tbuckley/cabot-search huggingface dataset:
Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427.
Authors: David F. McDermott, Jae-Lyun Lee, Cezary Szczylik, Frede Donskov, Jahangeer Malik, Boris Yakovlevich Alekseev, James M. G. Larkin, Vsevolod Borisovich Matveev, Rustem Airatovich Gafanov, Piotr Tomczak, Scott S. Tykodi, Poul F. Geertsen, Pawel J. Wiechno, Sang Joon Shin, Frederic Pouliot, Teresa Alonso Gordoa, Wenting Li, Rodolfo F. Perini, Charles Schloss, Michael B. Atkins
Journal: Journal of Clinical Oncology (2018)

4500 Background: Programmed death-1 (PD-1) inhibitor–based combination therapy shows clinical benefit in first-line accRCC. However, data are limited on clinical impact of first-line PD-1 inhibitor monotherapy. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, 2-cohort, phase 2 study that evaluates efficacy and safety of the PD-1 inhibitor pembrolizumab (pembro) as first-line monotherapy in accRCC and anccRCC. Results from the accRCC cohort (cohort A) are presented. Methods: Patients (pts) with histologically confirmed accRCC who received no prior systemic therapy were eligible. Additional key eligibility criteria included measurable disease (RECIST v1.1, independent central review [ICR]) and Karnofsky performance status ≥70%. Pembro 200 mg was administered intravenously Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point: objective response rate (ORR) per RECIST v1.1, ICR. Additional end points included duration of response, safety, and biomarkers associated with response. Results: At data cutoff (Oct 6, 2017), median (range) follow-up was 7.2 (0.9-11.7) mo. 110 pts were enrolled; 107 included in the efficacy analysis (opportunity for ≥1 postbaseline assessment). Median age (range) was 64 (29-87); 78% were male. 37.3%, 47.3%, and 15.5% of pts had IMDC risk categories of favorable, intermediate, and poor, respectively. Confirmed ORR by ICR was 33.6% (n = 36; 95% CI, 24.8-43.4) with 1 complete response (0.9%) and 35 (32.7%) partial responses. ORR for pts with favorable, intermediate/poor risk IMDC was 27.5% and 37.3%, respectively. Median duration of response was not reached (range, 1.4+ to 8.2+). 73.6% of pts experienced a treatment-related adverse event (AE); most common (≥10%) were fatigue (23.6%), pruritus (21.8%), diarrhea (16.4%), rash (13.6%), and arthralgia (11.8%). 18.2% experienced a grade 3-5 treatment-related AE; 1 patient had grade 5 pneumonitis. Conclusions: Pembro monotherapy demonstrated promising efficacy and acceptable tolerability in pts with accRCC. Potential tissue-based biomarkers associated with response will be presented. Clinical trial information: NCT02853344.
Treatment outcomes of 257 patients with locally advanced nasopharyngeal carcinoma treated with nimotuzumab plus intensity-modulated radiotherapy with or without chemotherapy: A single institution experience.
Authors: Wang Fang Zheng, Chuner Jiang
Journal: Journal of Clinical Oncology (2017)

6079 Background: To report the long-term outcome and toxicitie of locally advanced nasopharyngeal carcinoma (NPC) treated with nimotuzumab plus intensity- modulated radiotherapy (IMRT) with or without chemotherapy. Methods: From October 2009 to March 2014, 257 newly histology-proven, non-metastatic NPC patients were retrospectively enrolled. They are aged 10-76 years. The distribution of disease was stage III in 150 (58.4%), stage IV A in 88 (34.2%), and stage IV B in 19 (7.4%). All the patients received the treatment of nimotuzumab plus IMRT, and 239 cases were used for cisplatin-based chemotherapy. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group. The accumulated survival was calculated according to the Kaplan-Meier method. Log-rank test was used to compare the survival difference. Multivariate analysis was performed using Cox’s proportional hazard model. Results: All patients had completed the combined treatment. With a median follow-up of 48 months (range, 13–94 months), the estimated 3-year and 5-year overall survival rates were 92.6% and 86.2%, respectively. Univariate analysis showed that age, T stage, clinical stage and neoadjvant chemotherapy were related with OS. Multivariate analysis indicated that age and clinical stage were independent prognosticators. The median cycle for nimotuzumab addition was 12 weeks. The incidence of grade 3–4 acute mucositis and leukocytopenia were 10.9% and 9.3%, respectively, with no cases of skin rash and infusion reaction. Xerostomia was the most common late complication, and the degree of dry mouth in most survivors was mild-to-moderate at the last follow-up time. Conclusions: Nimotuzumab plus IMRT with or without chemotherapy showed promising outcomes in terms of loco-regional control and survival, without increasing the incidence of radiation-related toxicities for patients.
Primary tumor location as a prognostic implication in patients undergoing resection for colorectal liver metastasis: A propensity score-matched analysis.
Authors: Yuichi Goto, Carlos Castro Benitez, Oriana Ciacio, Gabriella Pittau, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Koji Okuda, Yoshito Akagi, Hiroyuki Tanaka, René Adam
Journal: Journal of Clinical Oncology (2018)

