tbuckley/cabot-search huggingface dataset:
Tissue plasminogen activator in gastrointestinal adenocarcinoma: What is its role?
Authors: Andrey A. Maslov, Oleg I. Kit, Elena M. Frantsiyants, Larisa S. Kozlova, Elena A. Dzhenkova, Natalya V. Soldatkina, Irina S. Tishchenko, Sergey V. Tumanyan, Yuriy A. Gevorkyan, Nikolay S. Samoylenko, V. I. Aleynov, Anton G. Milakin, Sergey I. Poluektov, Petr N. Gabrichidze
Journal: Journal of Clinical Oncology (2019)

e15532 Background: The aim of the study was a comparative analysis of the tissue plasminogen activator activity (tPA-Ag and tPA-act) in adenocarcinoma of the esophagus (EA), stomach (SA), pancreatic head (PHA), sigmoid colon (SCA) and rectum (RA). Methods: Tissues of tumors, perifocal area (PA) and resection line tissues were studied by ELISA in 143 patients (38-74 years) with EC (n = 12, G2, T 2-3 N 0-1 M 0 ), SC (n = 28, G2, T 2-3 N 0-1 M 0 ), PHC (n = 46, G2, Т 2-4 N 0 M 0 ), SCC (n = 31, G2, T 2-3 N 0-1 M 0 ) and RC (n = 26, G2, T 2-3 N 0-1 M 0 ). Statistical analysis was performed using the Statistica 10 program. Results: Tumor levels of tPA-Ag were the highest in SA: SA˃RA˃SCA˃EA˃PHA, but in EA, SCA and RA were lower than in the resection line (p &lt; 0.01). Tumor levels of tPA-Ag in SA were similar to the values in PA, and were 3.1-213 times higher than in other tumors. Perifocal levels of tPA-Ag were the highest in SA: SA˃SCA and RA˃EA˃PHA, but in EA and PHA they were lower than in the resection line tissues (p &lt; 0.01), in SCA and RA – similar, in SA – exceeded the levels in all samples by 1-2 orders of magnitude (p &lt; 0.0001). Levels of tPA-Ag were similar in resection line tissues in SCA and RA, being 2.5-128 times higher than in other tumors. The highest tPA-act was observed in perifocal and tumor tissues in SA (p &lt; 0.0001, compared to other tumors): SA˃SCA˃RA˃EA˃PHA (p &lt; 0.01). tPA-act in PHA tumors was 1.3 times higher (p &lt; 0.05) than in resection line tissues and 40.5 times lower than in PA. In SCA, tPA-act was similar in tumor and PA, but was 1.3 times lower (p &lt; 0.05) than in resection line tissues. In RA, tPA-act decreased from the resection line to the tumor by 1.3 and 2.3 times, respectively. Conclusions: The role of tPA in gastrointestinal adenocarcinomas differs: in EA, SCA and RA it has protective functions, as its levels in the tumor are lower than in the resection line. SA was accompanied by an enhanced secretion of tPA-Ag and the formation of tPA-act in tumors, with their subsequent evasion into PA. In PHA, the tPA distribution was similar, but the high rate of tPA activation led to the depletion of both forms of tPA, while still retaining their advantage in the tumor and PA, compared with the resection line.
Immunotherapy efficacy and safety of programmed cell death 1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in pan-cancer: A systematic review and meta-analysis.
