and advantage over the standard regimen. Methods: A total of 21 patients with HCC participated in the study. The treatment was performed by Liposomal Cisplatin. Assessment of cancer cells sensitivity to platinum group medicines was performed using RT-PCR method by expression of DNA methyltransferase I gene. During 24 hours, with 2-hour intervals, circulating tumor cells (CTC) were taken from peripheral venous blood. At the end, in all samples circadian regimens of DNA methyltransferase I gene expression were studied. According to obtained results, the circadian peak of gene expression was registered at 02:00-04:30 am time interval. Results: According to the study design of the 21 patients 12 ones received treatment based on chronotherapy regimens (investigated group, infusions were made at 02:00-04:30 am), 9 patients received treatment with standard regimen (control group, infusion was performed at 10:00-12:00 am). Infusions were performed according to the protocol with 1 week intervals for 9 weeks (a single infusion dose 150mg/m 2 ). The treatment efficiency was evaluated 9 weeks later by the following parameters: AFP serum level and computer tomography of the liver. Results of the study demonstrated significant differences in treatment efficacy. During chemotherapy performed in chronotherapy regimen in patient's blood plasma, the AFP concentration decreased on average by 36.5% compared to the initial value, however in the control group the AFP concentration decreased on average by 13.7%. By CT positive dynamics was detected in both groups, but with significant advantage in case of chronotherapy regimen, size reduction of tumor growth by 27.1% on average was associated with fibrous transformation and prominent decrease of vascularization was found. In the control group, size reduction of the tumour growth was seen, however only by 6.3% on average. Patients clinical condition as well as CBC data differed with significant prevailing in case of chronotherapy. Conclusions: Obtained results confirm high clinical significance of chronobiological features of gene expression in antitumour therapy as well as importance of the development of new, up-to-date protocols for HCC – highly aggressive tumour therapy based on chronotherapy principles.
End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).
Authors: Sandra M. Swain, David Miles, Sung-Bae Kim, Young-Hyuck Im, Seock-Ah Im, Vladimir Semiglazov, Eva Ciruelos, Andreas Schneeweiss, Estefania Monturus, Emma Clark, Adam Knott, Eleonora Restuccia, Mark Benyunes, Javier Cortes
Journal: Journal of Clinical Oncology (2019)

1020 Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p &lt; .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.
Association of Team Sports Participation With Long-term Mental Health Outcomes Among Individuals Exposed to Adverse Childhood Experiences
Authors: Molly C. Easterlin, Paul J. Chung, Mei Leng, Rebecca Dudovitz
Journal: JAMA Pediatrics (2019)

<h3>Importance</h3> Adverse childhood experiences (ACEs) are associated with long-term poor mental health. Less is known about factors that improve long-term mental health among those with ACEs. <h3>Objective</h3> To evaluate, among those exposed to ACEs, whether team sports participation during adolescence is associated with better mental health in adulthood and whether the association between team sports participation and mental health varies by sex. <h3>Design, Setting, and Participants</h3> This study used data from 9668 individuals who participated in waves 1 (1994-1995) and 4 (2008) of the National Longitudinal Study of Adolescent to Adult Health. Individuals were included if they had complete data on exposure to ACEs (physical and sexual abuse, emotional neglect, parental alcohol misuse, parental incarceration, and living with a single parent) and a valid sample weight. Statistical analysis was performed from November 6, 2017, to January 4, 2019. <h3>Main Outcomes and Measures</h3> The association between team sports participation in grades 7 to 12 (wave 1) and diagnosis of depression and/or anxiety and current depressive symptoms (determined by Center for Epidemiologic Studies Depression scale–10 scores) at ages 24 to 32 years (wave 4) among individuals exposed to ACEs. Multivariable logistic regression models were weighted based on propensity scores for factors associated with team sports participation and controlled for individual, family, and school characteristics. Interaction terms tested whether associations between team sports participation and mental health varied by sex. <h3>Results</h3> Of 9668 individuals included in the study (4470 male [50.0%]; mean [SD] age, 15.2 [1.75] years), 4888 (49.3%) reported 1 or more ACE and 2084 (21.3%) reported 2 or more ACEs. Among those with ACEs, team sports participation during adolescence was significantly associated with lower odds of receiving a diagnosis of depression (unadjusted rate, 16.8% vs 22.0%; propensity score–weighted [PSW] adjusted odds ratio [aOR], 0.76; 95% CI, 0.59-0.97) or anxiety (11.8% vs 16.8%; PSW aOR, 0.70; 95% CI, 0.56-0.89) and having current depressive symptoms (21.9% vs 27.5%; PSW aOR, 0.85; 95% CI, 0.71-1.01). There were no significant differences in associations between team sports participation and mental health by sex. Stratified analyses showed significant associations for all outcomes among males (depression: PSW aOR, 0.67 [95% CI, 0.46-0.99]; anxiety: PSW aOR, 0.66 [95% CI, 0.45-0.96]; depressive symptoms: PSW aOR, 0.75 [95% CI 0.56-0.99]) but only 1 outcome among females (anxiety: PSW aOR, 0.73; 95% CI, 0.54-0.98). <h3>Conclusions and Relevance</h3> Among individuals affected by ACEs, team sports participation in adolescence was associated with better adult mental health. Team sports may be an important and scalable resilience builder.
Male gender is associated with seizure risk in low-grade glioma (LGG) patients.
Authors: Jasmin Jo, Kathryn Sara Nevel, Ryan Sutyla, Mark E Smolkin, M. Beatriz Lopes, David Schiff
Journal: Journal of Clinical Oncology (2019)

