tbuckley/cabot-search huggingface dataset:
A novel function of SMC1 as a transporter of xenobiotics.
Authors: Rachana Yendala, Lukman Tijani, Kyaw Zin Thein, Henry Palangdao Igid, Mohamed Shanshal, Sanjay Awasthi, Fred L. Hardwicke
Journal: Journal of Clinical Oncology (2017)

e14107 Background: Structural Maintenance of Chromosome 1 (SMC1) is a component of the cohesin complex involved in the DNA-damage repair. Studies have shown that it is overexpressed in Colon Ca, Glioblastoma ,Triple-negative breast cancer (TNBC) and contributes to their characteristic drug resistance. Because of its structural homology to the ABC-membrane transporter proteins (mediate multi-drug resistance in cancer cells by catalyzing ATP-dependent efflux of many structurally unrelated amphiphilic xenobiotics) and because of its marked over-expression in tissues of knockout mice lacking the other known transporter RLIP76 (RALBP1), the present studies were directed at determining whether SMC1 was present in plasma membrane and could function as a multi-drug transporter capable of mediating multi-drug resistance. Methods: The intracellular localization of SMC1 was performed by immunocytochemistry in fixed and live H358 cells (human non small cell lung cancer cells). We demonstrated, for the first time that SMC1 can be purified to apparent homogeneity using a GS-E affinity chromatography method. Transport activity of SMC1 was tested by reconstituting purified SMC1 into artificial liposomes, later transfected into H358 and TNBC cells with confirmed SMC1 overexpression. Accumulation and efflux of amphiphilic chemo drugs were compared to control cells. Results: Immunofixation studies demonstrated no detectable immunological cross-reactivity between SMC1 and Ralbp1.SMC1 was found in the plasma membrane ,cytosol and nucleus.The uptake of Doxorubicin and Vinblastine in transfected cells was significantly lower and were two-fold resistant to DOX as compared with controls. These cells, when treated with SMC1 antibody/antisense also confirmed increased drug cytotoxicity as well as apoptosis. Conclusions: This study provides convincing evidence for the distribution of SMC1 in the plasma membrane, cytosol, and nucleus. It functions as a drug-transporter reducing intracellular accumulation of chemotherapy drugs in cancer cells.These findings indicate a dual role in defending these from apoptosis and suggest that strategies aimed at inhibiting SMC1 could be useful in reversing intrinsic or acquired drug-resistance of cancer cells.
Sintilimab (IBI308) in relapsed/refractory classical Hodgkin lymphoma: A multicenter, single-arm phase 2 trial in China (ORIENT-1 study).
Authors: Yuankai Shi, Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Shan Zeng, Peng Liu, Hui Zhou, Xiao Li
Journal: Journal of Clinical Oncology (2018)

7536 Background: Classical Hodgkin’s lymphoma (cHL), characterized by chromosome 9p24.1 alteration and PD-1 ligands overexpression, is sensitive to PD-1/PD-L1 blockage in previous studies. This study will confirm the efficacy and safety of sintilimab (IBI308), a promising anti-PD-1 monoclonal antibody, in Chinese patients with relapsed/refractory (R/R) cHL. Methods: ORIENT-1 (NCT03114683) is a multicenter, single-arm, phase 2 study. Patients who failed 2 or more lines of systemic therapy, including autologous hematopoietic stem cell transplantation (HSCT) were enrolled. Sintilimab was given 200 mg intravenously every 3 weeks, until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) according to 2007 IWG criteria. The cut-off date for this analysis was Feb 8, 2018. Results: Among 96 treated patients enrolled between Mar 30th 2017 and Nov 1st 2017, the median number of previous chemotherapies was 3 (range: 1~13). 54.2% patients received prior radiotherapy and 18.8% failed HSCT. With median treatment cycles of 9 (range: 1~14), ORR was 74.0% (71/96, 97%CI: 64.2%, 83.7%) per IRRC review. 23 patients (24.0%) achieved complete response (CR). The median duration of response has not been reached. At the time of analysis, 64 of 71 complete and partial response patients had an on-going response. The most common treatment-related adverse event (TRAE) was pyrexia (43.8%, 42/96), and 92.9% were grade 1~2. Most of pyrexia happened in the day of first infusion and recovered within 1 day. Other common TRAEs were hypothyroidism (13.5%) and TSH increase (11.5%), and all were grade 1~2. The most common grade 3~4 TRAEs were pyrexia (3.1%) and thrombocytopenia (2.1%). No patient died. Conclusions: Till now, ORIENT-1 study is the largest cHL study in China. Patients in our study were sensitive to sintilimab, with 74.0% ORR and 24.0% CR rate. The safety profile was consistent with the findings of other anti-PD-1 monoclonal antibodies in cHL patients. Sintilimab could be a new treatment option for R/R cHL patients in China. Clinical trial information: NCT03114683.
Association of high tissue TMB and atezolizumab efficacy across multiple tumor types.
Authors: Fatema A. Legrand, David R. Gandara, Sanjeev Mariathasan, Thomas Powles, Xian He, Wei Zhang, Suchit Jhunjhunwala, Dorothee Nickles, Richard Bourgon, Erica Schleifman, Sarah M. Paul, Edward E. Kadel, Marcin Kowanetz, Craig Cummings, Yan Li, David Fabrizio, Eric Peters, Priti S. Hegde, Lukas Amler, David S. Shames
Journal: Journal of Clinical Oncology (2018)

