tbuckley/cabot-search huggingface dataset:
The impact of tumor molecular profile-directed treatment on survival in recurrent ovarian cancer.
Authors: Kate Eleanor Oliver, Nianqing Xiao, David Spetzler, Neil T. Phippen, Ryan T Oleszewski, William P. McGuire
Journal: Journal of Clinical Oncology (2014)

5591 Background: We sought to determine whether tumor molecular profile-directed treatment of recurrent ovarian, primary peritoneal and fallopian tube carcinomas influenced survival. Methods: With IRB approval, Caris Life Sciences, Ltd maintains the Caris Registry, a database of clinicopathologic and outcome variables from consenting patients whose tumors underwent molecular profiling. Molecular profiling was performed using a multiplatform approach to stratify agents by degree of potential therapeutic benefit. The Caris Registry was queried for all patients with a diagnosis of ovarian, primary peritoneal and fallopian tube carcinomas enrolled between 2010 and 2014. Patients were stratified based on chemotherapeutic agents employed during their disease course: the molecularly-guided (MG) cohort received at least one agent designated to be of potential benefit and no agents with potential lack of benefit while the non-molecularly-guided cohort (non-MG) received at least one agent with potential lack of benefit. Survival was calculated from the date of profiling and from the date of diagnosis to the date of death/censoring using the Kaplan-Meier method. Results: Of 445 patients identified in the registry, 90 were excluded due to non-invasive pathology, non-epithelial histology, and missing or ambiguous treatment information. Of the remaining 355 eligible and evaluable patients, 166 formed the MG cohort and the remaining 189 were assigned to the non-MG cohort. There were no significant differences in baseline clinicopathologic characteristics between the two groups. Patients in the MG cohort experienced significantly longer post-profiling survival when compared with patients in the non-MG cohort, HR 0.64 (CI 0.41 – 0.97, p = 0.03). Additionally, there was a trend toward longer overall survival in the MG cohort. Conclusions: Tumor molecular profile-directed treatment significantly improves post-profiling survival in patients with recurrent ovarian, primary peritoneal and fallopian tube carcinomas. Despite immature outcome data, trends toward improved overall survival were also demonstrated.
Pharmacist-led lung cancer biomarker detection.
Authors: Emer Ann Sheridan, John Stephenson, Patrick McHugh, Henry Chrystyn, Brown Philip, Rachel Airley
Journal: Journal of Clinical Oncology (2014)

TPS11133 Background: Patients at risk of lung cancer may have subclinical disease present for years before diagnosis. Exhaled breath condensate (EBC) is water vapour which contains aerosolized particles in which a large number of metabolites are detectable. Lung malignancy, inflammation and therapeutic intervention influence these biomolecules. This project aims to use EBC as a non-invasive means of detecting biomarkers, differentiating between lung malignancy, lung inflammatory disorders and the generally healthy population. In doing so, there is potential for early diagnosis of lung cancer in a public health setting. This will involve the design of a novel care pathway where pharmacists administer non-invasive breath tests to at-risk patients and flag up and distinguish early signs of malignant or inflammatory lung disease. Methods: A cohort of histologically confirmed lung cancer patients (both SCLC and NSCLC) a cohort of patients with inflammatory lung disease (asthma and COPD) and a control cohort of volunteers from the general population will be recruited to a proof of principle study aiming to collect breath samples. These will be profiled for mRNA expression of a range of candidate biomarkers using both custom and commercially available qRT-PCR pathway arrays. This will be extended to both genomic and proteomic analysis. A putative biomarker signature has been identified in silico using Gene Expression Omnibus and Oncomine databases. To aid differentiation between stable or progressing COPD/asthma and early signs of lung cancer, we have incorporated groups of tumour biomarkers with increased expression in lung cancer e.g., those associated with the hypoxic tumour microenvironment. This theoretical signature comprises approximately 100 genes. These genes have all been mined with a threshold of at least a two fold change and statistical significance of P = 10-4. For this comparative study a multiple ANOVA approach will be utilised. Potentially a large number of outcomes may be considered, variable reduction techniques (e.g. principal component analysis) will be utilised to reduce the dimensionality of the study. The study will run alongside chemical analysis, working towards a highly specific, selective and combined biological and chemical signature.
Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity
Authors: Sanjib Chaudhary, Koelina Ganguly, Sakthivel Muniyan, Ramesh Pothuraju, Zafar Sayed, Dwight T Jones, Surinder K Batra, Muzafar A Macha
Journal: JNCI Journal of the National Cancer Institute (2018)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with high morbidity and mortality. Racial disparity in HNSCC is observed between African Americans (AAs) and whites, effecting both overall and 5-year survival, with worse prognosis for AAs. In addition to socio-economic status and demographic factors, many epidemiological studies have also identified factors including coexisting human papillomavirus (HPV) infection, primary tumor location, and a variety of somatic mutations that contribute to the prognostic incongruities in HNSCC patients among AAs and whites. Recent research also suggests HPV-induced dysregulation of tumor metabolism and immune microenvironment as the major regulators of HNSCC patient prognosis. Outcomes of several preclinical and clinical studies on targeted therapeutics warrant the need to elucidate the inherent mechanistic and population-based disparities underlying patient responses. This review systematically reports the underlying reasons for inconsistency in disease prognosis and therapy responses among HNSCC patients from different racial populations. The focus of this review is twofold: aside from discussing the causes of racial disparity, we also seek to identify the consequences of such disparity in terms of HPV infection and its associated mutational, metabolic, and immune landscapes. Considering the clinical impact of differential patient outcomes among AA and white populations, understanding the underlying cause of this disparity may pave the way for novel precision therapy for HNSCC.
A phase 1 dose-escalation study of EC1456, a folic acid-tubulysin small-molecule drug conjugate, in adult patients (pts) with advanced solid tumors.
Authors: Wael A. Harb, Ramesh K. Ramanathan, Daniela E. Matei, Binh Nguyen, Edward A. Sausville
Journal: Journal of Clinical Oncology (2014)

