tbuckley/cabot-search huggingface dataset:
Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers
Authors: Erik S. Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W. Botros, Vladimir Makarov, Nadeem Riaz, Vinod Balachandran, Steven Leach, Debrah M. Thompson, Timothy A. Chan, Agnieszka K. Witkiewicz
Journal: Clinical Cancer Research (2017)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance.Results: PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers, and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neoantigen burden, immunologic, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunologic therapy approaches. In addition, a subtype with low levels of neoantigens and minimal lymphocyte infiltrate was associated with improved overall survival.Conclusions: The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC. Clin Cancer Res; 23(15); 4429-40. ©2017 AACR.
Survey On Directed Family Cord Blood Banking for Transplantation Among the National Cord Blood Bank Network in Italy.
Authors: Paola Saracco, Letizia Lombardini, Maria Screnci, Laura Salvaneschi, Anna Tamburini, Riccardo Saccardi, Simonetta Pupella, Mauro Pagliarino, Paola Bargamaschi, Serena Urbani, Luigina Fazio, Alberto Bosi, Giuliano Grazzini, Alessandro Nanni Costa
Journal: Blood (2009)
Long-term use of fentanyl pectin nasal spray in patients with breakthrough pain in cancer.
Authors: Donald Taylor, Lukas Radbruch, Julia Revnic, Luis M. Torres, John E Ellershaw, Michael Sidney Perelman
Journal: Journal of Clinical Oncology (2013)

9563 Background: Given that patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use. The objective of this study was to investigate the use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients taking regular opioid therapy. Methods: A total of 401 adult patients, taking at least 60 mg/day oral morphine or equivalent, with an average of 1 to 4 episodes of BTPc per day, who were either newly enrolled or had completed a randomized controlled trial with FPNS, entered into an open-label assessment study (NCT00458510). Of these, 171 patients, continued into an extension period. Up to 4 episodes of BTPc per day were treated with FPNS at titrated doses between 100 µg and 800 µg. Patients returned to the clinic at 4-week intervals for assessment and reporting of any adverse events (AEs). Results: There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for more than 1 year, while the maximum duration was 3 years and 8 months. In total, 2% of patients withdrew from the study due to lack of efficacy. Seventy-four percent of patients did not change their FPNS dose. The most common AEs, aside from disease progression, were: insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of treatment-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced treatment-related nasal AEs, which, with the exception of 1 severe event, were all mild or moderate. Conclusions: FPNS appeared to provide a sustained benefit and was well tolerated during the long-term treatment of BTPc. Clinical trial information: NCT00458510.
Personalized gene expression profiling-guided (MAGE) therapy in heavily treated metastatic breast cancer (MBC): A pilot study.
Authors: Manuel Sureda, Joseba Rebollo, Elena Ma Martínez, Francisco J. Fernández-Morejón, Vicente Munoz, Ramon Gonzalez Manzano, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2015)