e15504 Background: Primary tumor location is an important prognostic factor for colorectal cancer, including colorectal liver metastases (CLM). We assessed the implications of primary tumor location for outcome using propensity score matching (PSM), and we assessed factors of poor outcome by focusing on postoperative recurrence. Methods: Patients who underwent CLM resection at our hospital between 2004 and 2015 were included. CLM from the cecum, ascending and transverse colon were defined as Rt-CLM; CLM from the splenic flexure, descending and sigmoid colon were defined as Lt-CLM. Patients were stratified by PSM, and clinicopathological data were retrospectively reviewed. Results: Of 547 eligible patients, 164 had Rt- and 383 had Lt-CLM. After PSM, 138 patients in each group were studied. The 5-year overall survival (OS) rate for Rt- and Lt-CLM was 31% and 61%, respectively (P < 0.01). The 5-year disease-free survival (DFS) rate for Rt- and Lt-CLM was 18% and 20%, respectively (P = 0.87). On multivariate analysis, right-sided primary tumor location was an independent risk factor for OS (HR 1.79 [1.26-2.50], P < 0.01) but not for DFS (HR 1.29 [0.82-2.05], P = 0.27). Among patients within the PSM cohort, 33 (23.9%) and 43 patients (31.2%) had liver-first recurrence, whereas 16 (11.6%) and 18 patients (13.0%) had lung-first recurrence, for Rt- and Lt-CLM, respectively. OS rates of patients with lung-first recurrence did not differ regarding the primary tumor locations (P = 0.53), whereas the 5-year OS rates of patients with liver-first recurrence for Rt-CLM was worse than that of patients with Lt-CLM (28% vs. 67%, P < 0.01). Both the size (P = 0.04) and the number (P < 0.01) of recurrences were larger in patients with liver-first recurrence for Rt-CLM. Chance of repeat hepatectomy was significantly decreased in patients with Rt-CLM (53.3% vs. 75.5%, P = 0.03). Conclusions: Right-sided primary tumor location is an important prognostic factor for OS but surprisingly not for DFS after resection of CLM. This disparity is mainly caused by increased aggressiveness of liver-first recurrence for Rt-CLM in terms of size and number of nodules, which made repeat hepatectomy less accessible.
TCT-383 Clinical Utility of a Novel On-site Virtual Fractional Flow Reserve Parallel Computing System: Comparison with Invasive Fractional Flow Reserve
Authors: Hyung-Bok Park, Yeonggul Jang, Minh Tuan Nguyen, Byunghwan Jeon, Reza Arsanjani, Sang-Wook Lee, Hyuk-Jae Chang
Journal: Journal of the American College of Cardiology (2018)
Regarding “Combination of pediatric and adult formulas yield valid glomerular filtration rate estimates in young adults with a history of pediatric chronic kidney disease”
Authors: Luciano Selistre, Muriel Rabilloud, Vandréa De Souza, Jean Iwaz, Mariana Bertoldo, Carlos Poli De Figueiredo, Sandrine Lemoine, Pierre Cochat, Laurence Dubourg
Journal: Kidney International (2018)
First-in-human phase 1 study of the PARP/tankyrase inhibitor 2X-121 (E7449) as monotherapy in patients with advanced solid tumors and validation of a novel drug response predictor (DRP) mRNA biomarker.
Authors: Elizabeth Ruth Plummer, Divyanshu Dua, Nicola Cresti, Aneta Suder, Yvette Drew, Peter Stephens, Marie Foegh, Steen Knudsen, Sharon McGonigle, Barbara Ink, Debashis Sarker
Journal: Journal of Clinical Oncology (2018)