e13520 Background: Up to 90% of LGG patients present with seizures, but the risk of developing seizure is not known. Our goal was to determine the association between clinical and molecular factors with seizure incidence in LGG patients. Methods: Retrospective study from 2/2002-1/2015 involving 291 patients ≥18 years old, with diagnosis of WHO grade II glioma. Intractable seizure was defined as patients needing ≥2 anti-epileptic drugs. Chi-square tests of association were used to test for associations between factors and outcome measures. Results: Study population was 54% men, median age of 51, with oligodendroglioma (47%), oligoastrocytoma (25%), astrocytoma (21%), NOS (7%). Among patients with molecular testing (87%), 32% had IDH mutation (IDHmt) and 1p/19q co-deletion, 37% IDHmt and 1p/19q intact and 18% IDH wildtype LGG. Sixty-eight percent of patients had seizures prior to LGG diagnosis; 41% intractable seizures. A trend toward higher incidence of pre-operative seizure was observed in IDHmt LGG patients (p = 0.09). On univariate analysis (Table), oligodendroglioma was significantly associated with a higher risk of intractable seizures. Male gender was strongly associated with the risk of seizure at presentation, seizure development after surgery, and intractable seizures. Conclusions: Consistent with historical data, the majority of our patients presented with seizure; oligodendroglioma with higher risk of intractable seizures. Unexpectedly, gross resection did not favorably predict seizure outcome, possibly due to our small study population. Our study only showed a trend towards higher seizure occurrence in IDHmt LGG patients. Our finding of association between male gender and seizure risk in LGG patients mirrors that of Pallud et al (Brain 2014) and warrants further investigation into the possible molecular basis of sex differences in epileptogenesis in LGG.[Table: see text]
NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer.
Authors: Jennifer J. Knox, Mairead Geraldine McNamara, Daniel H. Palmer, T.R. Jeffry Evans, David Goldstein, John A. Bridgewater, Juan W. Valle
Journal: Journal of Clinical Oncology (2019)

TPS4156 Background: Cisplatin and gemcitabine (CisGem) is the global standard of care for 1 st -line treatment of patients (pts) with advanced biliary tract cancer (BTC). No agents have regulatory approval for this disease. CisGem achieves an objective response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (ABC-02). Key cancer resistance mechanisms limit gemcitabine efficacy. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome resistance mechanisms associated with poor gemcitabine response. Promising signs of efficacy have been observed with single agent in a phase I study in solid tumors (Blagden et al 2018) and in the phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg /m 2 d1, d8 q 21 days for the 1 st -line treatment of advanced BTC. 14 pts have been enrolled across 2 cohorts (NUC-1031: 625 mg/m 2 and 725 mg/m 2 ). In 11 pts evaluable for response ORR was 64% (1 CR, 6 PRs) and DCR was 73%. PFS/OS data is maturing. The combination was very well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D in combination with cisplatin is 725 mg/ m 2 . Safety, coupled with encouraging efficacy signal has led to initiation of a global Phase III development program. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus CisGem for the 1 st -line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), that is not resectable and who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m 2 NUC-1031 + 25 mg/m 2 cisplatin or 1000 mg/m 2 gemcitabine + 25 mg/m 2 cisplatin, administered on Days 1 and 8 of a 21-day cycle, respectively. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT02351765.
Cyclooxygenase inhibitor use during checkpoint blockade immunotherapy and effect on time to progression for metastatic melanoma patients.
Authors: Shang-Jui Wang, Karishma Khullar, Nikhil Yegya-Raman, Sinae Kim, Ann W. Silk, Jyoti Malhotra, Michael A. Gentile, Janice M. Mehnert, Salma K. Jabbour
Journal: Journal of Clinical Oncology (2019)