12000 Background: PD-L1 expression has limitations as a biomarker for checkpoint immunotherapy (CI). Prior atezolizumab (atezo) monotherapy studies suggest improved efficacy in high tissue tumor mutational burden (tTMB-H) cohorts. We report a large retrospective analysis associating tTMB with neoantigen load (NAL) and CI efficacy across multiple studies, tumor types and lines of therapy. Methods: Tissue TMB was evaluated by the FoundationOne (F1) assay across 7 atezo monotherapy studies: NSCLC n= 342 (FIR, BIRCH, POPLAR, OAK), metastatic urothelial carcinoma (mUC) n=400 (IMvigor210, 211), and other advanced solid tumors n=245 (PCD4989g). Pooled data yielded a biomarker evaluable population (BEP) of 987 patients (pts); 175 (17.7%) had TMB-H defined as ≥16 mutations/megabase (mut/Mb). Efficacy endpoints were overall response rate (ORR) and duration of response (DoR). Survival analysis is ongoing. Neoantigen load (NAL) was calculated by whole-exome sequencing (WES) and RNA-Seq. Results: tTMB was associated with efficacy across tumor types and lines of therapy. In the BEP, ORR was 16.4% (95% CI 14.2, 18.9), vs. 29.7% (95% CI 23.1, 37.1) in tTMB-H (≥16 mut/Mb, N=175), and 13.5% (95% CI 11.3, 16.1) in tTMB-Low (<16 mut/Mb, N=812). DoR benefit was also observed: median DoR=29.0 mths (95% CI 18.6, NA) in tTMB-H vs. 16.6 mths (95% CI 13.8, 23.1) in BEP and 13.8 mths (95% CI 12.5, 17.4) in tTMB-Low cohorts. This association was not seen in control cohorts of randomized studies OAK, POPLAR, and IMvigor211. Pooled ORR in controls was 14.9% in BEP, 14.4% in tTMB-H and 15.1% in tTMB-Low. Survival analysis by tTMB is ongoing. tTMB-H also identified a population independent of PD-L1 status. tTMB by F1 was positively correlated with WES-based NAL in mUC (Pearson=0.85, N=218) and NSCLC (Pearson=0.78, N=70). NAL was associated with atezo ORR in mUC (p=2.7 x 10-9). Conclusions: High tTMB (≥16 mut/Mb) is associated with improved atezo response and DoR across NSCLC, mUC and melanoma and lines of therapy. tTMB-H by F1 may serve as a surrogate biomarker for NAL and may complement PD-L1 expression in providing predictive value. Ongoing studies are prospectively evaluating both tissue TMB and blood-based TMB for efficacy with CI. Clinical trial information: NCT02008227 NCT01903993 NCT02031458 NCT01846416 NCT02951767 NCT02302807 NCT01375842.
Phase II trial of dose dense (weekly) paclitaxel with pembrolizumab (MK-3475) in platinum-resistant recurrent ovarian cancer.
Authors: Robert Michael Wenham, Sachin M. Apte, Mian M. Shahzad, Jae K Lee, Denise Dorman, Hye Sook Chon
Journal: Journal of Clinical Oncology (2016)