Authors: Jianchun Duan, Longgang Cui, Guoqiang Wang, Zhengyi Zhao, Shiqing Chen, Jia Song, Lei Yang, Chuang Qi, Zhili Fang, Qing Wang, Yuzi Zhang, Jing Zhao, Yuezong Bai, Shangli Cai, Lei Xiong, Zhijie Wang, Xiaochen Zhao, Jie Wang
Journal: Journal of Clinical Oncology (2019)

e14113 Background: Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment, while whether PD-1 and PD-L1 inhibitors deliver different clinical outcomes remains obscure. Here we carried out a systematic review and meta-analysis to compare the efficacy and safety profile of PD-1 and PD-L1 inhibitors in pan-cancer patients. Methods: We systematically searched PubMed, Cochrane library, and Embase from January 2000 to December 2018 for randomized controlled trials that compared PD-1/PD-L1 inhibitors with standard treatment in patients with solid tumors. We also reviewed abstracts and presentations from all major conference proceedings. Retrospective studies and trials that compared anti-PD-1/PD-L1 with other immunotherapies were excluded. The primary outcome was the difference in overall survival (OS). Studies were stratified into comparison groups upon studies mirrored with trial design and patient characteristics. Effect size in each comparison group was pooled first, the difference in overall survival was estimated, and the overall effect sizes was pooled using a random-effects model. Results: A total of 3864 publications were retrieved through initial literature search, 17 randomized controlled trials involving 9549 patients with solid tumors were included for this meta-analysis. PD-1 inhibitors exhibited significantly improved OS over PD-L1 inhibitors either in overall population (HR 0.75, 95% CI 0.64-0.87), as monotherapy (HR 0.79, 95% CI 0.65-0.96), or combination with chemotherapy (HR 0.66, 95% CI 0.53-0.82). PD-1 inhibitors also showed improved progression free survival (PFS) over PD-L1 inhibitors in overall population (HR 0.70, 95% CI 0.53-0.94). No significant difference was observed for safety profile between PD-1 inhibitors and PD-L1 inhibitors as monotherapy. PD-1 inhibitors plus chemotherapy have less Grade 3-5 adverse events than PD-L1 inhibitors plus chemotherapy (overall RR 0.84, 95% CI 0.75-0.93). Sensitivity analysis presented a satisfactory consistency of the overall estimates across these analyses. Conclusions: PD-1 inhibitors exhibited better clinical performance for survival outcome and safety profile over PD-L1 inhibitors. Future studies and explorations of the underlying mechanisms are needed for the further optimization of treatment strategies in clinical practice.
Circulating tumor DNA (ctDNA) in metastatic melanoma (MM) patients (pts) with brain metastases (mets).
Authors: Jenny HJ Lee, Alexander M. Menzies, Matteo S. Carlino, Richard Kefford, Richard A. Scolyer, Georgina V. Long, Helen Rizos
Journal: Journal of Clinical Oncology (2019)

9581 Background: Brain mets are common in pts with MM, occurring in up 50% of pts. Serial ctDNA levels at baseline and early on therapy predict objective response (OR) and overall survival (OS) in MM pts without brain mets receiving immune checkpoint inhibitors (ICI). The predictive utility in pts with brain mets is unknown. Methods: BRAF/NRAS ctDNA at baseline and early on ICI therapy (week 3-8) was analysed using mutation specific digital droplet PCR (detection threshold 2.5 copies/ml plasma) in MM pts with brain mets. Intracranial (IC) and extracranial (EC) disease volume (sum of product of diameters of ALL mets [SPD]) and OR, progression-free survival (PFS) and OS were analyzed. Results: 48 pts with brain mets were studied, 40 with concurrent EC disease (SPD EC med 892mm 2 [25-22417mm 2 ], IC med 200mm 2 [9-1487mm 2 ]) and 8 with isolated IC mets (SPD med 150mm 2 [66-1035mm 2 ]). At baseline, ctDNA was detectable in 28 (58%) pts, 28/40 (70%) with IC + EC mets and 0/8 with isolated IC mets. Baseline ctDNA reflected EC disease volume (Pearson’s r = 0.4, p = 0.01) but not IC volume (r = 0.1, p = 0.5). Baseline ctDNA did not associate with IC or EC OR or PFS, however, undetectable ctDNA was associated with superior OS (HR 0.4, p = 0.01). Early on therapy, ctDNA predicted EC response but not IC response; EC OR was 65% if ctDNA undetectable and 6% if detectable (p &lt; 0.01), IC OR was 35% if undetectable and 12% if detectable (p = 0.1). Nevertheless, undetectable ctDNA early on therapy was associated with a superior PFS (HR 0.3, p &lt; 0.01) and OS (HR 0.2, p &lt; 0.01), indicating survival is largely determined by extracranial disease activity. In the 8 pts with IC disease only, 7/8 had disease progressive disease as best response. 1/8 subsequently developed detectable ctDNA at week 12, with multiple new EC mets seen at first restaging scan at this time. Conclusions: ctDNA does not appear to be a useful biomarker for detecting brain mets nor monitoring brain response in melanoma pts receiving ICI. This has important implications when using ctDNA in the setting of surveillance in the metastatic and adjuvant setting.