e21029 Background: In tumors, cyclooxygenase (COX) activity leads to biosynthesis of prostaglandin E2 which can inhibit T-cell and dendritic cell function, thereby allowing immune evasion. Preclinical models have shown therapeutic synergy between COX inhibitors (COXi) and anti-PD-1 inhibition (PD-1i) immunotherapy (IT). We hypothesized that patients (pts) treated with checkpoint blockade IT and concurrent COXi would have improved responses compared to those treated with IT and no COXi. Methods: We retrospectively analyzed 65 metastatic melanoma pts who received IT (PD-1i/PD-L1i/CTLA4i) between 5/2011-11/2017 on their 1 st course of IT. Of these pts, 38.5% (N = 25) took concurrent COXi (aspirin, NSAIDs, or selective COX-2i) and 61.5% (N = 40) did not. We compared differences in baseline characteristics and time to progression (TTP) between IT-treated melanoma pts who did or did not receive COXi, using the Kaplan-Meier method and Cox regression. TTP was defined as time from IT start to progression of disease (POD) as determined by the treating physician based on CT or PET/CT scans, or last known alive. Results: Mean age was 66 yrs; male: 64.6%; BRAF mutant: 29.2%, ECOG 0/1/2: 60%/35.4%/4.6%; steroid use: 47.7% during IT; and prior non-checkpoint blockade IT: 13.8%. IT was stopped due to POD in 53.8% of pts, IT toxicity 6.2%, completed therapy 24.6%, and treatment holiday 15.4%. There were no significant differences in baseline characteristics between pts who did or did not receive COXi during IT, except for mean age (70 (COXi) versus 63 yrs (no COXi), p = 0.019). Pts that received COXi had longer TTP (median 245 days) vs without COXi (median 85 days, p = 0.0002). On multivariate analysis, COXi was associated with longer TTP (HR 0.34, p = 0.0004) after accounting for age, gender, steroid use, and ECOG PS ≥1. Immune-related toxicity was not significantly different with or without COXi (p = 0.73). Conclusions: Our findings suggest that in metastatic melanoma pts treated with IT, concurrent COXi use may result in a longer TTP, without increasing toxicity. These findings warrant further study to continue to augment outcomes for pts.
Association of immune gene expression profiling with vinflunine clinical benefit in metastatic urothelial cancer (mUC).
Authors: Guillermo de Velasco, Marta Dueñas, Alejandra Bernardini, Alvaro Pinto, Teresa Alonso-Gordoa, Javier Puente, María Pilar González-Peramato, Jesus Paramio, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2019)

e16034 Background: There are limited treatment options for mUC after platinum-based chemotherapy failure. Immune checkpoint inhibitors (ICI) have shown a durable benefit but only in a minority of patients (20-25%). Vinflunine remains as a therapeutic option without validated biomarkers. In this study, we sought to analyze the molecular determinants of vinflunine response in mUC. Methods: mUC patients from 4 University Hospitals in Spain who received second-line vinflunine after platinum-based chemotherapy were classified in non-responders (NR: progressive disease ≤3 months; N = 10) or responders (R: response ≥ 6 months, N = 14). Targeted- sequencing of 275 cancer-related genes and a PanCancer Immune Profiling Panel were performed on pre-treatment tumors. Selected genes were evaluated by RT-qPCR and protein expression was detected by immunohistochemistry. Results: The most common alteration, TP53 mutations, had a similar frequency in R (7/14, 50%) and NR (4/10, 40%). Mutations in 5 genes: ERBB3 (4/14; 28,6%), KTM2C (4/14; 28,6%), PI3KCA (4/14; 28,6%), ARID2 (3/14; 21,4%) and FGFR3 (3/14; 21,4%) were identified only in R. Mutations in ERBB4 (3/10, 33,3%) and BCOR (2/10, 20%) were identified only in NR. Estimated TMBs were not significantly different among the R (13 per Mb) and NR (9 per Mb) samples. According to gene expression profiling, NR had high cytotoxic cells infiltrate and T cells as well as high counts of TILs compared to R. In addition, expression of IDO, MAGE A4, and SOCS1, that has been associated with response to ICIs, were down-regulated in R compared with NR. Conclusions: Gene profiling showed that low-expression levels of immune-related genes are significantly associated with clinical benefit from vinflunine. Validation and complementary studies are ongoing in patients treated with ICIs.
Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy
Authors: Myrna G. Serrano, Hardik I. Parikh, J. Paul Brooks, David J. Edwards, Tom J. Arodz, Laahirie Edupuganti, Bernice Huang, Philippe H. Girerd, Yahya A. Bokhari, Steven P. Bradley, Jamie L. Brooks, Molly R. Dickinson, Jennifer I. Drake, Robert A. Duckworth, Stephen S. Fong, Abigail L. Glascock, Sophonie Jean, Nicole R. Jimenez, Joseph Khoury, Vishal N. Koparde, Ana M. Lara, Vladimir Lee, Andrey V. Matveyev, Sarah H. Milton, Shreni D. Mistry, Sarah K. Rozycki, Nihar U. Sheth, Ekaterina Smirnova, Stephany C. Vivadelli, N. Romesh Wijesooriya, Jie Xu, Ping Xu, Donald O. Chaffin, Amber L. Sexton, Michael G. Gravett, Craig E. Rubens, Karen D. Hendricks-Muñoz, Kimberly K. Jefferson, Jerome F. Strauss, Jennifer M. Fettweis, Gregory A. Buck
Journal: Nature Medicine (2019)
Pregnancies in subjects on oncology clinical trials: Analysis from the Cancer Therapy Evaluation Program (CTEP) database.
Authors: Arjun Mittra, James Murray, Naoko Takebe, Alice P. Chen, S. Percy Ivy
Journal: Journal of Clinical Oncology (2019)