TPS5612 Background: Recurrent epithelial ovarian, fallopian, and peritoneal cancer (EOC) is the leading cause of gynecologic cancer death. EOC is an immunogenic tumor and infiltrating lymphocytes express the negative regulatory immune receptor programmed cell death 1 (PD1). Paclitaxel induces proinflammatory cytokine secretion and immune cell activation. Weekly (QW) administration of paclitaxel (P) can have responses in platinum- and taxane-resistant cancers and is considered one of the preferred regimens to treat these cancers. Methods: This is a phase 2 study with a primary endpoint to estimate the 6-month progression free survival (PFS) of QWP with Q3W pembrolizumab (PBro) and to compare with historical QWP. Secondary endpoints include safety, response rate, disease control rate, duration of response, and median overall survival. Subjects must have persistent or recurrent EOC within 6 months of prior platinum therapy and may have had up to 3 prior therapies (but no QWP or prior immunotherapy). They may have measurable or non-measurable disease (provided CA-125 criteria are met). Standard laboratory parameters must be met and they must have a performance status of 0-2. P is given as 80 mg/m2 QW with PBro at 200 mg Q3W. Two dose level reductions are allowed. First cycle is 4 weeks with an initial test dose week of P for evaluation of allergic reactions. Subsequent infusions are given without steroids. Archival tissue or core biopsy is required for evaluation of PD-L1 and immune infiltrates. Genomic blood is collected pretherapy and peripheral blood mononuclear cells (PBMC) are collected pretherapy, Cycle 2 day 1, and Cycle 4 day 1 for additional correlative studies. This trial will have 37 evaluable patients enrolled. Under the assumption that the 6-month PFS in the historical control arm is 0.25, it is expected that treatment arm will result in a 50% reduction in the risk of progression at 6 months (6-mo PFS = 0.5). Currently, 10 patients have been enrolled. Clinical trial information: NCT02440425.
HPV in tumor tissue, perifocal area and healthy tissue of patients with vulvar cancer.
Authors: Galina Andreevna Nerodo, Oleg Ivanovich Kit, Tatyana A. Zykova, Victoria A. Ivanova, Ekaterina A. Nerodo, Olga A. Bogomolova
Journal: Journal of Clinical Oncology (2016)

e17036 Background: The purpose of the study was to detect HPV in tumor tissue, perifocal area and healthy tissue of patients with vulvar cancer. Methods: Tissue samples from tumor, perifocal area and healthy tissue of 69 vulvar cancer patients aged 60-83 years were studied. DNAs of high-risk and low-risk HPV were determined by the Real-Time PCR. Results: DNAs of HPV 11 were found in 8.6% of patients, DNAs of high-risk HPV – in 30.4%. HPV 16 and 18 were the most frequent (28.5% each), 16 and 31 in association – 14.2%. High-risk HPV DNAs were found in 25% in perifocal area: HPV 16 – 50%, associations of genotypes – 25%. HPV DNAs in healthy tissue – 21.05%: HPV 16 – 25%, 53 – 25%, associations – 25%. Thus, HPV DNAs were found in 25.8% of the samples, including HPV 16 - 33.3%, 18 and 31 – 13.3% each, 52 and 53 – 6.6% each and 16 in associations (with 18,31,39,45,59) – 19.8%. Solitary genotypes were determined in 85.7%, in associations – 14.3%; perifocal area: 75% - solitary genotype, 25% - in associations; healthy tissue – equally. Of all detected genotype samples, HPV 16 was found in 37.5% in tumor tissue, in 33.3% - in perifocal area and in 42.8% - in healthy tissue. Conclusions: Thus, HPV infection in patients with vulvar cancer is registered not only in the tumor, but in perifocal area and healthy tissue as well; HPV 16 and 18 prevail.
Racial and socioeconomic disparities in mantle cell lymphoma.
Authors: Nikesh Shah, Yuan Liu, Yizhao Xi, Christopher Flowers, Jean Louise Koff, Madhusmita Behera, Jonathon Brett Cohen
Journal: Journal of Clinical Oncology (2018)