Contralateral breast cancer risk according to first breast cancer characteristics among United States women from 1992 to 2015.
Authors: Cody Ramin, Diana Withrow, Brittny Davis Lynn, Gretchen Gierach, Amy Berrington de González
Journal: Journal of Clinical Oncology (2019)

1549 Background: After recent advances in breast cancer treatment and increasing uptake of contralateral prophylactic mastectomies, estimates of contralateral breast cancer (CBC) risk by year of diagnosis and other patient characteristics are needed to help inform decision making. Methods: We estimated CBC risk in 399,032 1-year survivors of a first primary breast cancer (stage I-III) in the US Surveillance, Epidemiology, and End Results Database (1992-2015). CBC was defined as an invasive second breast cancer diagnosed in the opposite breast 12+ months after the first breast cancer diagnosis. We estimated standardized incidence ratios (SIRs) and 5-year cumulative incidence of CBC by calendar period, age, breast cancer subtype, and receipt of hormonal therapy for the initial breast cancer. SIRs were calculated as the observed number of CBCs among survivors compared to the expected number of first breast cancers in the general population. Cumulative incidence was estimated in women without contralateral prophylactic mastectomies and accounted for competing risks. Results: Among 399,032 breast cancer survivors, 11,365 cases of CBC were diagnosed through 2015. Risk of CBC was elevated over the entire study period (SIR = 2.23, 95% CI = 2.19-2.27). SIRs for CBC declined over calendar period and this decreasing trend was observed irrespective of age, estrogen receptor (ER) status, and hormonal therapy. Survivors had an overall 5-year cumulative incidence of CBC of 1.49% (95% CI = 1.44%-1.54%), which decreased over time to 1.31% (95% CI = 1.23%-1.41%) in 2008-2014. For recent diagnoses, the 5-year cumulative incidence of CBC was higher after ER-negative (1.80%, 95% CI = 1.55%-2.07%) and triple negative tumors (1.98%, 95% CI = 1.52%-2.55%), and lowest for women who received hormonal therapy (1.01%, 95% CI = 0.90%-1.13%). Conclusions: Although CBC risk is declining in the US from 1992-2015, survivors have approximately twice the risk of an incident breast cancer (in the contralateral breast) compared to the general population. The 5-year cumulative risk of CBC is highest after ER-negative/triple negative tumors highlighting the need for medical surveillance and targeted interventions among these patients.
Case 6-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, E.A. Nardell, E.J. Mark
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 57-year-old man was admitted to the hospital because of progressive dyspnea and marked tracheobronchial obstruction.The patient was born in Wisconsin and helped to raise chickens for five years during his childhood. He had frequent bouts of pharyngitis in childhood and "pleurisy" as a teenager and became aware of limited ventilatory reserve at the age of 14 years, although he later served in the National Guard without great difficulty. At the age of 20 years he began to smoke one pack of cigarettes daily. At 34 years dyspnea and cough developed, and one year later he . . .
Emerging therapies for small cell lung cancer
Authors: Sen Yang, Zhe Zhang, Qiming Wang
Journal: Journal of Hematology & Oncology (2019)

Currently, chemotherapy remains the standard treatment for first- and second-line management of small cell lung cancer (SCLC). Immunotherapy has made progress in the treatment of SCLC, and nivolumab, pembrolizumab, atezolizumab, and durvalumab have led to significant improvements in clinical outcomes of SCLC. Regarding options in other classes of therapy, the cytotoxic drug lurbinectedin was granted orphan drug status based on a remarkable objective response rate of 39.3%. In addition, an increase in progression-free survival (PFS) was achieved in a phase II study of anlotinib (ALTER 1202). Future prospects for even better outcomes in SCLC lie in novel ways to integrate immunotherapy and small-molecule TKI drugs. Innovative clinical trial designs are needed to efficiently explore the increasing number of options with new drugs and new combinations thereof for SCLC.
