tbuckley/cabot-search huggingface dataset:
Immunotherapy (IO) versus non-IO for oncology drugs: Comparing survival benefits (SB) using restricted <i>mean</i> survival time.
Authors: Amanda Putri Rahmadian, Seanthel Delos Santos, Shruti Parshad, Louis Everest, Matthew C. Cheung, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2018)

6617 Background: Current measures of absolute SB (median survival time/rate at fixed times on Kaplan-Meier (KM) curves) and relative SB (hazard ratios) are limited in properly capturing SB for IO trials. Restricted mean survival time (RMST) captures entire area under KM curves, directly measuring SB. This study aimed to quantify the magnitude of SB in recent oncology drugs using RMST difference and RMST ratio (absolute and relative SB, respectively), and compare those of IO and non-IO. Methods: All Food and Drug Administration approved oncology drugs from 01/2011-11/2017 and randomized control trials (RCTs) used for approval were identified. RCTs with overall survival (OS) or progression-free survival (PFS) as primary endpoints and published KM curves were included. Curves were extracted using established methods (Guyot et al., 2012) with DigitizeIt. RMST differences, ratios, and confidence intervals (CI) were calculated and meta-analyzed using random-effects models to estimate overall absolute and relative SB of contemporary oncology drugs, and to compare those of IO and non-IO. Meta-regression was used to adjust for confounders (crossover, time horizon, year approved, trial phase, companion diagnostics, and approval type). Results: 94 RCTs with 51 639 patients were included (13 IO and 81 non-IO). Overall RMST differences (absolute SB) were 1.55 mos for OS (95% CI 1.32-1.77) and 2.99 mos for PFS (95% CI 2.65-3.33). Overall RMST ratios (relative SB) were 1.11 for OS (95% CI 1.09-1.13) and 1.42 for PFS (95% CI 1.36-1.48). IO PFS RMST difference was less than non-IO (1.56 mos vs. 3.23 mos, p < 0.00001), while RMST ratios were similar (1.33 vs. 1.43, p = 0.16). Contrastingly, IO OS RMST difference was larger than non-IO by 0.6 mos (2.02 mos vs. 1.43 mos, p = 0.02). OS RMST ratios were slightly larger for IO than non-IO (1.18 vs. 1.09, p = 0.0006). Meta-regression showed the adjusted SB for OS was 0.83 mos greater for IO vs. non-IO, p = 0.01. Conclusions: Overall, absolute SB of recent oncology drugs are modest. Unlike popular belief, observed SB of IO drugs are not dramatically superior to non-IO drugs. RMST differences and ratios of oncology drugs in clinical trials should be routinely reported to fully measure SB.
Development of a prognostic model for glioblastoma patients treated with standard therapy: A prospective study from a single institution.
Authors: Hans Skovgaard Poulsen, Kirsten Grunnet, Jan Nyrop Jakobsen, Ib Jarle Christensen, Signe Regner Michaelsen, Michael Kosteljanetz, Ulrik Niels Lassen, Thomas Urup
Journal: Journal of Clinical Oncology (2018)

e14086 Background: Glioblastoma is the most malignant and lethal primary brain tumor. Standard therapy comprises maximal safe surgical resection, radiation therapy plus concomitant and adjuvant temozolomide (TMZ). Despite this aggressive treatment the prognosis varies greatly with a median overall survival (OS) of less than 15 months and a 2 year-OS of 30%. In order to improve the treatment, stratification of glioblastoma patients according to favorable and poor prognostic groups is needed. Accordingly, the aim of this study was to develop a prognostic model for glioblastoma patients treated with standard therapy outside clinical trials. Methods: The study included 622 consecutive, non-selected glioblastoma patients with WHO performance status (PS) 0-2 administered postoperative radiation therapy (RT) with concomitant and adjuvant TMZ as first-line therapy between years 2005-2015 at Rigshospitalet, Denmark. Prognostic models were generated by means of multivariate logistic and Cox regression analysis modeling the endpoints: Response and progression-free survival (PFS) and overall survival (OS). Results: Median age was 60 years. Median OS and PFS were 16 and 7 months, respectively. Second line therapy showed that reoperation and /or Bevacizumab (BEV)/Irinotecan or BEV/lomustine increased survival compared to untreated patients. Patient age, WHO PS, use of steroid, tumor multifocality, extent of resection, O6- methylguanine-DNA methyltransferase (MGMT) activity correlated with patient OS and PFS both in univariate and multivariate analyses. Prior history with low grade glioma was correlated to prolonged OS in univariate but not in multivariate analyses. No correlation to OS was found to preoperative tumor size, IDH1 mutation or P53- and EGFR-protein expression. A model based on the significant features mentioned above was able to predict survival probability for the individual patient with a C index of 67 %. Conclusions: The survival of RT/TMZ-treated glioblastoma patients can be predicted with reasonable precision and can be used for stratification in clinical scientific protocols and individual patient treatment. A detailed update will be presented.
Leading US cancer researcher failed to disclose industry ties in dozens of articles
Authors: Owen Dyer
Journal: BMJ (2018)

