tbuckley/cabot-search huggingface dataset:
The addition of chemotherapy to adjuvant therapy in patients with intermediate risk HNSCC may cause harm.
Authors: Siddharth Sheth, Doug Farquhar, Maheer Masood, Andrew F Olshan, Trevor Hackman, Jared Weiss
Journal: Journal of Clinical Oncology (2018)

e18057 Background: In the phase III EORTC 22391 and RTOG 95-01 trials, HNSCC patients who had extracapsular extension (ECE) and/or positive surgical margins (PSM) were found to have improved survival outcomes following adjuvant therapy (AT) with concurrent chemoradiation (CRT) compared to radiation therapy (RT) alone. Optimal treatment of HNSCC with other unfavorable clinical or pathologic outcomes remains controversial. Using a large database of HNSCC patients in North Carolina, we categorized patients based on their surgical pathologic risk factors and described treatment patterns and associated survival outcomes. Methods: Patients were identified from the Carolina Head and Neck Cancer Study (CHANCE). Based on pathology features, patients were divided low risk (n = 236), intermediate risk (n = 209), and high risk (n = 258). High risk included all patients with ECE and/or PSM. Intermediate risk was defined as pathological T3/T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), or positive lymph nodes without ECE. Kaplan-Meier curves were constructed and stratified by pathologic risk characteristics. Hazard ratios (HR) were calculated by Cox proportional hazard models. Results: We identified 703 HNSCC patients who received primary surgical resection. Only 31% of high-risk patients received CRT compared to 49% who received RT. In intermediate risk patients, 22% received CRT, 48% received RT and 30% had no AT. High-risk patients who received AT compared to no AT trended towards inferior 3- and 5- year OS (p > 0.05). Conversely, we found that intermediate risk patients who received adjuvant CRT had increased risk of mortality (HR 1.4) compared to no AT or RT alone. Conclusions: Our results show widespread practice variation in HNSCC patients receiving AT based on their pathologic risk features. Particularly striking is the low rate (31%) of high risk patients receiving CRT despite standard of care guidelines. Our retrospective data raises the hypothesis of harm to intermediate risk patients when chemotherapy is added to AT. These worse outcomes may be related to treatment associated side effects and baseline patient characteristics. Further analyses are planned to evaluate these observations.
Clinical and economic outcomes associated with sequential treatment in <i>BRAF</i> mutant advanced melanoma patients.
Authors: Ahmad A. Tarhini, David F. McDermott, Apoorva Ambavane, Komal Gupte-Singh, Corey Ritchings, Valerie Aponte-Ribero, Agnes Benedict, Sumati Rao, Meredith M. Regan, Michael B. Atkins
Journal: Journal of Clinical Oncology (2018)

9538 Background: Patients with BRAF mutant advanced melanoma can use immunotherapies (IO) and BRAF+MEK inhibitors. We evaluated the clinical and cost outcomes associated with treatment sequences for BRAF mutant advanced melanoma. Methods: A discrete event simulation was developed to estimate cost (USD) and life-years (LYs), over patient lifetime. In the absence of head-to-head trial data, a matching adjusted indirect treatment comparison (MAIC) was conducted. Treatment sequences and corresponding efficacy data sources are presented below (table). Safety and cost data were obtained from published literature. Results: Treatment sequences starting with IO followed by BRAF+MEK appear to be associated with 3.7–5.2 years of additional survival vs sequences starting with BRAF+MEK followed by IOs. This was primarily due to a longer treatment-free interval (TFI) of 2.5–4.4 years after first-line (1L) IOs and longer time on BRAF+MEK as second-line (2L) post-IO therapy. LYs and TFI were higher with sequences starting with anti-PD-1+anti-CTLA-4 vs anti-PD-1 alone. Sequences starting with anti-PD-1+anti-CTAL4 ($77,918) or anti-PD-1 monotherapy ($85,813) had lower average cost/LY compared to BRAF+MEK ($107,266). Conclusions: Initiating 1L treatment with IO appeared to provide longer survival benefit compared to BRAF+MEK, driven by long TFI and, in many cases, lack of subsequent therapy need, leading to lower average cost/LY. Because these data may be biased by unaccounted for and unknown factors, findings will require validation in prospective randomized clinical trials (EA6134 - NCT02224781). 1L 2L Total Costs ($) Total LYs Cost per LY ($) BRAF+MEK1 Anti-PD-12 $345,693 3.22 $107,266 Anti-PD-1+Anti-CTLA-43 BRAF+MEK3 $656,692 8.43 $77,918 Anti-PD-13,a BRAF+MEK3 $595,727 6.94 $85,813 Sources: 1. MAIC, COMBI-v & COMBI-d (23.8 & 23 m) 2. CheckMate 037 (24 m), KEYNOTE-002 (10 mb). 3. CheckMate 067 & 069 (25.7 & 16.9 m). Notes: m, mean months; BRAF+MEK, dabrafenib+trametinib; Anti-PD-1+Anti-CTLA-4, nivolumab+ipilimumab; Anti-PD-1: nivolumab/pembrolizumab; aPembrolizumab assumed similar efficacy as nivolumab; bMedian.
Abstract 19010: Low HDL-C Carries Residual Risk Even at Target LDL-C Among Patients in the Cholesterol Treatment Trialists' Collaboration Studies
Authors: Anthony C Keech, Robert Rosenson, Elizabeth Barnes, Frank Sacks, John Simes, H A Neil
Journal: Circulation (2010)