Distinct mutational landscape between HR+ and HR- HER2+ early-stage breast cancer patients.
Authors: Bo Chen, Ning Liao, Guo-Chun Zhang, Yulei Wang, Xiaoqing Chen, Liping Guo, Li Cao, Hsiaopei Mok, Chong-Yang Ren, Kai Li, Minghan Jia, Cheukfai Li, Ling-Zhu Wen, Jiali Lin, Guangnan Wei, Ting Hou, Analyn Lizaso, Jing Liu, Charles M. Balch
Journal: Journal of Clinical Oncology (2019)

543 Background: HER2 targeted therapy has revolutionized the survival outcomes of early and advanced HER2+ breast cancer (BC). However, among HER2+ patients, the therapeutic response to HER2 inhibitors vary. To understand the molecular mechanism of the variability in therapeutic efficacies, the mutational landscape of HER2+ tumors need to be elucidated. Methods: 107 HER2+ Chinese stage I-III BC patients were included in the study, including 64 HR+ and 43 HR- patients. A majority of the patients were diagnosed with infiltrating ductal carcinoma (99/107). Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes spanning 1.64 MB of the human genome. Results: 1,119 alterations were detected, including 478 single nucleotide variants (SNVs), 14 insertions or deletions, 29 fusions, 593 copy number amplifications (CNA), 2 large genomic rearrangements and 3 CN deletions in 267 genes. Alterations in 99 genes were shared between HR+/HER2+ and HR-/HER2+ tumors; while 123 and 45 genes were only detected in either HR+/HER2+ or HR-/HER2+ tumors, respectively. CNA, splice site and frameshift mutations were significantly more in HR+/HER2+ patients ( p= 0.017). Specifically, CNA in SPOP, CCND1, FGF19, FGF3, FGF4, RNF43, RAD51C, ADGRA4 and MDM4 and various alterations in GATA3 were significantly more among HR+/HER2+ tumors ( p&lt; 0.05). In addition to HER2 amplifications, concurrent fusions in ERBB2 (67%, 4/6), SNVs in ERBB3 (100%, 3/3) and ERBB4 (100%, 1/1) were more likely to be detected in HR+/HER2+ tumors, while concurrent EGFR amplifications were exclusively detected in HR-/HER2+ tumors. The trend of concurrent mutations was consistent with mutation types detected in HER2- tumors based on HR status, wherein EGFR amplifications were more frequent in HR-/HER2- tumors, while SNVs in EGFR, ERBB2, ERBB3 and ERBB4 were more predominant in HR+/HER2- tumors. Based on KEGG pathway analysis, HR+/HER2+ tumors had more frequent alterations in TGFb ( p= 0.007), WNT ( p= 0.002) and homologous recombination ( p= 0.004) pathways than HR-/HER2+ tumors. Furthermore, our data revealed that HR+/HER2+ and HR-/HER2+ patients had comparable TMB ( p= 0.24), with a median TMB of 4.0 mutations/Mb for both. Conclusions: Our study revealed genetic heterogeneity between HR+ and HR- HER2+ tumors. The distinct genetic alterations are potentially relevant in the development of optimal treatment strategies for such patients.
Case 14-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, D.M. Vernick, M.L. Goodman
Journal: New England Journal of Medicine (1989)

Presentation of CaseAn 82-year-old woman was admitted to the hospital because of a left facial palsy and a mass in the left mastoid region.The patient was in her usual state of health until nine days earlier, when a peripheral left facial paralysis developed. X-ray films of the mastoid region showed an osteolytic lesion on the left side. Six days before entry a left mastoidectomy was performed elsewhere for removal of a suspected cholesteatoma. The operation revealed a soft-tissue mass that eroded the posterior wall of the external auditory canal and the lateral mastoid cortex; no cholesteatoma was found. . . .