2505 Background: A phase I study was done to establish the safety, MTD and anti-tumour efficacy of the novel PARP 1/2 and Tankyrase 1/2 inhibitor, 2X-121 (E7449). A novel tumor agnostic molecular biomarker, 2X-121 DRP, was developed to identify responders and non-responders. Methods: Patients (pts) with advanced solid tumors were eligible. 2X-121 was administered orally, once daily (QD), continuously. Archival tumor samples were obtained from consenting patients. Following completion of the study the 2X-121 DRP was applied in a blinded manner following a pre-specified analysis plan. This biomarker is based on expression of 414 genes predictive of response to 2X-121. Results: 41 pts were treated at 6 dose levels: 50, 100, 200, 400, 800 and 600 mg QD. Tumor types were pancreatic (n = 13), ovarian (n = 5), breast (4), lung (n = 4), colorectal (n = 4) and other (n = 11). Fatigue is the dose limiting toxicity. The MTD is 600 mg QD. The most frequently reported ( > 30% of pts) TEAEs were fatigue, chromaturia, decreased appetite, nausea, diarrhea, constipation, and vomiting. No significant hematological toxicity and no Gr4 or 5 AEs were reported. Two pts had partial response (PR, both ovarian cancer), 13 pts had stable disease (SD), with 8 of these > 24 weeks; 7/8 were pancreatic cancer pts. Sustained PARP inhibition of ~90% is seen at doses over 600mg QD in PBMCs. The 2X-121 DRP was applied to 13 patients from which adequate biopsy material was available evaluating the 414 gene signature. Patients with PR and durable SD were correctly identified. It divided patients in two groups, sensitive (N = 6) or resistant (N = 7) to 2X-121. The median time to progression was 296 and 155 days, respectively (HR = 0.29, P = 0.14). Overall survival (OS) differed between the two groups, with a median survival in excess of 800 days and 208 days, respectively (HR = 0.26, P = 0.07). Conclusions: 2X-121 was generally well tolerated at the MTD of 600 mg QD, with evidence of antitumor activity. The 2X-121 DRP predicted the responders irrespective of BRCA mutation status. Clinical trial information: NCT01618136.
Lowering the <i>P</i> Value Threshold
Authors: A. Cecile J. W. Janssens, Bart Penders
Journal: JAMA (2018)

To the Editor Dr Ioannidis argued that the proposal to lower the P value threshold for claiming statistical significance from .05 to .005 is a temporary solution to improve statistical inference and suggests additional training in methods and statistics for the scientific workforce.1,2
Incidence of type II diabetes mellitus among patients with chronic myelogenous leukemia (CML) receiving first or second line therapy with dasatinib or nilotinib.
Authors: Meg Franklin, Leah Burns, Samuel Perez, Deepak Yerragolam, Dinara Makenbaeva
Journal: Journal of Clinical Oncology (2016)

e18126 Background: Metabolic changes such as Type II Diabetes Mellitus (T2DM) have been reported in patients receiving BCR-ABL tyrosine kinase inhibitor (TKI) therapy. Incidence of T2DM in this population has not been reported in large, real-world studies. The purpose of this study was to determine incidence and risk for T2DM occurrence in insured patients receiving dasatinib or nilotinib for CML Methods: A retrospective cohort study using data from the MarketScan database from 2006-2014 was conducted. Patients ≥ 18 years with ≥ 2 claims for CML (ICD-9 205.10-205.12) and ≥ 1 prescription for dasatinib or nilotinib were eligible. Patients had continuous enrollment for ≥ 6 months prior to the first TKI prescription; no minimum follow-up time was required. Patients with a diagnosis of T2DM prior to index TKI were excluded. To identify T2DM occurrence, patients were followed from index prescription to the first occurrence of: discontinuation of therapy, switch in therapy, end of study period, or end of continuous enrollment. Development of T2DM was defined as ≥ 2 claims with an ICD-9 code for T2DM or 1 code and the presence of an anti-diabetic medication. Incidence was calculated as number of events divided by sum of the person time at risk for all subjects in the cohort. Cox proportional hazards analyses were used to estimate hazard ratios (HR) for T2DM while adjusting for baseline characteristics. Results: 2,028 patients met criteria (n = 1,288 dasatinib, n = 740 nilotinib). Overall 54.2% of patients received either drug as first line therapy. Mean age was 53.4 years, and 54% were male. Median follow-up time was 213 days for dasatinib and 242 days for nilotinib. Incidence rate of T2DM was 18.2 per 1000 person years (PY) (95% CI: 11.7, 27.1) for dasatinib, and 43.9 per 1000 PY for nilotinib (95% CI: 30.6, 61.1). The HR for occurrence of T2DM (dasatinib as reference) was 3.1 (95% CI: 1.8, 5.3), indicating patients on nilotinib had a 3 times higher risk of developing T2DM while adjusting for baseline characteristics. Conclusions: Patients receiving nilotinib for CML had a higher incidence rate and significantly higher adjusted risk for developing T2DM than patients receiving dasatinib.
Immune profile of BRAF mutated metastatic colorectal tumors with good prognosis.
Authors: Jeong Eun Kim, Jihun Kim, Yong Sang Hong, Sun Young Kim, Sang-Yeob Kim, Jaekyung Cheon, Tae Won Kim
Journal: Journal of Clinical Oncology (2018)