TPS2630 Background: The folate receptor (FR) is expressed in alarge number of epithelial tumors and is a valid anticancer target. EC1456 is a potent folic acid-tubulysin B hydrazide (TubBH) small-molecule drug conjugate that exerts its antitumor effects by inhibiting the polymerization of tubulin into microtubules and arresting cells in metaphase. EC1456 acts as a cell-specific cytotoxic agent and preferentially targets TubBH to cancer cells that express FR. Methods: This is a phase 1, multicenter, open-label, nonrandomized dose-escalation study (NCT01999738) to evaluate the maximum tolerated dose (MTD) of biweekly (BIW) EC1456 treatment in pts with solid tumors (part A) and assess preliminary efficacy in pts with FR-expressing tumors treated at the MTD (part B). Key eligibility criteria include: age ≥18 years; histologically confirmed metastatic or locally advanced solid tumor; Eastern Cooperative Oncology Group (ECOG) performance status 0–1. At baseline all pts undergo a 99mTc-etarfolatide scan to determine FR status. For part B, only FR(100%) pts, in whom all target lesions (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) express FR, are included. EC1456 is given intravenously BIW on weeks 1 and 2 (days 1, 4, 8, and 11) of a 4-week cycle. The dose-escalation scheme is shown in the Table. Cohorts will consist of 3–6 pts/dose level, and EC1456 escalation is via the standard 3+3 schema. All pts in a cohort must complete cycle 1 dose-limiting toxicity (DLT) evaluation before dosing is initiated at the next higher level. DLTs observed in cycle 1 will determine whether additional pts should be enrolled at the same dose, or a lower/higher dose level. The primary objective is to determine the MTD and recommended phase 2 dose of EC1456 in pts with advanced tumors. The secondary objectives include safety and pharmacokinetic analysis of EC1456 in pts with solid tumors, and preliminary efficacy evaluation in selected pts at MTD (part B). Enrollment to cohort 1 began in November 2013. Clinical trial information: NCT01999738. Level Dose (mg/m2) 1 0.5 2 1 3 1.5 4 2 5 2.5 6 3.5 7 4.5 8 6
Molecular Detection of Minimal Residual Disease Precedes Morphological Relapse and Could be Used to Identify Relapse in Pediatric and Young Adult B-Cell Acute Lymphoblastic Leukemia Patients Treated with Tisagenlecleucel
Authors: Michael A. Pulsipher, Xia Han, Máire Quigley, Gabor Kari, Susana Rives, Theodore W. Laetsch, Gary Douglas Myers, Hidefumi Hiramatsu, Gregory A. Yanik, Muna Qayed, Timothy Driscoll, Michael W. Boyer, Heather Stefanski, Jochen Büchner, Andre Baruchel, Peter Bader, Lan Yi, Creton Kalfoglou, Harlan Robins, Erik Yusko, Güllü Görgün, Eric Bleickardt, Stephane Wong, Stephan A. Grupp
Journal: Blood (2018)
BACCI: A phase II randomized, double-blind, placebo-controlled study of capecitabine bevacizumab plus atezolizumab versus capecitabine bevacizumab plus placebo in patients with refractory metastatic colorectal cancer.
Authors: Niharika B. Mettu, Donna Niedzwiecki, Patrick McKay Boland, Marwan Fakih, Christy Arrowood, Emily Bolch, Herbert Hurwitz, Axel Grothey
Journal: Journal of Clinical Oncology (2018)

