tbuckley/cabot-search huggingface dataset:
Modular phase I/II clinical trial evaluating the selective MET-kinase inhibitor OMO-1 in patients with advanced malignancies: Safety and proof of mechanism.
Authors: Martijn P. Lolkema, Elizabeth Ruth Plummer, Filip Yves Francine Leon De Vos, Martin David Forster, Eric Angevin, Marion Libouban, Ellen Jansen, Marc Tjwa, Eric Ciamporcero, Ann Meulemans, Annegret Van der Aa, Timothy Pietro Suren Perera, Glen Clack, Matthew Krebs, Sarah Patricia Blagden
Journal: Journal of Clinical Oncology (2019)

3062 Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.
Radiological response patterns in the phase 2 STELLAR trial of TTFields with chemotherapy for first-line treatment of malignant pleural mesothelioma (MPM).
Authors: Federica Grosso, Giovanni Luca Ceresoli
Journal: Journal of Clinical Oncology (2019)

8551 Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of patients with glioblastoma. In-vitro, human MPM cells were highly susceptible to TTFields. In the STELLAR study, patients with unresectable MPM treated with first line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 vs. 12.1 months). We report on analysis of radiological data from STELLAR patients whose tumors responded while receiving the combined therapy. Methods: The STELLAR trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (&gt;18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria included ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. Results: Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of these patients. The median time between treatment start and PR was 1.8 months (range: 1.4-4.4 months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial / pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within a median response duration of 5.7 months (range: 1.4-13 months), per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Conclusions: The STELLAR study met its primary endpoint of significant survival extension for previously untreated mesothelioma patients. Response rates were similar to the ones reported for the current standard of care treatment, but lasted longer with the addition of TTFields. Clinical trial information: NCT02397928.
Everolimus plus letrozole treatment of recurrent gynecologic cancers.
Authors: Kenneth David Miller, Frederick Min, James Barter, Corilynn Hughes, Lyudmila Kalnitskaya, Wanda Bell-Farrell, Sujana Lalagari, Alexis Solis, Jeanne Phelps, Christine Wade, Michael Tangrea, Marvin J. Feldman
Journal: Journal of Clinical Oncology (2019)

5567 Background: Hormonal therapy has limited activity in gynecologic (Gyn) cancer treatment. mTOR inhibitors plus aromatase inhibitors (AI's) improve the response rate and response duration in breast cancer patients. We studied this combination in heavily pre-treated women having estrogen receptor positive (ER+) Gyn cancers. Methods: This phase II study combines everolimus and letrozole for ER+ Gyn cancers with disease progression following primary and salvage chemotherapy. 19 patients participated (Ovary-10, Endometrium-7, and Primary Peritoneal Cancer-2). The mean age was 64, prior lines of therapy ranged from 2-7, and median time from diagnosis to study entry was 67 months (m) (range 10-348m). Results: There were no complete responders, but 7 of 19 (37%) patients treated had clinical benefit, with 1 PR and 6 with stable disease. In responding patients, the earliest time to best response was 2m and the median time to progression was 5m (range 5-40+m). The mean number of treatment cycles was 11. Toxicities: The most common adverse events were: hyperglycemia, rash, stomatitis, fatigue, and anemia. 7 patients required dose reductions, and 2 discontinued study drugs due to pneumonitis. The therapy was generally well tolerated in both women &lt; 65 and &gt; 65 years old. Toxicities were less common with reduced everolimus doses. Conclusions: Recurrent Gyn cancers become refractory to chemotherapy. We tested the combination of everolimus plus letrozole in heavily pretreated patients with ER + recurrent disease. 1 patient had a PR and 6 had stable disease with a range of 5-40+m. This oral regimen was generally well tolerated and allowed time without IV chemotherapy, while providing clinical benefit to patients with refractory ER+ Gyn cancers.
Epigenetic regulation of RUNX3 in systemic sclerosis pathogenesis: time to target?
Authors: Steven O'Reilly
Journal: Annals of the Rheumatic Diseases (2019)

Systemic sclerosis (SSc) is an idiopathic autoimmune disease, that is, characterised by inflammation, cytokine imbalances and vasculopathy that leads to skin and lung fibrosis. The disease has very limited options with none specifically targeting the fibrotic component, and only in recent times has an insight into the molecular pathways at work come to light. An aberrant immune system has long been associated with SSc, with clear alterations in innate immune cell numbers and activation and recently the role of type I interferons has been implicated in SSc,1 molecules normally associated with a different rheumatic disease: systemic lupus erythematosus. What is driving this increase in type I interferons, however, was unknown until now.