e18610 Background: While race and socioeconomic factors are associated with outcome in many malignancies, few studies have examined the impact of race and socioeconomic status on patients with mantle cell lymphoma (MCL). Methods: We used the National Cancer Database to identify patients with MCL diagnosed between 2004 and 2013. Chi-square and ANOVA were used to assess associations of covariates with race/ethnicity. Univariate and multivariable analyses (MVA) with overall survival (OS) used Cox proportional hazards models. OS from the time of diagnosis was the primary endpoint. Results: Of 18,120 MCL patients, 14,984 (83%) were white non-Hispanic (NH), 709 (4%) black NH, and 1,096 (6%) Hispanic. 6,798 (39%) patients had private insurance, 9,520 (55%) Medicare, and 635 (4%) Medicaid. Compared with white NH race, black race was associated with treatment at an academic/research program (51% vs 38%), B symptoms (28% vs 25%), Medicaid/uninsured status (15% vs 5%), and residence in regions with lower average education and income (all p < .001). Compared with NH black and Hispanic patients, more white NH patients received stem cell transplant (13% vs 10% vs 10%, p < .001). In a MVA, Hispanic ethnicity, private insurance, and treatment at an academic center were associated with better OS, while black race had inferior OS (See Table). Conclusions: We identified disparities by race/ethnicity in OS, insurance, and socioeconomic status for MCL. Further assessment of treatment patterns may elucidate new targets for improving access to care and health outcomes for rare cancers. Table 1 Select MVA of OS* HR (95% CI) p-value Race White Non-Hispanic 1.13 (1.01-1.27) 0.034 Black Non-Hispanic 1.28 (1.09-1.51) 0.003 Other 1.16 (1.01-1.34) 0.042 Hispanic - - Facility Type Community CP 1.12 (1.03-1.22) 0.010 Comprehensive Community CP 1.06 (1.00-1.12) 0.042 Integrated Network CP 1.02 (0.93-1.12) 0.666 Academic/Research Program - - Primary Payor Uninsured 1.44 (1.22-1.70) < .001 Medicaid 1.33 (1.15-1.54) < .001 Medicare 1.05 (0.98-1.13) 0.138 Private Insurance - - CP: Cancer Program *Other co-variates with significant OS differences include region income and high school degree, B symptoms, type of treatment received, time to treatment, and stage.
Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial
Authors: Reinhard Dummer, Paolo A Ascierto, Helen J Gogas, Ana Arance, Mario Mandala, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion Sileni, Caroline Dutriaux, Jan Willem B de Groot, Naoya Yamazaki, Carmen Loquai, Laure A Moutouh-de Parseval, Michael D Pickard, Victor Sandor, Caroline Robert, Keith T Flaherty
Journal: The Lancet Oncology (2018)
STATEC: A randomised trial of non-selective versus selective adjuvant therapy in high risk apparent stage 1 endometrial cancer.
Authors: Tim Mould, Alison Brand, Hans Nijman, Jonathan A. Ledermann, Richard J Edmondson, Jeremy Twigg, Emma Hudson, Carien L. Creutzberg, Naveena Singh, Raji Ganesan, Amanda Feeney, Laura Farrelly, Laura Hughes, Allan Hackshaw, Abigail Sharp, Peey Sei Kok, Henry C. Kitchener
Journal: Journal of Clinical Oncology (2018)

TPS5615 Background: The benefit of lymphadenectomy on survival in stage 1 endometrial cancer remains uncertain. STATEC is a surgical trial designed to evaluate the use of nodal status after lymph node dissection to tailor adjuvant treatment in patients with high risk apparent stage I endometrial cancer. Methods: DESIGN: Randomised (1:1), controlled, two-arm, phase III, multicentre, international, non-inferiority trial. ELIGIBILITY: High risk apparent FIGO stage I endometrial cancer on diagnostic endometrial sampling OR hysterectomy. If randomisation occurs after hysterectomy and BSO: FIGO grade 3 endometrioid or mucinous carcinoma, high grade serous, clear cell, undifferentiated or dedifferentiated carcinoma or mixed cell adenocarcinoma or carcinosarcoma. STRATIFICATION: participating site, histology, lymphovascular space invasion, timing of hysterectomy and bilateral salpingo-oophorectomy (BSO). TREATMENT: Arm 1: Hysterectomy and BSO, plus intraoperative bilateral pelvic and para-aortic lymph node dissection + adjuvant therapy if node positive or stage III. Arm 2: Hysterectomy and BSO+ adjuvant therapy based on stage and uterine factors. ENDPOINTS: Overall survival (primary), disease-free, endometrial cancer-event free and endometrial cancer-specific survival, pelvic and extra-pelvic relapse-free survival, cost-effectiveness, surgical adverse events, quality of life and performance of sentinel lymph node assessment (secondary). QUALITY ASSURANCE: surgical specimen processing and microscopy to local specialist gynaecological oncology site pathologists, central pathology (10% of UK patients) and surgical imaging of all Arm 1 patients. Recruitment: 4 years, with 5 years follow up. STATISTICS: Using the exponential parameter of 0.0040, allowable hazard ratio of 1.272, a sample size of 2000 (500 deaths) will provide 85% power, and 5% two-sided statistical significance. With 80% power, the minimum sample size is 1720 patients (430 deaths). CURRENT ENROLMENT (as of February 2018): STATEC is open in the UK, Australia and New Zealand. 7 patients have been enrolled. STATEC is registered with. Clinical trial information: NCT02566811.
Hyponatraemia as a risk factor in renal cell carcinoma treatment with nivolumab.
Authors: Christian Grohe, Simon Gwynn, Richard Evans
Journal: Journal of Clinical Oncology (2017)