One of America’s most prominent breast cancer doctors failed to disclose pharmaceutical industry ties worth millions of dollars in authoring dozens of articles in major journals, according to a report by the New York Times and ProPublica.

Jose Baselga, physician-in-chief at Memorial Sloan Kettering Cancer Center in New York City, neglected to mention multiple directorships and consultancy fees when completing conflict of interest disclosure forms for leading publications including the New England Journal of Medicine and the Lancet , the report found.

Baselga also left out his industry payments when writing for Cancer Discovery , the journal of the American Association for Cancer Research (AACR), even though he was the joint editor-in-chief and president of the association.

“I acknowledge that there have been inconsistencies, but that’s what it is,” he told the New York Times and ProPublica investigative team, asking their opinion on how he should solve the problem. “It’s not …
Descriptive analysis of the use of ipilimumab (IPI) in previously treated patients with unresectable stage III or IV metastatic melanoma (MM) in four university hospitals of Quebec, Canada.
Authors: Catherine Jolivet, Rahima Jamal, Karl Belanger, Nathalie Marcotte, Chantal Guevremont, Ghislain Berard, Marie-Claude Michel, Elaine Pelletier, France Varin, Louise Deschenes, Daniel Froment, Paul Farand, Raghu Rajan, Nathalie LeTarte
Journal: Journal of Clinical Oncology (2016)

e21020 Background: IPI was approved in Quebec in 2012 for treatment of mm patients with an ECOG of 0-1 after failure to chemotherapy. We measured the clinical benefit and adverse events (AE) profile of IPI in patients treated in the 4 university hospitals of Quebec. Methods: The medical files of patients treated with at least one dose of IPI between January 1st 2011 and December 31st 2014 were retrospectively analyzed and followed until June 30th, 2015. Study objectives were to measure overall survival (OS), overall response rate, disease control rate (DCR) and toxicity and to compare them to published data. Response was evaluated at 3 and 6 months after the first dose. A Kaplan Meier curve for survival was obtained with SPSS software. Results: Our cohort consisted of 51 patients (76.5% men) with a median age of 64 and ECOG of 0 or 1 (96%). 18% had previously treated brain metastases and 18% were BRAF mutant. IPI was used as a second-line of treatment in 86% and as a third-line of treatment in 14% of patients. Dacarbazine (DTIC) was used in 70% of patients as first-line of treatment. Induction with 4 doses of IPI was completed in 59% of patients. Median OS was 9 months. DCR was 29% with a complete response, partial response and stable disease of 2%, 15% and 12% respectively. The response could not be evaluated in 11/51 (21%) patients due to death from progression of disease (10/11) or loss to follow-up (1/11). 23 patients (45%) received subsequent treatment at progression. All grade autoimmune related AE were recorded in 55% of patients: rash (35%), diarrhea (22%) and enterocolitis (14%). Grade 3 AE’s were seen in 8% of patients in the form of either diarrhea, colitis or hypopituitarism. Seven patients (14%) had to interrupt definitely their treatment due to toxicity and 22% required corticosteroid treatment for reversal of their symptoms. There were no grade 4 toxicities or treatment related deaths. Conclusions: This retrospective study done in university-affiliated cancer centers in Quebec demonstrates external validity with IPI yielding efficacy and safety results comparable to those reported in the registration trial.
A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic cancer patients (GrantPax).
Authors: Johannes Betge, Nicolai Haertel, Jing Chi-Kern, Sebastian Belle, Nadine Schulte, Martin Maenz, Ulrich Wedding, Matthias Philip Ebert
Journal: Journal of Clinical Oncology (2017)