TPS873 Background: Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil based chemotherapy regimen, often in combination with anti-VEGF therapy. Upon disease progression, multiple studies have suggested a benefit for continued anti-VEGF therapy. There is increasing evidence that VEGF plays a role in cancer immune evasion. Targeting of inflammatory and immune checkpoints are attractive approaches to enhance the benefits of anti-VEGF therapy. The safety and activity of the anti-PD-L1 antibody atezolizumab with bevacizumab and with 5-FU, oxaliplatin, and bevacizumab have been recently reported; the combinations were well-tolerated and suggested clinical activity. Therefore, bevacizumab may increase the immunogenicity of colorectal cancers, and the combination of atezolizumab plus bevacizumab may be associated with clinically meaningful response rates and disease control. Furthermore, there may be candidate biomarkers that may identify those patients most likely to benefit from this combination. Methods: In this randomized, double-blind, multicenter, placebo-controlled phase II study, 135 patients with mCRC will be randomized 2:1 to receive capecitabine/bevacizumab/atezolizumab or capecitabine/bevacizumab/placebo. Patients with prior PD-L1/PD-1 therapy are ineligible. Primary and secondary efficacy will be conducted using ITT analysis. Safety analyses will include all randomized patients who receive at least one dose of study treatment. The primary objective is PFS. The secondary objectives are ORR, OS, safety, and tolerability. The primary comparison will be superiority of the active treatment for the PFS endpoint, atezolizumab versus placebo testing at 1-sided α = 0.1 (log rank test). A PFS hazard ratio of 0.618 (active treatment versus placebo) is detectable with 86% power (1 sided α = 0.1). No interim analyses for futility or efficacy will be conducted. A subset analysis will be performed in the microsatellite-high patients looking at potential differences in PFS and OS. Trial is active and currently recruiting patients. Clinical trial information: NCT02873195.
Racial differences characterizing Hispanics with hepatocellular carcinoma.
Authors: Stephanie A. Berg, Mary Modayil, Tad D. Nair, James T. Bui, Ron C. Gaba, Yue Huang, Scott Cotler, Neeta K. Venepalli
Journal: Journal of Clinical Oncology (2014)