e14528 Background: In the general hospital population, the incidence of hyponatraemia is reported at varying levels up to 40%. In a retrospective analysis of 3,357 cancer patients (4,702 admissions) hyponatraemia was noted in 47%. A strong and independent association between hyponatraemia and longer length of stay with higher mortality was highlighted. The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. This poster offers recommendations for the improved diagnosis and management of hyponatraemia patients with renal cell carcinoma treated with nivolumab. Hyponatraemia occurs in 20% of patients with renal cell carcinoma and is associated with reduced survival. Patients with hyponatraemia before treatment had a median overall survival of 5.5 months compared with 18.6 months for those with normal sodium values. Methods: Key publications concerning the incidence, evaluation and management of hyponatraemia in patients with RCC as well as unpublished data from Phase III registration studies were reviewed and the data examined to consider impacts on current oncology practice Results: Hyponatraemia is a negative prognostic indicator in cancer. Data show that effective treatment of hyponatraemia in cancer patients reduces mortality. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity. This may suggest a more complex impact on outcomes in cancer patients than simply the mortality associated with hyponatraemia. The presentation of hyponatraemia in cancer patients is complex and may be caused by the direct impacts of disease, iatrogenic factors or different treatment approaches Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients, potentially representing a modifiable risk factor, with resultant impact on patient survival. The clinician should be aware of the potential for Immuno-oncology agents to precipitate hyponatraemia and consider that the correct diagnosis and management of hyponatraemia may further enhance efficacy and survival.
Concomitant chemoradiotherapy using modified TPF (docetaxel, cisplatin and 5-FU) for the patients with advanced sino-nasal squamous cell carcinoma.
Authors: Kiyoto Shiga, Katsunori Katagiri, Daisuke Saitoh, Shin-ichi Oikawa, Aya Ikeda, Kodai Tuchida
Journal: Journal of Clinical Oncology (2018)

e18018 Background: Efficacy of TPF chemotherapy has been reported mainly in the neo-adjuvant setting for head and neck squamous cell carcinoma so far. The aim of this study was to determine the safety and efficacy of CCRT using modified TPF protocol in patients with advanced sino-nasal SCC (SNSCC). Methods: Patients with previously untreated, histologically proven T3~4 disease of the nasal cavity and sinuses were eligible for the study. Nineteen patients of the SNSCC were enrolled between August 2011 and September 2015. Treatment consisted of radiotherapy administered once daily to a total dose of 70 Gy, concomitant with 120-hour infusions of 5-FU (600 mg/m2/day), Docetaxel (50 mg/m2, day 2) and Cisplatin (60 mg/m2, day 2) given during first and fifth week of radiotherapy. These drug doses were determined from the results of our former phase I study to assess the dose limiting toxicity of this protocol. Mean and median follow-up period were 38.4 and 37 months. Results: Six patients with SNSCC underwent this modified TPF protocol. Thirteen patients with SNSCC originated from maxillary sinus underwent CCRT using CDDP. Twelve of them underwent arterial infusion of CDDP by super-selective angiography via external carotid artery. Bone marrow suppression was the most common adverse event observed through this study. Grade 4 neutropenia was observed in 2 (33%) of the patients with SNSCC who underwent modified TPF. Grade 4 creatinine was observed in one patient who underwent modified TPF and second course of TPF was cancelled. Although all patients showed dermatitis and mucositis at any grade, other grade 3 or 4 adverse events in patients with SNSCC were not common. Complete remission was obtained in all patients but two with SNSCC from frontal sinus origin and maxillary sinus origin. The disease-specific and over-all survival rates at 36 months of the patients with SNSCC were 89.5% and 82.0%, respectively. Conclusions: Our results suggested that CCRT using modified TPF was feasible and very effective in patients with advanced SNSCC. Moreover, the effectiveness of the treatment was almost equal with the other treatment such as intra-arterial infusion of CDDP.