First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).
Authors: Kim N. Chi, Neeraj Agarwal, Anders Bjartell, Byung Ha Chung, Andrea Juliana Pereira de Santana Gomes, Robert W. Given, Álvaro Juárez Soto, Axel Stuart Merseburger, Mustafa Ozguroglu, Hirotsugu Uemura, Dingwei Ye, Kris Deprince, Vahid Naini, Jinhui Li, Shinta Cheng, Margaret K. Yu, Ke Zhang, Julie S. Larsen, Sharon Anne McCarthy, Simon Chowdhury
Journal: Journal of Clinical Oncology (2019)

5006 Background: TITAN was designed to determine whether APA, a selective next-generation androgen receptor inhibitor, plus ADT improves radiographic progression-free survival (rPFS) and overall survival (OS) compared with PBO plus ADT in pts with mCSPC. Methods: In this randomized, double-blind phase 3 study, pts with mCSPC regardless of extent of disease were randomized (1:1) to APA (240 mg/d) or PBO, added to ADT, in 28-day cycles. Pts with prior treatment (tx) for localized disease or prior docetaxel for mCSPC were allowed. All pts received continuous ADT. Dual primary end points were rPFS and OS. Secondary end points were time to a) initiation of cytotoxic chemotherapy, b) pain progression, c) chronic opioid use, d) skeletal-related event. Time-to-event end points were estimated by Kaplan-Meier and Cox proportional hazards methods. This first planned OS interim analysis took place after ~50% of expected events. Results: 525 pts were randomized to APA and 527 to PBO. Median age was 68 y; 8% had prior tx for localized disease; 11% had prior docetaxel. 63% and 37% had high- or low-volume disease, respectively. At median 22.6 mo follow-up, 66% APA and 46% PBO pts remained on tx. APA significantly improved rPFS (HR, 0.48; 95% CI, 0.39-0.60; p &lt; 0.0001), with a 52% reduction in risk of death or radiographic progression; benefit was observed across all subgroups analyzed. Median rPFS was not reached in the APA group and 22.1 mos in the PBO group. APA also significantly improved OS (HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death. Median OS was not reached in the APA or PBO group. Time to initiation of cytotoxic chemotherapy was significantly improved with APA (HR, 0.39; 95% CI, 0.27-0.56; p &lt; 0.0001). Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of PBO pts to receive APA. Rates of grade 3/4 adverse events (AEs) (42% APA, 41% PBO) were similar, and discontinuations due to AEs (8% APA, 5% PBO) were low. Conclusions: In the TITAN study in pts with mCSPC, including pts with high- and low-volume disease and prior docetaxel, addition of APA to ADT significantly improved rPFS and OS, and the safety profile was tolerable. These results support the addition of APA to ADT for tx of pts with mCSPC. Clinical trial information: NCT02489318.
Features of adolescent and young adult cancer patients in Japan.