e17564 Background: Hepatocellular carcinoma (HCC) incidence and mortality rates are disproportionately higher in Hispanic (H) and African-American (B) versus White (W) patients (pts). While H have the fastest rising rates of HCC in the US, little is known about race specific risk factors and disease characteristics. Identification of clinical factors associated with HCC in H is critical to address racial disparities in HCC incidence rates and outcomes. Methods: We retrospectively reviewed HCC pts treated at U of Illinois-Chicago between 2005-2011. Demographics, disease characteristics, HCC factors, treatment patterns, and survival outcomes were analyzed with descriptive statistics, chi-square p values, and kaplan-meier curves. Results: Mean age of HCC pts (N=195) at diagnosis was 59.7 years + 9.8 (19.5% female; 22% aged 65 or older; 61.5% Medicare or Medicaid; 4.1% no insurance; 22.6% H; 31.2% B). Compared to B and W, H pts were more likely to have hyperlipidemia, NASH, require dialysis, and less likely to have Hepatitis C or a smoking history. Compared to B, H were more likely to have metabolic syndrome, diabetes (DM2), higher median MELD, ascites, encephalopathy (HE). H had a shorter survival than B and W pts (p=0.020) despite similarities in HCC factors and treatment; race was the only predictive variable on multivariate analysis. Conclusions: H pts with HCC have higher incidence of modifiable risk factors, more aggressive liver disease characteristics, and shorter survival. Total N=195 H 44 B 61 W 90 p- value Demographics Age (years +- SD) 59.7 + 9.8 62.5 + 12.5 58.7 + 10.2 58.9 + 7.7 NS Female (%) 38 (19.5) 11 (29.0) 17 (44.7) 10 (26.3) 0.0223 Smoking history (%) 126 (65) 16 (36.3) 43 (70.5) 67 (75.2) <0.0001 Comorbid Conditions Hyperlipidemia (%) 31 (25.4) 16 (55.2) 5 (13.2) 10 (18.2) 0.0001 Dialysis (%) 7 ( 3.6) 5 (11.4) 0 2 (2.3) 0.0057 DM2 (%) 91 (46.7) 29 (65.9) 19 (31.1) 43 (47.8) 0.0019 Metabolic syndrome (%) 27 (14.1) 8 (18.2) 3 (4.9) 16 (18.4) 0.0453 Disease characteristics Cirrhosis (%) HCV NASH 132 (67.7) 35 (18.0) 18 (40.9) 15 (34.9) 49 (80.3) 5 (8.2) 65 (72.2) 15 (16.7) <0.0001 0.0021 HE (%) 65 (33.3) 16 (36.4) 8 (13.1) 41 (45.6) 0.0003 Ascites (%) 73 (40.6) 18 (42.9) 13 (24.1) 42 (50.0) 0.0006 MELD (Median + SD) 11.0 ± 4.6 11.5 ± 4.4 9.0 ± 3.1 12.0 ± 5.1 0.0002
Clinical Outcome Following Reinstitution of Anticoagulation after Major Gastrointestinal Bleed: A Single Institutional Analysis
Authors: Daniel E Ezekwudo, Susanna Gaikazian, Nwabundo Anusim, Anish S Konde, Dana Zakalik, Marianne Terese Huben, Michael Stender, Joseph Anderson, Ishmael Jaiyesimi
Journal: Blood (2018)
Next-generation sequencing in carcinoma of unknown primary (CUP) and novel combinatorial strategies in a heterogeneous mutational landscape: Implications for personalized medicine.
Authors: Ishwaria Mohan Subbiah, Gauri R. Varadhachary, Apostolia Maria Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Gerald Steven Falchook, Filip Janku, Ralph Zinner, Sinchita Roy-Chowdhuri, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2014)

e22154 Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conducted an exploratory analysis of next-generation sequencing (NGS) of relapsed/refractory CUP. Methods: We identified 21 CUP patients referred to our phase I clinic where FFPE sections from archival tissue were available for a targeted NGS assay in a CLIA laboratory (Foundation One, MA). The current assay interrogates exons in 236 genes and 47 introns of 19 genes involved in rearrangements for point mutations, insertions/deletions, copy number alterations, and variants of unknown significance. Results: Of 21 patients tested, 19 (90%) demonstrated genomic alterations with a median of 4 aberrations within each specimen (range 0 – 10, total of 81 alterations). 12 (57%) patients demonstrated one or more alterations in known tumor suppressor genes, including TP53 in 9 patients,11 (52%) had impaired epigenetic regulation and DNA methylation, 11 (52%) had mutations in cell cycle regulators, most commonly in the cyclin dependent kinases, while 10 (48%) patients had alterations within the PI3K/AKT/MTOR (4 with PIK3CA mutations) or MAPK signaling regulators (3 with KRAS mutations), and 9 (43%) patients had unique alterations in transcriptional regulators. Conclusions: Every patient with CUP had a unique molecular profile with no two patients demonstrating an identical panel of mutations. However, our exploratory analysis identifies two potential novel combinatorial strategies, the first targeting epigenetic dysregulation with impaired cell cycle arrest seen together in 9 (43%) patients, and the second targeting the activation of PI3K/AKT/MTOR and RAS/RAF/MEK signaling with impaired cell cycle arrest seen together in 8 (38%) patients. Efforts to translate these therapeutic targets to the bedside and to match these patients to therapies on early phase clinical trials are in progress.
Factors Impacting Progression-Free Survival after CD19-Specific CAR-T Cell Therapy for Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
Authors: Alexandre V. Hirayama, Jordan Gauthier, Kevin A. Hay, Jenna M. Voutsinas, Qian V. Wu, Ted Gooley, Daniel Li, Alyssa Sheih, Janaki Purushe, Sindhu Cherian, Xueyan Chen, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Rachel N. Steinmetz, Tinh-Doan Phi, Ryan C. Lynch, Aude G. Chapuis, Brian G. Till, Hans-Peter Kiem, Jorge Ramos, Mazyar Shadman, Ryan D. Cassaday, Utkarsh H. Acharya, Stanley R. Riddell, David G. Maloney, Cameron J. Turtle
Journal: Blood (2018)
Contemporary Drug Treatment of Chronic Heart Failure With Reduced Ejection Fraction
Authors: Hans-Peter Brunner-La Rocca, Gerard C. Linssen, Frank J. Smeele, Annemarie A. van Drimmelen, Henk-Jan Schaafsma, Paul H. Westendorp, Philip C. Rademaker, Hendrik J. van de Kamp, Arno W. Hoes, Jasper J. Brugts
Journal: JACC Heart Failure (2018)
PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer
Authors: Roman M. Chabanon, Gareth Muirhead, Dragomir B. Krastev, Julien Adam, Daphné Morel, Marlène Garrido, Andrew Lamb, Clémence Hénon, Nicolas Dorvault, Mathieu Rouanne, Rebecca Marlow, Ilirjana Bajrami, Marta Llorca Cardeñosa, Asha Konde, Benjamin Besse, Alan Ashworth, Stephen J. Pettitt, Syed Haider, Aurélien Marabelle, Andrew N.J. Tutt, Jean-Charles Soria, Christopher J. Lord, Sophie Postel-Vinay
Journal: Journal of Clinical Investigation (2018)