e22071 Background: Genomic-based profiling of tumors constitutes an encouraging approach that favors the selection of active regimens minimizing the possibility of futile therapies. Previous experience with this technique has been reported (ASCO'12 # 3,064; Am J Clin Oncol. 2014). In MBC, general condition of the pts, the multiplicity of existing therapies and the heterogeneity of the regimes employed in the current practice makes the impact of the personalized approach specially relevant. Methods: Pts with previously treated progressive MBC, a life expectancy of 3 mo and non bone metastatic lesions had immediately frozen biopsies, RNA isolation and quality validation after confirmation of viable tumor in more than 30% of the sample. mRNA was hybridized to a whole human genome oligonucleotide microarray. Genes related to the sensitivity and resistance profile for the most frequently used drugs were studied in tumor and normal tissue to evaluate the differential expression associated with malignant phenotype. Therapy was selected according to MAGE profiling, drug availability, and patient’s acceptance. RECIST (v1.1) criteria were used to define clinical response. PFS and OS were evaluated according Kaplan Meier method. Results: From Nov 2010 to Oct 2014, 27 procedures of MAGE were performed in 24 pts. Previous treatment included a median of 4 lines of therapy (1-8), considering all the hormone manipulations as a unique line. MAGE profiling revealed a median of 8 (4-16) potentially active drugs, most of them commercially available. Partial Response was observed in 13/24 pts (54%); Disease Stabilization in 8/24 (33%) and Progression in 3/24 (12%). Actuarial median PFS were 10 mo (95% CI 8.34-11.65) and 3 mo (95%CI 1.8-4.23) for PR and DS respectively. Actuarial OS for the entire series was 15 mo (95% CI 8,28-21,72). Conclusions: MAGE-guided treatment in MBC heavily treated pts is feasible and offers encouraging possibilities to guide antitumor therapy in this setting. It reduces empirical exposure to inactive drugs and favours more tolerable and effective treatments in a frail population, requiring special efforts in order to improve quality of life and life span. Further studies are warranted.
The Clinical Utility of FDG PET-CT in Evaluation of Bone Marrow Involvement by Diffuse Large B Cell Lymphoma
Authors: Hyo Jung Kim, Boram Han, Dok Hyun Yoon, Ho Young Kim, Shin Kim, Min Young Kang, Hee Sung Hwang, Young Kyung Lee, Dae Young Zang, Cheolwon Suh
Journal: Blood (2011)
Influence of KRAS status, pattern of metastatic disease and age on survival in stage IV colorectal cancer.
Authors: Lynda M. O'Riordan, MinYuen Teo, Cliona O'Donnell, Jane Sze Yin Sui, Sarah Louise Picardo, Deirdre Kelly, Michael Thomas McCarthy, John McCaffrey
Journal: Journal of Clinical Oncology (2015)

e14683 Background: Colorectal cancer remains a significant cause of cancer related mortality worldwide. KRAS status has been used as a negative predictive marker. Its effect on the natural history of advanced disease remains to be clarified. The aim of this study is to examine patterns of metastatic disease at presentation and progression, as well as the interaction with age, resectability and overall survival. Methods: We conducted a retrospective review of patients treated with 5FU based doublet chemotherapy at our institution between 2011-2014. Data gathered included age at diagnosis, sites of metastatic disease at presentation, histology, chemotherapy regimens, duration of response, and patterns of progression. Data was analysed using standard statistical methods Results: 59 patients were identified. The median age at diagnosis was 60. The most frequently used chemotherapy regimen was FOLFOX, and all eligible patients ultimately received targeted agents. 58% of patients were KRAS-wild type(WT), 32% KRAS-mutated(mt), and in 8% it was not tested. 75% of patients had 2 or more sites of metastatic disease at presentation, which was not significantly different between KRAS-WT and KRAS-mt groups, or age (p = 0.492 and p = 0.729 respectively). Looking at sites of metastatic disease, 40% of KRAS-mt patients had 1 site of non-regional lymph node metastasis compared to < 10% in KRAS-WT(p = 0.041), although there was no statistical difference when age was analysed(p = 0.472). At the time of disease progression 90% of KRAS-mt patients progressed within an existing site of disease, compared to 70% in the KRAS-WT group (p = 0.393). 30% of the KRAS-WT group and 37% of the KRAS-mt group had surgical resection of sites of disease. Overall survival for the KRAS-WT group was 38 months, versus 32.7 months for the KRAS-mt group, p = 0.554. Conclusions: This study shows that age or KRAS status do not influence survival in our patient population. Site and distribution of metastatic disease was equal between the two groups. Our excellent survival is contributed to by the proactive approach taken by our surgical colleagues in resecting sites of metastatic disease, combined with the increasing range of systemic therapies available to us.
A phase I trial of ABT-751 and carboplatin (C) in patients (pts) with previously treated non-small cell lung cancer (NSCLC)
Authors: K. H. Dragnev, J. R. Rigas, W. M. Disalvo, S. A. Simeone, A. E. Hagey, G. B. Gordon, E. Dmitrovsky
Journal: Journal of Clinical Oncology (2006)