TPS10124 Background: Nab-paclitaxel/gemcitabine ( nab-P/gem) is an effective 1 st line regimen for metastatic pancreatic ductal adenocarcinoma (mPDAC). Elderly mPDAC patients (pts) may as well benefit from nab-P/gem. Geriatric assessments to evaluate the functional reserve of these pts may allow individualization of treatment. Therefore, the aim of this study is to determine whether comprehensive geriatric assessments (CGAs) can predict the benefit from combined nab-P/gem therapy for elderly mPDAC pts in 1 st line. A stratified treatment approach shall result in patient groups with a stable or improving CGA performance during the 1 st cycle of treatment. Methods: GrantPax (NCT02812992) is a multicenter, open label phase 4 interventional trial with stratified parallel treatment groups (n = 45 per arm). The hypothesis is that individualized assessment directed treatment algorithms identify elderly pts (≥70 yrs), who benefit from combined nab-P/gem therapy. The study uses a CGA to stratify pts as GOGO, SLOWGO or FRAIL. Depending on test outcome, pts receive chemotherapy (GOGO: nab-P/gem; SLOWGO: gem mono) or best supportive care (FRAIL). After 1 st cycle of chemotherapy (4 wks) a CGA and safety assessment will be performed to assign pts to their definite treatment arm. The primary objective is that CGA-stratified pts do not decline in their CGA performance in response to chemotherapy, measured as a loss of 5 points or less in Barthels activities of daily living (ADL1 vs. ADL2 during CGA core assessment). The expected proportion of pts with ADL decline in each treatment group is 6%. Under this assumption it shall be shown with 80% power at one-sided significance level alpha of 0.05 that the proportion of pts with functional decline is less than 20% (n = 43 per group; ADL decline: n = 2 per group). Secondary endpoints are CGA scores during the course of therapy (CGA1-4), response rates, safety, survival rates, duration of treatment, cumulative dose, quality of life and discrepancy between CGA strata estimation by the investigator and true CGA assessment. GrantPax is the first trial realizing a CGA-driven treatment to individualize cancer therapy for elderly pts. Clinical trial information: NCT02812992.
Incidence of hypomagnesemia in a pertuzumab-treated population.
Authors: Jonathan Thomas, Avan Armaghani, Yu Wang, Karen Colleen Daily
Journal: Journal of Clinical Oncology (2018)

e18820 Background: Most HER2+ breast cancers treated in the U.S. today will receive Pertuzumab (P). Other EGFR inhibitors Cetuximab and Panitumumab have recommendations to monitor magnesium; however, no such guidelines exist for P. Magnesium is not included in metabolic panels and was not reported in the clinical trials that led to approval of P in neo/adjuvant and metastatic settings. After observing hypomagnesemia in patients receiving P, we performed a retrospective review of the prevalence of hypomagnesemia in patients treated with P. Methods: Upon IRB approval we reviewed the medical records of patients receiving P at the University of Florida 1/1/12 - 12/15/17. The following was extracted: start and stop date of P; up to 20 serum magnesium levels; concurrent use of platinum, proton pump inhibitor or diuretic; alcohol abuse; and any incidence of hypokalemia while receiving P. Hypomagnesemia was defined as at least one value of 1.5 mg/dL or less. Results: Of the 79 patients who received P, 51 had at least one magnesium value. Half of the evaluable patients (26/51) had hypomagnesemia. Neither diuretic use (6/51, 11.76%) nor proton pump inhibitor use (10/51, 19.61%) was associated with hypomagnesemia. Alcohol abuse was not reported for any patients. The association of platinum with hypomagnesemia was significant (P-value 0.002). In the 25 patients who did not receive platinum, 7 patients (28%) had hypomagnesemia. The association between hypokalemia and hypomagnesemia was significant (P-value 0.0118). Of the 28 patients who did not have a magnesium value, 6 patients (21.43%) had hypokalemia. Conclusions: Half of evaluable patients treated with P had hypomagnesemia. Half of our population received platinum; however, even in those without platinum, 28% had hypomagnesemia. Because hypokalemia and hypomagnesemia were significantly associated, it is intriguing that 21.43% of patients without a magnesium level had hypokalemia. We plan to use this hypothesis-generating work to design a prospective trial of magnesium levels in patients receiving P. Identification of an association of P and hypomagnesemia, if one exists, could establish guidelines to check and replete magnesium, improving the safety and tolerability of P.
Detect T790M in cell free tumor DNA of Chinese advanced non-small cell lung cancer adenocarcinoma patients by different platforms and evaluate clinical outcomes of T790M positive patients with osimertinib monotherapy.
Authors: Zhiyong Liang, Ying Cheng, Yuan Chen, Weiping Liu, You Lu, Jie Wang, Gang Wu, Jian-Ming Ying, Xu-Chao Zhang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2017)