e15586 Background: BRAF mutated (mBRAF) metastatic colorectal cancers (mCRC) are known to be related to poor prognosis and low response to current chemotherapy. We investigated immune profile of mBRAF tumors to define other mechanism related to prognosis. Methods: A total of 2313 patients (pts) with mCRC were treated and received BRAF testing between Jan 2005 and OCT 2015 at Asan Medical Center. We analyzed clinical outcomes of all pts and investigated immune profile of mBRAF tumors using multiplex immunohistochemistry of immune related markers; cytokeratin (CK), programmed death-ligand 1(PD-L1), Programmed cell death protein 1 (PD-1), cluster of differentiation 8(CD8). Results: Out of 2313 tumors, 2190 were wild type BRAF (wBRAF) and 123 were mBRAF tumors; 119 had BRAF mutation of V600E; 3 of K6001E; 1 of V600E and K600E. Overall survival (OS) were longer in wBRAF than mBRAF tumors (32.8 vs. 14.6 months, p < 0.0001). Fifteen out of 121 (12.2%) mBRAF patients showed OS longer than 30 months, which is comparable to wBRAF mCRC. Further analysis of immune profile was available in 99 mBRAF tumors. Excluding 17 pts received metastasectomy related to good prognosis and 24 pts without information of microsatellite instability (MSI) status or MSI-high tumors, immune profile were compared in 58 pts according to prognosis group; good (6 pts, OS > 30 months), intermediate (27 pts, 12-36 months), poor (25 pts, < 12 months). In microsatellite stable (MSS) mBRAF tumors with good prognosis, proportion of PD-L1- positive tumor cell was lower, while stromal CD8-positive cell infiltration was higher. Conclusions: Clinical outcomes of unselected mBRAF mCRC patients treated in real clinical practice were generally similar to previous studies. But, distinct subgroup of mBRAF patients showed comparable survival to wBRAF. With immune profile analysis, lower PD-L1 expression and higher stromal CD8-positive cell infiltration was shown in mBRAF tumors with good prognosis.
Impact of a cognitive computing clinical trial matching system in an ambulatory oncology practice.
Authors: Tufia C. Haddad, Jane Helgeson, Katharine Pomerleau, Marissa Makey, Phillip Lombardo, Sadie Coverdill, Alexandra Urman, Melissa Rammage, Matthew P. Goetz, Nicholas LaRusso
Journal: Journal of Clinical Oncology (2018)