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non–small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ–induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.
The outcomes of the treatment of centrally located brain gliomas diagnosed with stereotactic biopsy.
Authors: Gabriela Karczewska, Piotr Blaszczyk, Krzysztof Roszkowski
Journal: Journal of Clinical Oncology (2014)

e13009 Background: An analysis of the treatment outcomes of brainstem-located brain tumors, treated between February 2006 and November 2012, was conducted. Clinical profile: tot. 80 patients (diagnosed histopathologically using stereotactic biopsy): Glioblastoma Multiforme (GBM)= 40 (50%); Astrocytoma anaplasticum (AA)=22 (27.5%); Astrocytoma fibrillare (AF)=16 (20%), undiagnosed (UD) =2 (2.5%). Methods: All patients were subjected to radiation therapy at appropriate doses as follows: GBM—60 Gy/30 fr; AA—60 Gy/30 fr; AF—54 Gy/27 fr; UD—54 Gy/27 fr. Median age: GBM—56 (24–80); AA—48 (20–72); AF—39 (17–55); UD—n/a (9 and 46). Results: Median overall survival: GBM—3 mo.; AA—7 mo.; AF—22 mo. Among the patients who have survived to date, there are 8 (20%) GBM patients (the longest survival values are 41 mo. and 28 mo.); 10 (45.5%) AA patients (the longest survival values are 77 mo. and 69 mo.) and 7 (44%) AF patients (the longest survival values are 41 mo. and 40 mo.). Conclusions: Stereotactic biopsy enables the correct diagnosis of centrally located brain tumors and should become the diagnostic method of choice in such cases. A therapy targeted at the particular tumor type is then possible, which potentially increases the chance of survival for some patients.
Wound Botulism Outbreak Among Persons Who Use Black Tar Heroin — San Diego County, California, 2017–2018
Authors: Corey M. Peak, Hilary Rosen, Amanda Kamali, Alyssa Poe, Mahtab Shahkarami, Akiko C. Kimura, Seema Jain, Eric McDonald
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

During September 29-October 6, 2017, the County of San Diego Public Health Services (COSD) was notified of two patients with suspected wound botulism and a history of using black tar heroin. On October 9, COSD, which had reported an average of one wound botulism case per year during 2001-2016, sent a health alert through the California Health Alert Network, notifying Southern California providers of these two patients, including their signs and symptoms and black tar heroin exposure. In collaboration with the California Department of Public Health, COSD conducted an investigation to identify additional cases, determine risk factors for illness, estimate cost of medical care, and develop recommendations to prevent further illness. By April 18, 2018, nine (eight confirmed and one probable) patients with wound botulism were identified, all of whom were hospitalized; one of the nine died. All nine were persons who inject drugs; seven specifically reported using black tar heroin and six practiced subcutaneous injection known as skin popping. Clinically compatible signs and symptoms included muscle weakness, difficulty swallowing, blurred vision, drooping eyelids, slurred speech, difficulty breathing, loss of facial expression, or descending paralysis. All patients were treated with heptavalent botulism antitoxin (BAT). Wound botulism is likely underrecognized because of its rarity and the overlapping signs and symptoms with opioid intoxication, overdose, and other neurologic syndromes including Guillain-Barré syndrome, the Miller Fisher variant of Guillain-Barré syndrome, and myasthenia gravis. Prompt diagnosis, administration of BAT, and provision of supportive care can help stop the progression of paralysis and be lifesaving.