Authors: Hideo Suzuki, Yuka Aida, Hiroko Fukushima, Hiroko Bando, Sachie Hashimoto, Eiichi Ishikawa, Ai Muroi, Toyomi Satoh, Ayumi Shikama, Ikuo Sekine
Journal: Journal of Clinical Oncology (2019)

e13081 Background: The number of deaths because of cancer among adolescent and young adults (AYAs) in Japan is about 2,300 per year, which accounts for 17.3% of all deaths in these populations. This study aimed to investigate the clinicopathological features of AYA cancer patients. Methods: Patients registered to the Ibaraki Cancer Registry from our hospital between 2007 and 2017 were included in this study. The proportion of patients by cancer types were calculated by age groups and gender. Results: There were 27281 cancer patients in the registry, among whom, 1972 patients (7.2%) were aged between 15 and 39 years (AYA group) and 2445 were aged between 64 and 66 years (reference group). Female patients were the majority (68.2%) in the AYA group, whereas male patients were the majority (59.7%) in the reference group. Among male patients, central nervous system (22.3%) and germ cell (22.3%) tumors were the most common types in the AYA group, whereas prostate (14.7%) and lung (11.3%) cancers were the dominant ones in the reference group. Among female patients, cervical (35.8%) and breast (14.5%) cancers were the top two cancer types in the AYA group, whereas breast (19.3%) and lung (8.2%) cancers were the dominant ones in the reference group. The proportion of cancer types by 5-year age bands showed three distinctive patterns that could be associated with their etiology. Pattern 1 included central nervous system neoplasm, ovarian cancer, hematopoietic malignancy, bone sarcoma, soft tissue sarcoma, and germ cell tumor, in which the proportion peaked in teenage year group and gradually decreased in the older age groups. Pattern 2 included thyroid, breast, cervix, and uterine cancers, as well as malignant melanoma and lymphoma, which peaked in the twenties and thirties. The other cancer types belonged to pattern 3, in which the proportion increased with age and peaked in the sixties. Conclusions: Cancers in AYAs had a distinctive pattern compared to that in older age patients. The proportion of each cancer by age groups showed three different patterns.
Empaglifozin has cardioprotective and anti-inflammatory effects during doxorubicin treatment: A preclinical study.
Authors: Nicola Maurea, Vincenzo Quagliariello, Carmela Coppola, Domenica Rea, Antonio Barbieri, Claudio Arra, Gerardo Botti
Journal: Journal of Clinical Oncology (2019)

e23057 Background: Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), reduces the risk of hospitalization for heart failure or cardiovascular death in type 2 diabetic patients. We aimed to study if EMPA could have cardioprotective and anti-inflammatory effects in Doxorubicin (DOXO) - Induced cardiotoxicity. Methods: we tested the effects of EMPA alone or in combination with DOXO in HL-1 adult cardiomyocytes evaluating: mitochondrial viability, lipid peroxidation, Leukotriene-B4 expression, p65-NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function, Global Longitudinal Strain (GLS) were measured using 2D speckle tracking echocardiography in C57BL6 mice pretreated with EMPA (10 mg/kg/day) per os for 3 days. EMPA was then administered for additional 7 days, alone and in combination with DOXO (2.25 mg/kg/day ip). Cardiac lysates were processed for analysis of pro-inflammatory Interleukins. Results: EMPA, co-incubated with DOXO, is able to increase the cardiomyocyte viability of 33,6 and 82,3 % at 100 and 500 nM, respectively (compared to only DOXO treated cells). EMPA inhibits the lipid peroxidation by decreasing MDA and 4-HNA production of around 23,6 and 28,7 %, at 100 nM and of 47,8 and 52,1 % at 500 nM, respectively, compared to untreated cells. Moreover, EMPA has anti-inflammatory activity with a reduction of Leukotriene B4 expression and p65-NFkb activation of 58,4 and 64,3 % at 500 nM, respectively (compared to only DOXO treated cells). EMPA also decreased the expression of Interleukin 1β (of 28,5 and 68,8 %), Interleukin-8 (of 21,2 and 57,3 % ) and Interleukin-6 (of 28,1 and 49,8 %) at 100 and 500 nM, respectively, compared to only DOXO exposed cells. Preclinically, after 7 days with DOXO, GLS decreased. Interestingly, in mice treated with EMPA+DOXO, EMPA prevents the GLS’s reduction : GLS was 19.24 ± 1.5 (p &lt; 0,01) vs DOXO alone. In DOXO-EMPA groups, the heart IL-1β, IL-6 and IL-8 tissue extract were reduced of 48, 54,4 and 58,2 % compared to only DOXO groups. Conclusions: EMPA has strong anti-inflammatory and cardioprotective effects in DOXO-Induced cardiotoxicity and these effects are mainly mediated by a reduction of the lipid peroxidation, Leukotriene-B4 and NF-κB activation.