17098 Background: NSCLC is the leading cause of cancer mortality for men and women in the United States. More effective treatments are needed to prolong survival and improve quality of life. Platin-containing chemotherapy doublets are commonly used in NSCLC treatment. ABT-751 is a novel oral anti-microtubule agent targeting the colchicine binding site. As single agent, it was well-tolerated and showed a preliminary signal of activity in previously treated NSCLC. In vivo studies demonstrated additive activity between ABT-751 and cisplatin in a NSCLC xenograft model. Methods: A phase I trial of ABT-751 and C was conducted in pts with advanced previously treated NSCLC. Primary objective - maximum tolerated dose (MTD). Secondary objectives - toxicities, efficacy, and surrogate markers of response (cell cycle changes and cyclin D1 expression) in buccal swabs from pts at the phase II dose. Six dose levels - 1: ABT-751 100mg bid, C AUC 4.5; 2: ABT-751 125 mg bid, C AUC 4.5; 3: ABT-751 125 mg bid, C AUC 6; 4: ABT-751 150 mg bid, C AUC 6; 5: ABT-751 175 mg bid, C AUC 6; 6: ABT-751 200 mg bid, C AUC 6. ABT-751 was taken orally twice a day for 14 days in a 21 day cycle, C was administered intravenously on day 4 during cycle 1 and on day 1 on subsequent cycles. Rapid dose escalation was used for the first 3 dose levels followed by cohorts of at least 3 patients for the remaining dose levels. Results: Eight pts were enrolled, all stage IV NSCLC, 4 women, median age 62 (47–73), all KPS 80, 6 had one and 2 had 2 prior therapies. A median of 3.5 (1–4) cycles was administered. Dose-limiting toxiticies of grade 3 fatigue and grade 4 thrombocytopenia and neutropenia were observed in 2/5 patients on dose level 4. Common grade 2 toxicites were constipation and peripheral sensory neuropathy (levels 2–4). MTD was dose level 3. Seven pts were evaluable for response, 2 had partial responses (levels 2 and 4, both had one prior therapy), 4 had stable disease, 1 had disease progression. Median time to progression was 18.7 weeks (6–24+). Pharmacokinetic analyses and buccal swabs are being performed. Conclusions: The recommended phase II doses are ABT-751 125 mg twice daily for 14 days and carboplatin AUC 6 on a 21-day cycle. This regimen is well tolerated and shows preliminary evidence of activity for previously treated NSCLC. [Table: see text]
Patterns of antidepressant use in cancer patients (pts): An analysis from SOAPP (ECOG E2Z02: Symptom Outcomes and Practice Patterns).
Authors: Judith Manola, Fengmin Zhao, Andrew H. Miller, William F. Pirl, Lynne I. Wagner, Michael Fisch
Journal: Journal of Clinical Oncology (2012)

9016 Background: Antidepressant (AD) use is common in outpatient oncology, but the pattern and determinants of prescribing for commonly used AD are unknown. Methods: 3106 pts with cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites in a study of symptoms. Five depression case-finding methods were explored : 3 based on MDASI items reported by patients (1) sadness/ depression&gt;=4, (2) distress&gt;=4, (3) interference with mood&gt;=7 or enjoyment&gt;=7; 2 based on clinician’s report (4) presence of psychological distress, (5) depression being listed as one of top 3 symptoms. AD use (excluding tricyclic antidepressants and psychostimulants) was examined by depression status. Logistic regression models were used to examine the effect of demographic and clinical characteristics on AD use. Results: Rates of depressive symptoms varied by casefinding method (1=29%, 2=28%, 3=14%, 4=24%, 5=11%); 47% (1457) pts were defined as having depressive symptoms by at least one method. AD were prescribed in 25% of depressed pts compared to 14% of non-depressed pts. After adjusting for other covariates, factors associated with greater use of AD included depression (OR=1.7, P&lt;0.01), family history of depression (OR=2.2, P&lt;0.01), female sex (OR=1.8, P&lt;0.01), younger age (OR=1.2, P=0.04), non-Hispanic White race (OR=2.0, P&lt;0.01), prior chemo/immune/ hormonal treatment (OR=1.5, P&lt;0.01), more concurrent medication use (OR=3.3, P&lt;0.01), anxiolytics use (OR=2.0, P&lt;0.01), sedative use (OR=2.1, P&lt;0.01), receiving counseling (OR=1.6, P=0.04), patient’s perception of poor QOL (OR=1.3, P=0.02), duration of current treatment &gt;1 year (OR=1.6, P&lt;0.01), and being enrolled by a CCOP (OR=1.8, P=0.01). These significant associations remained regardless of the case-finding method used for depression, with only slight changes in the magnitude of ORs. Conclusions: Depressive symptoms are common in outpatients with cancer. One-fourth of solid tumor pts with depressive symptoms are taking an AD. Antidepressant prescribing varies by type of institution, race/ethnicity, age, concomitant medication exposure and several other clinical factors.
Role of cMET expression in non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.
Authors: Hyun Chang, Xianglan Zhang, Da Rae Kim, Gun Min Kim, Se Hyun Kim, Joo-Hang Kim, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2012)