In this issue, Affandi et al show that plasmacytoid dendritic cells (pDCs) are important and the central transcription factor RUNX3 is critical.2 The authors showed that RUNX3 expression is severely reduced in SSc patients, in pDCs, and this is observed across both limited and diffuse subsets of the disease. The level of RUNX3 was reduced both at the gene and protein levels and, importantly, correlated significantly with the Rodnan skin score. pDCs are rare type I interferon-producing cells that can present antigen. These cells can release high levels of type I interferon and can also contribute to pathology by the activation of effector T cells, cytotoxic T cells and conventional dendritic cells (DCs). Thus, it is conceivable that the pDCs in SSc are contributing to the disease pathology through the release of interferon and the activation of T cells, which are known to release profibrotic molecules capable of activating fibroblasts to myofibroblasts.3 RUNX3 is one of three mammalian Runt-domain transcription factors encoded by the highly conserved RUNX gene family. RUNX genes are key regulators of lineage-specific gene expression and regulate T cell development and RUNX3 …
Dual prognostic role of 2‐oxoglutarate‐dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance
Authors: Wai Hoong Chang, Donall Forde, Alvina G. Lai
Journal: Cancer Communications (2019)

Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family.A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signatures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses.Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n = 2627): bladder urothelial carcinoma (P = 0.039), renal papillary cell carcinoma (P = 0.013), liver cancer (P = 0.033 and P = 0.025), lung adenocarcinoma (P = 0.014), pancreatic adenocarcinoma (P < 0.001 and P = 0.040), and uterine corpus endometrial carcinoma (P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n = 4134): bladder urothelial carcinoma (P = 0.039), cervical squamous cell carcinoma and endocervical adenocarcinoma (P = 0.035), head and neck squamous cell carcinoma (P = 0.038), renal clear cell carcinoma (P = 0.012), renal papillary cell carcinoma (P = 0.002), liver cancer (P < 0.001, P < 0.001), lung adenocarcinoma (P = 0.011), pancreatic adenocarcinoma (P = 0.002, P = 0.018, P < 0.001), and gastric adenocarcinoma (P = 0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor down-regulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regulators. Low KDM8 expression in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling.Two pan-cancer prognostic signatures of oxygen-sensing genes were identified. These genes can be used for risk stratification in ten diverse cancer types to reveal aggressive tumor subtypes.
Role of Adjuvant Multimodality Therapy After Curative-Intent Resection of Ampullary Carcinoma
Authors: Brett L. Ecker, Charles M. Vollmer, Stephen W. Behrman, Valentina Allegrini, John Aversa, Chad G. Ball, Courtney E. Barrows, Adam C. Berger, Martha N. Cagigas, John D. Christein, Elijah Dixon, William E. Fisher, Mollie Freedman-Weiss, Francisco Guzman-Pruneda, Robert H. Hollis, Michael G. House, Tara S. Kent, Stacy J. Kowalsky, Giuseppe Malleo, Ronald R. Salem, Roberto Salvia, Carl R. Schmidt, Thomas F. Seykora, Richard Zheng, Amer H. Zureikat, Paxton V. Dickson
Journal: JAMA Surgery (2019)

Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined.To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype.This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates.Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy.Overall survival.A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41).Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined.
Author Correction: Multi-trait analysis of genome-wide association summary statistics using MTAG
Authors: Patrick Turley, Raymond K. Walters, Omeed Maghzian, Aysu Okbay, James J. Lee, Mark Alan Fontana, Tuan Anh Nguyen-Viet, Robbee Wedow, Meghan Zacher, Nicholas A. Furlotte, Patrik Magnusson, Sven Oskarsson, Magnus Johannesson, Peter M. Visscher, David Laibson, David Cesarini, Benjamin M. Neale, Daniel J. Benjamin
Journal: Nature Genetics (2019)
Oral chemotherapy follow up on a Brazilian private health care unit.
Authors: Mauro Zukin, Marcos Coelho Simões Travassos Soares, Nathalia Fonseca Gamboa, Fabiano Hosken Pombo, Lucyana Carvalho
Journal: Journal of Clinical Oncology (2019)

e18311 Background: Oral antineoplastic therapy is a growing reality, and ensures greater comfort and better quality of life for patients. However, this modality of treatment requires greater attention of the professionals to avoid dispensing errors and to guarantee adherence to the treatment. The goal of this study is to present a method to follow up cancer patients to reduce percentage of problems related to medication and improve oral antineoplastic adherence. Methods: The study was conducted at a private oncology clinic in Rio de Janeiro during the year 2018. In the first dispensation, patients received verbal and written pharmaceutical advice on posology, proper storage, safe handling requirements and strategies to avoid adverse side effects and food and drugs interactions. There were also given nutrition, sexuality, rights and duties guidelines. To improve adherence and to avoid forgetfulness or duplicity of dosing, patients received a medication calendar. Pharmacist made dispensing, managed adverse side effects and assessed adherence of patient using a model based on Morisky Medication Adherence Scale. Patients that answered "yes" to any questions were considered non-adherents. All information was registered in medical record. Non-compliances were considered: wrong medicine, incorrect dose and delays of any administrative reason. Results: In 2018, on average 1487 dispensings were made and 1053 patients’ adherence behavior were measured. 94.37% were considered adherent. Monthly percentage of non-compliance was 1.5% of dispensings. Conclusions: The present study demonstrates that with education and pharmaceutical follow-up since the first dispensation, it is possible to guarantee a safer and more effective treatment for patients using oral cancer medication. It is imperative to maintain the objective of developing better techniques for dispensing, guiding and guaranteeing high adherence.
Outcomes of first-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Chun Loo Gan, Shaan Dudani, J Connor Wells, Andrew Lachlan Schmidt, Ziad Bakouny, Bernadett Szabados, Francis Parnis, Shirley Wong, Jae-Lyun Lee, Guillermo de Velasco, Sumanta K. Pal, Ian D. Davis, Ravindran Kanesvaran, Lori Wood, Christian K. Kollmannsberger, Rana R. McKay, Benoit Beuselinck, Frede Donskov, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2021)