e18239 Background: The NCI Cancer Therapy Evaluation Program (CTEP) has developed guidance and reporting measures to balance inclusion of younger cancer patients on trials with minimizing potential risks. CTEP began mandating the use of 2 forms of contraception for all participants of child bearing potential starting in the early 2000s in trials of thalidomide in multiple myeloma. The development of oncology clinical trials using other known teratogens such as Hedgehog Inhibitors led to development of comprehensive guidance on enrolling women on clinical trials. In 2012, CTEP further updated its guidelines to develop a reporting system for pregnancies occurring on clinical trial. Methods: We performed a retrospective analysis of the CTEP Adverse Event Reporting System (AERS) to identify unanticipated pregnancies in subjects or their partners while on oncology clinical trials. Results: 33 events were identified between 2011 and 2018, including 21 female and 11 male. One female subject got pregnant twice on the same trial. In female subjects, there were 4 live births, 1 active pregnancy, 5 spontaneous abortions, 5 medical termination of pregnancy and 1 death of the mother due to cancer. Outcome of pregnancy was not reported for 6 female subjects. Of the live births: 3 received an immunotherapy checkpoint inhibitor, and 1 received trastuzumab. Of 5 spontaneous abortions: 3 received cytotoxic chemotherapy, one radiation and one trastuzumab. Of 12 male subjects whose partners got pregnant: 3 live births, 2 active pregnancy, no pregnancy loss. Outcome of pregnancy was not reported for 6 male subjects. Conclusions: Though uncommon, pregnancies on clinical trial still occur despite requiring subjects to use 2 effective forms of contraception. With the increasing number of younger subjects being included in clinical trials for cancer, information about pregnancy outcomes in patients being treated with experimental agents is scientifically valuable and important to collect from study subjects and their partners. Since not all anti-cancer agents are of equal teratogenic potential, it is vital that this data continues to be collected and reported, including long term follow up of the pregnancy and the health of the child.
Fatal adverse events associated with pembrolizumab in cancer patients: A meta-analysis.
Authors: Gol Minoo Golshani, Amna Falak Sher, Shenhong Wu
Journal: Journal of Clinical Oncology (2019)

2561 Background: Pembrolizumab, an immune checkpoint inhibitor (ICI) against programmed cell death-1(PD-1) protein has emerged as an effective treatment for many cancers. Although better tolerated than chemotherapy, it has unique immune related adverse event and little is known about its risk of fatal adverse events (FAE). Therefore, we conducted a meta-analysis of clinical trials to determine the incidence and risk of fatal adverse events with pembrolizumab. Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases from PUBMED, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models. Results: A total of 11 clinical trials of pembrolizumab, with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%).The incidence of FAE significantly varied among different tumor types (P=0.02), ranging from 0.2% in melanoma to 3.1% in breast cancer.The incidence of FAE was significantly higher (P&lt;0.001) with chemotherapy plus pembrolizumab (7.0%, 95%CI: 4.9-10%) as compared to pembrolizumab alone (0.7%, 95% CI: 0.4-1.2, p=&lt;0.001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR=1.24 (95% CI: 0.8-1.89, P=0.31). Conclusions: Pembrolizumab is similar to chemotherapy in the risk of fatal adverse events in cancer patients. Combination of pembrolizumab with chemotherapy increased the risk of FAE in comparison with pembrolizumab alone. Further studies are needed to identify risk factors. [Table: see text]