6550 Background: Only 3-5% of cancer patients participate in clinical trials even though up to 20% are eligible. Cognitive computing has promising potential to assist trial enrollment efficiency and accuracy by performing background analytics. The Watson for Clinical Trial Matching (CTM) cognitive system utilizes natural language processing to derive patient and tumor attributes from unstructured text in the electronic health record that can be matched to complex eligibility criteria in trial protocols. Screening patients for trials was performed on an ad hoc basis with traditional methods prior to implementation of the CTM system in the Mayo Clinic breast oncology practice. Methods: The Watson CTM system was trained by Mayo subject matter experts and implemented in July 2016. Systemic therapy trials enrolling breast cancer patients were included in the system. Clinical research coordinators validated Watson-derived clinical trial matches on the day prior to patient clinic visits. They gave the oncology providers a list of matched trials for each patient to facilitate treatment decision making at point of care. Enrollment and timing metrics were tracked and compared with manual screening methods. Results: Watson CTM facilitated screening of all breast cancer patients for systemic therapy trials with matches validated by coordinators in 40% of patients. Over the 18 month (mo) period following implementation, 6.3 patients/mo were enrolled to breast cancer systemic therapy trials compared with 3.5 patients/mo in the period prior. The average monthly enrollment increased by 80%. This was further increased to 8.1 patients/mo when including accruals to breast cancer cohorts of phase I trials within the experimental therapeutics program. Time to match patients to trials with the CTM system was faster than manual methods but variable depending on the role of the screener and the depth of the matching. Conclusions: Implementation of the Watson for CTM system with a screening coordinator team was associated with an increase in breast cancer clinical trial enrollment. The system enabled high volume screening in an efficient manner and promoted awareness of clinical trial opportunities within the breast oncology practice.
Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma
Authors: Shelly Kalaora, Yochai Wolf, Tali Feferman, Eilon Barnea, Erez Greenstein, Dan Reshef, Itay Tirosh, Alexandre Reuben, Sushant Patkar, Ronen Levy, Juliane Quinkhardt, Tana Omokoko, Nouar Qutob, Ofra Golani, Jianhua Zhang, Xizeng Mao, Xingzhi Song, Chantale Bernatchez, Cara Haymaker, Marie-Andrée Forget, Caitlin Creasy, Polina Greenberg, Brett W. Carter, Zachary A. Cooper, Steven A. Rosenberg, Michal Lotem, Ugur Sahin, Guy Shakhar, Eytan Ruppin, Jennifer A. Wargo, Nir Friedman, Arie Admon, Yardena Samuels
Journal: Cancer Discovery (2018)

The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies.Significance: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy. Cancer Discov; 8(11); 1366-75. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333.
The relationship between carnitine pharmacokinetics and fatigue in patients treated with cisplatin-containing chemotherapy.
Authors: Tatsuhiko Kashii, Kouichi Tanabe, Shinya Kajiura, Toshiro Miwa
Journal: Journal of Clinical Oncology (2015)

e20545 Background: A large majority of patients who receive chemotherapy suffer from fatigue, which lowers their QOL and activities and also has a negative influence on therapeutic efficacy. Although supportive care for those undergoing chemotherapy has steadily progressed, the pathogenesis and treatment of fatigue during chemotherapy is still unknown. Carnitine is an amino acid with a molecular weight of 161, and it has an important role in energy production. A decreased level of plasma carnitine has been reported in the case of cancer patients who developed cachexia. It has been reported that carnitine is excreted in the urine after the administration of platinum-type anticancer drugs. We examined the relationship between carnitine pharmacokinetics in patients who received chemotherapy including cisplatin (CDDP) and fatigue. Methods: Eight patients (6 male/2 female, median age 65.0 yrs (46-70), 3 SCLC/3 NSCLC/2 malignant mesothelioma) who received standard chemotherapy including CDDP were examined. We performed 24-hour urine collection and took blood samples on day 1 (before the administration of chemotherapy), day 2, 3, 4, and 8 to measure free carnitine concentration, total carnitine concentration, and acylcarnitine concentration in the plasma and urine. We simultaneously evaluated fatigue levels using the CTCAE, STAT Japanese version, and “Functional Assessment of Chronic Illness Therapy-Fatigue” (FACIT-F). Results: The total carnitine concentration in the plasma samples was: day 1: 68.1±18.3 (μmol/L, mean ± SD) , day 2: 97.3±29.1, day 3: 101.5±29.0, day 4: 102.5±38.0, day 8: 84.9±29.2. Total urine carnitine concentration was: day 1: 296.0±312.1, day 2: 1310.4±637.1, day 3: 623.0±357.3, day 4: 251.4±214.3, day 8: 394.2±314.8. Fatigue levels were the most severe on day 4 and did not improve thereafter. Conclusions: The carnitine concentration in the urine samples was increased the most on day 2 and was inclined to decrease to baseline status by day4. Future studies will be planned to investigate the protective effects of carnitine administration for fatigue in patients treated with CDDP-containing chemotherapy. Clinical trial information: UMIN000011596.