e18092 Background: We performed this study to investigate whether activation of cMET is associated with sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. Methods: This retrospective study included 69 NSCLC patients with available tumor tissue, treatment response and survival data. cMET and hepatocyte growth factor (HGF) status was evaluated by immunohistochemistry. Results: A positive cMET, cMET[pY1003], cMET[pY1234/1235] and HGF were identified in 89%, 44%, 20% and 89% of cases, respectively. Positive cMET[pY1003] expression was associated with better objective response rate (OR) and clinical benefit rate (CBR) (OR, P = 0.033 and CBR, P = 0.039). Positive cMET[pY1234/1235] was significantly associated with a longer overall survival (OS) (P = 0.012) and time-to progression (TTP) (P = 0.031). Multivariable model confirmed that cMET[pY1234/235]-positive patients had a significant reduction in the risk of death and disease progression than cMET[pY1234/1235] –negative patients [OS; hazard ratio(HR)=0.29, P = 0.008 and TTP; HR=0.43; P=0.024] Conclusions: cMET expression in tumor tissue could be useful for predicting the clinical outcome of EGFR-TKIs treatment. Our results suggest that cMET expression in tumor tissue could be used to refine the selection of NSCLC patients expected to benefit from EGFR-TKIs treatment.
Phase II trial evaluating a 2 weekly regimen of irinotecan (IR) and 5-FU/leucovorin (LV) in patients with metastatic pancreatic cancer refractory to chemotherapy
Authors: M. Ng, A. R. Norman, D. Cunningham, J. Waters, J. Oates, P. Ross
Journal: Journal of Clinical Oncology (2004)

4229 Background: Advanced pancreatic cancer has a poor prognosis despite treatment with gemcitabine. There is no established second line therapy and few trials have addressed this. IR is active in pancreatic cancer and exhibits synergy with 5-FU in preclinical studies. We conducted a phase II trial to evaluate the efficacy and toxicity of a 2 weekly regimen of IR combined with 5-FU/LV in relapsed and refractory metastatic pancreatic cancer. Methods: Patients with metastatic disease who progressed during chemotherapy or within 3 months of completion were recruited. IR (180mg/m2), LV (125mg/m2) and 5-FU (400mg/m2 bolus followed by 1200mg/m2 48hour infusion) were given 2 weekly to a maximum of 24 weeks. Response was evaluated after 12 weeks of treatment by CT. Treatment was stopped at disease progression or unacceptable toxicity. Results: Fifteen patients (7M,8F) were recruited and 13 were evaluable for response. The median age was 60 years (36 – 71). All patients were ECOG performance status 0–2. Thirteen patients had previously received gemcitabine alone or as a combination, nine patients had received 5-FU based regimens and five patients had ≥ 2 lines of prior treatment. A median of 5 cycles was given (2–12). Five patients (38%) had SD of whom 3 had reduction in CA19–9 levels > 30%. Eight patients had PD and two died (pulmonary embolism and peritonitis). The median failure free survival (FFS) was 76 days (95% CI 39–112) and FFS at 1 year was 8.3% (95% CI 6.9–48.8). The median overall survival (OS) was 97 days (95% CI 77–116) and OS at 1 year was 18.7% (95% CI 3.3–44). Median duration of disease stabilisation was 181days (82–249). Fourteen patients were evaluable for toxicity, 50% had grade 3/4 neutropenia and 14% had grade 3 neutropenic sepsis. 28% had grade 3 lethargy, 14% had grade 3 diarrhoea and 7% had grade 3 stomatitis. Pain control improved in 4/11 patients, anorexia and weight loss improved in 3/4 patients. Conclusions: The combination of 2 weekly IR and 5-FU/LV produces disease stabilisation, CA19–9 response and symptom improvement in this chemoresistant population with encouraging survival rates at one year. No significant financial relationships to disclose.
Vital Directions for Health and Health Care
Authors: Victor J. Dzau, Mark B. McClellan, J. Michael McGinnis, Sheila P. Burke, Molly J. Coye, Angela Diaz, Thomas A. Daschle, William H. Frist, Martha Gaines, Margaret A. Hamburg, Jane E. Henney, Shiriki Kumanyika, Michael O. Leavitt, Ruth M. Parker, Lewis G. Sandy, Leonard D. Schaeffer, Glenn D. Steele, Pamela Thompson, Elias Zerhouni
Journal: JAMA (2017)