TPS9104 Background: EGFR T790M mutation occurs in approximately 50-60% of non-small cell lung cancer adenocarcinoma (NSCLC) patients with acquired EGFR-TKI resistance, based on tumor re-biopsies using an invasive clinical procedure. Recently, Cell free tumor DNA (ctDNA) has emerged as a specific and sensitive blood-based biomarker and studies have demonstrated ctDNA as a feasible and minimally invasive alternative to tissue biopsy. Data on different technology platforms used for EGFR T790M detection in blood in China is limited. We aim to compare the methods currently available in hospital practise, including cobas EGFR Mutation Test (Roche Molecular Systems), super-ARMS, digital PCR and NGS, to compare each platform and clinically validate each as companion diagnostic to osimertinib. Methods: This is an open-label, multi-center study in 250 locally advanced or metastatic NSCLC patients with documented EGFR sensitizing mutation and progression on previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods: cobas, super-ARMS, digital PCR and NGS in order to evaluate the concordance, sensitivity and specificity of T790M testing in plasma between the cobas test and the other platforms. T790M positive patients by any of the four platforms will receive osimertinib treatment (administered orally as one 80 mg tablet once a day in ASTRIS study, NCT02474355) and the clinical outcomes (PFS, ORR, OS) will be followed. Patients will continue to receive osimertinib until disease progression (PD), as assessed by investigators. Digital PCR and NGS will be used to monitor the molecular evolution of T790M and C797S in plasma from NSCLC patients during osimertinib treatment. NGS will also be used to explore acquired resistance mechanisms before osimertinib treatment and after PD. 23 of planned 250 patients have been enrolled in the study as of January 2017. Clinical trial information: NCT02997501.
Systematic literature review of efficacy, safety, and tolerability outcomes of interventions in patients with distant metastatic Merkel cell carcinoma.
Authors: Paul Nghiem, Murtuza Bharmal, Lisa Mahnke, Hemant Phatak, Jürgen C. Becker
Journal: Journal of Clinical Oncology (2016)