276 Background: Ipilimumab and nivolumab (IPI-NIVO) and IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE) are now standard of care 1L treatment options for mRCC. However, there is limited head-to-head comparative evidence between these strategies. Methods: Using the IMDC dataset, patients treated with a 1L IOVE combination (pembrolizumab axitinib, avelumab axitinib and nivolumab cabozantinib) were compared with those treated with IPI-NIVO. The outcomes of interest were overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). A preplanned subgroup analysis of the IMDC intermediate/poor risk population was conducted. Hazard ratios were adjusted for IMDC risk factors. Results: 723 patients were included for analysis (N=571 for IPI-NIVO and N=152 for IOVE). The median age was 60 in both groups. The proportion of patients with IMDC favorable, intermediate and poor risk disease in IPI-NIVO vs. IOVE groups were 9% vs. 33%, 58% vs. 53%, 33% vs. 14%, respectively. In the intermediate/poor risk groups (Table), ORR and median TD were lower and shorter in IPI-NIVO vs IOVE while no difference in median TTNT and OS was detected. The HR for death adjusting for IMDC criteria for IPI-NIVO vs. IOVE was 0.92 (95% CI 0.61-1.40, p=0.71). IMDC risk groups and the presence or absence of sarcomatoid histology, brain, liver or bone metastases were not associated with differences in OS between these treatments (all p&gt;0.2). Patients that had dose delays or steroid use (defined as &gt;40mg of prednisone equivalent/day) for immune related adverse events (irAEs) were associated with longer median TTNT (21.6 vs. 9.5 mons, p=0.02) and OS (NR vs. 44.4 mons, p=0.01) despite similar treatment durations (7.6 vs. 8.9 mons, p=0.77) compared to those without dose delays or steroid use. Conclusions: We were unable to detect any differences in OS between IPI-NIVO and IOVE regimens in the IMDC intermediate/poor risk groups and amongst various subgroups. Patients who experienced irAEs requiring dose delay or steroids had longer overall survival. [Table: see text]
Racial disparities in outcome among head and neck cancer patients in the United States: An analysis using SEER-Medicare linked database.
Authors: Ikumi Suzuki, Kevin J. Cullen, Ranee Mehra, Søren Bentzen, Olga G. Goloubeva
Journal: Journal of Clinical Oncology (2019)

6051 Background: Despite overall decline in cancer mortality, African Americans suffer from higher mortality in most cancer types including cancers of the head and neck. These differences likely result from a complex interplay of clinical and non-clinical factors. We aim to estimate disparities in overall survival across racial groups in HNSCC in the United States. Methods: This study used SEER-Medicare linked database. We identified all patients aged 66 years or older diagnosed with HNSCC as their first cancer from 1992 to 2011. We excluded those in HMO, diagnosed by death certificate or autopsy, non-SCC, unknown race, and missing month and/or year of diagnosis. Further exclusions included metastatic disease, salivary gland cancers, receiving no treatment in the first 180 days, and unknown stage. Analytic data set included oropharynx, oral cavity, nasopharynx, hypopharynx, and larynx. Primary treatment was defined as any treatment modality received within 180 days after diagnosis. Overall survival (OS) parameters were estimated across ethnic groups by the Cox regression model stratified by site and stage of cancer at diagnosis, adjusted for clinical and demographic characteristics, and propensity score weighted. Results: Our study population included 15, 547 patients. Median OS was 3.5 years (95% CI: 3.4-3.7) across all ethnic groups. African Americans (AA) had inferior outcome with median OS of 2.0 years (95% CI: 1.9-2.3) compared to 3.7 years (95% CI: 3.6-3.8) for Caucasian Americans (CA) (p &lt; 0.0001). This difference was seen despite AA patients receiving comparable treatments and presenting at similar stage of disease, except for cancers of the oral cavity where AA were more likely to present with advanced disease (67% versus 47%; P &lt; 0.001). The difference was most pronounced in the oropharynx where median OS was 1.9 years (95% CI: 1.7-2.1) for AA and 3.8 years (95% CI: 3.5-4.1) in CA (P &lt; 0.0001). AA also had consistently worse OS over time from 1992 to 2011. This study clearly demonstrated AA have inferior outcomes despite similar treatments, comorbidities, age at diagnosis, stage at presentation, tumor location, year of diagnosis and sex. Conclusions: The current study demonstrates inferior overall survival for African American head and neck cancer patients independent of primary site and treatment modalities.