Recent discussion has focused on questions related to the repeal and replacement of portions of the Affordable Care Act (ACA). However, issues central to the future of health and health care in the United States transcend the ACA provisions receiving the greatest attention. Initiatives directed to certain strategic and infrastructure priorities are vital to achieve better health at lower cost.To review the most salient health challenges and opportunities facing the United States, to identify practical and achievable priorities essential to health progress, and to present policy initiatives critical to the nation's health and fiscal integrity.Qualitative synthesis of 19 National Academy of Medicine-commissioned white papers, with supplemental review and analysis of publicly available data and published research findings.The US health system faces major challenges. Health care costs remain high at $3.2 trillion spent annually, of which an estimated 30% is related to waste, inefficiencies, and excessive prices; health disparities are persistent and worsening; and the health and financial burdens of chronic illness and disability are straining families and communities. Concurrently, promising opportunities and knowledge to achieve change exist. Across the 19 discussion papers examined, 8 crosscutting policy directions were identified as vital to the nation's health and fiscal future, including 4 action priorities and 4 essential infrastructure needs. The action priorities-pay for value, empower people, activate communities, and connect care-recurred across the articles as direct and strategic opportunities to advance a more efficient, equitable, and patient- and community-focused health system. The essential infrastructure needs-measure what matters most, modernize skills, accelerate real-world evidence, and advance science-were the most commonly cited foundational elements to ensure progress.The action priorities and essential infrastructure needs represent major opportunities to improve health outcomes and increase efficiency and value in the health system. As the new US administration and Congress chart the future of health and health care for the United States, and as health leaders across the country contemplate future directions for their programs and initiatives, their leadership and strategic investment in these priorities will be essential for achieving significant progress.
Effect of metformin and statins in high-grade brain tumors.
Authors: Guek Eng Lee, Iain B. Tan, Chee Kian Tham
Journal: Journal of Clinical Oncology (2013)

2091 Background: Metformin and statins are thought to have anti-cancer properties. Metformin induces AMPK activation and may be implicated in potentiating the therapeutic outcome of temazolamide. Statins at low dose are thought to have anti-cancer properties by inhibiting pro-angiogenic factors with resultant inhibition of tumor growth, but statins at high dose are thought to have counter-productive effects. Hyperglycaemia was shown to be associated with a poorer outcome in patients with newly diagnosed glioblastoma. Hence we investigate the effect of metformin and statins in high grade brain tumours. Methods: Among 249 patients with brain tumour, we identified 142 patients with high grade gliomas. 116 patients did not receive metformin or statins and 26 patients received metformin or statins. Patients’ demographics, clinical and histopathological characteristics were recorded. Overall survival was evaluated. Results: Among 142 patients with high grade gliomas, there were 86 patients with glioblastoma multiforme, and 56 patients with anaplastic astrocytoma or anaplastic oligodendroma. Median age was 60 years old. The average value of HbA1c value for patients on metformin was 7.2%. The average dose of simvastatin used was 20 mg and average total cholesterol was 5.1mmol/l. For patients who did not receive metformin or statins, the median survival was 72.9 months (95% confidence interval, 47.8 – 98.1); patients who received metformin or statins, the median survival was 39.1 months (95% confidence interval, 21.7 – 56.4) p = 0.24. Conclusions: There is a trend towards shorter overall survival of patients who received metformin and statins. Despite the anti-cancer properties of metformin and statins, patients with diabetes mellitus and hyperlipidaemia still fare worse. The effect of diabetes mellitus, hyperlipidaemia, as well as sugar and cholesterol control deserves a larger cohort study in patients with high grade brain tumours.