e21018 Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with a poor prognosis once metastasized. There are currently no approved treatments for patients (pts) with metastatic MCC. A systematic literature review was conducted to assess the current treatment landscape and to understand clinical outcomes associated with interventions in the treatment of pts with metastatic MCC. Methods: Embase, MEDLINE, MEDLINE-In-Process, and CENTRAL were searched for studies published from database inception to Nov 2015; key conferences were searched for relevant studies from 2011 to 2015. All study designs assessing any line of therapy for the treatment of pts with advanced or metastatic MCC were eligible for inclusion; however, this analysis focuses on cohort studies evaluating pts with distant/systemic metastases. Case series/reports were analyzed separately. Results: Most eligible studies identified in the literature were case series/reports, with only 5 cohort studies that evaluated pts with distant/systemic metastases. Interventions assessed included a combination of platinum-based chemotherapy, cyclophosphamide, vincristine, etoposide, or topotecan. First- (1L) and second-line (2L) cohort studies (n = 5 with 1 study comprising both 1L and 2L cohorts) reported overall response rates of 23-61% (complete response: 3-37%; partial response: 20-40%; stable disease: 3-15%) with an estimated median duration of response of 3-4 months. Response rates were lower in the 2L setting (23%) compared with 1L setting (53-57%).Median overall survival was reported in 2 of the 5 studies (9-9.5 months), with 1 study also reporting median progression-free survival (3.1 months). None of the studies collected quality of life data. The most common chemotherapy-related adverse events were renal failure, neutropenia, and myelosuppression. Conclusions: The literature on pts with distant metastatic MCC is sparse, with most studies being case series. Although initial responses to chemotherapy were reported, duration of response was short. There is a strong need for trials to evaluate novel agents that can induce durable responses in metastatic MCC
Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical Revascularization
Authors: Iris Baumgartner, Lars Norgren, F. Gerry R. Fowkes, Hillary Mulder, Manesh R. Patel, Jeffrey S. Berger, W. Schuyler Jones, Frank W. Rockhold, Brian G. Katona, Kenneth Mahaffey, William R. Hiatt
Journal: Journal of the American College of Cardiology (2018)
Abstract B12: HPV-positive tumor cell lines exhibit major alterations in Toll-like receptor pathways and depend on HMGB1 expression
Authors: Mirian Galliote Morale, Walason da Silva Abjaude, Aline Montenegro da Silva, Luisa Lina Villa, Enrique Boccardo
Journal: Clinical Cancer Research (2018)

Abstract Cervical cancer is one of the leading causes of cancer death in women worldwide. Persistent infection with high-risk human papillomavirus (HPV) types is the main risk factor for the development of cervical cancer precursor lesions and is usually characterized by innate immune system evasion. The innate immune system is the first line of defense against pathogens and homeostatic changes. Toll-like receptors (TLR) are a family of membrane proteins that actively participate in this process by recognizing molecular patterns derived from pathogens and from cellular danger signals. Alterations in TLR expression and activation may be important for the control of HPV infections and could play a role in the progression of HPV-associated lesions and cancers. In the present study, we analyzed the expression of 84 genes involved in TLR signaling pathways in cervical cancer cell lines and primary human keratinocytes. We observed that 80% of the differentially expressed genes were downregulated in cervical cancer cell lines relative to normal keratinocytes. Major alterations were detected in genes coding for several TLR signaling proteins, including adaptor molecules MyD88 and SARM1, NFκB activation complex components such as Ube2N and TRAF6, and effector proteins such as HMGB1. Specifically, HMGB1, a protein related to stimulation of inflammation after TLR activation, showed increased expression levels in the HPV-positive cell lines HeLa and SiHa relative to normal keratinocytes. HMGB1 silencing also reduced cell viability, proliferation, and colony formation capacity of cervical cancer cell lines. In addition, silenced cervical cancer cell lines exhibited increased activated caspase-3 levels and hypodiploid cell population suggestive of apoptosis triggering. HPV infection may interfere with TLR pathways at different levels, resulting in the impairment of their activation and function and potentially leading to innate immune system evasion. Our results suggest that TLR pathway proteins such as TLR4, SARM1, and HMGB1 may play other roles related to tumor development. In conclusion, HMGB1 is a key factor in the survival of HPV-positive tumor cells, which warrants further studies to evaluate its potential as a therapeutic target or tumor biomarker. Citation Format: Mirian Galliote Morale, Walason da Silva Abjaude, Aline Montenegro da Silva, Luisa Lina Villa, Enrique Boccardo. HPV-positive tumor cell lines exhibit major alterations in Toll-like receptor pathways and depend on HMGB1 expression [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B12.
TCT-711 Achieving target LDL following percutaneous coronary revascularization – contemporary results in a nationalized health care system
Authors: Trevor Simard, Pietro Di Santo, Francisco Ramirez, Richard Jung, Alisha Labinaz, Ian Pitcher, Pouya Motazedian, Rebecca Rochman, Robert Moreland, Jeffrey Marbach, Paul Boland, Kiran Sarathy, Saleh Alghofaili, Juan Russo, Etienne Couture, Derek So, Aun-Yeong Chong, Michel Le May, Benjamin Hibbert
Journal: Journal of the American College of Cardiology (2018)