Background: For patients treated to reduce lipid-mediated risk, statins are first-line therapy to achieve low levels of LDL-c. Although low HDL-c levels and elevated TGs are associated with higher ...
TCT-117 The Burden of Restenosis after Coronary Stent Implantation in the United States: Temporal Trends, Clinical Presentation, Treatment Strategies, and In-Hospital Outcomes
Authors: Issam Moussa, Gregg Stone, Paul Teirstein, Kevin Kennedy, Martin Leon, Antonio Colombo, Robert Yeh, Jeffrey W. Moses, John Spertus
Journal: Journal of the American College of Cardiology (2018)
Determination of the potential of detecting 3q gain as a valuable biomarker in the management of patients with human papilloma virus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Upendra P. Hegde, Eric Kershnar, Robert Dowsett, Sophie Masternak, Yogita Verma, Triantafyllos Tafas, Michael Kilpatrick
Journal: Journal of Clinical Oncology (2017)

e17534 Background: The most recurrent structural chromosomal aberration in HPV associated cervical cancer is gain of the 3q26 locus testing of which has clinical utility in management of patients with cervical lesions. A significant proportion of OPSCC are HPV mediated, suggesting the possibility of a common disease mechanism. The objective of this study is to determine the potential clinical validity of assessing 3q gain as a biomarker in the management of patients with HPV associated OPSCC. Methods: An oral swab using a cytological brush was obtained of the region containing visualized tumor site in newly diagnosed HPV associated OPSCC patients following written informed consent of an IRB approved protocol at the University of Connecticut. The swabs were obtained at the diagnosis and serially after chemotherapy and/or chemo-radiotherapy as well as at 3 months after treatment completion. The specimens’ 3q gain status was determined by fluorescent in situ hybridization (FISH) analysis, utilizing robotic fluorescence microscopy for detection of rare cells demonstrating high 3q26 copy number Results: 54 specimens were collected from 13 patients, of which slides were prepared, hybridized and analyzed from 50. Data was not available in four specimens due to insufficient cells while for eight patients, multiple specimens were obtained before, during and after 3 months of treatment. Depending on the specimen’s cellularity, up to 170,969 cells were analyzed. Cells with &gt; 4 copies of the 3q26 locus were detected in 32 of the 50 analyzable specimens. For several patients, the number of cells with more than four 3q26 signals detected in the later time points of treatment was lower than the number detected at diagnosis. Conclusions:This preliminary dataset demonstrates the ability to detect gain of the 3q26 locus in cells collected by cytological brushing of the region containing an OPSCC. The approach offers the possibility of a minimally invasive method to determine the 3q26 gain status as a reliable biomarker of HPV associated OPSCC that might have value in early diagnosis and management.
Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome
Authors: Xiao-Kun Li, Qing-Bin Lu, Wei-Wei Chen, Wen Xu, Rong Liu, Shao-Fei Zhang, Juan Du, Hao Li, Ke Yao, Di Zhai, Pan-He Zhang, Bo Xing, Ning Cui, Zhen-Dong Yang, Chun Yuan, Xiao-Ai Zhang, Zhe Xu, Wu-Chun Cao, Zeping Hu, Wei Liu
Journal: Science Translational Medicine (2018)

Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome.
A phase II clinical trial of metformin as a cancer stem cell targeting agent in stage IIc/III/IV ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Ronald J. Buckanovich, Jason Brown, Jessica Shank, Kent A. Griffith, R. Kevin Reynolds, Carolyn Johnston, Karen McLean, Shitanshu Uppal, J. Rebecca Liu, Lourdes Cabrera, Geeta Mehta
Journal: Journal of Clinical Oncology (2017)

5556 Background: Epidemiologic and preclinical studies suggest that Metformin has antitumor effects which may be due to an impact on cancer stem-like cells (CSC). We present a phase II trial of metformin administered in combination with chemotherapy for patients with advanced stage epithelial ovarian cancer (EOC). Primary endpoints were 18 month progression free survival (PFS) and CSC number in Metformin treated tumors. Methods: Thirty-eight patients with confirmed stage IIC(n=1)/III(n=25)/IV(n=12) EOC were treated with either neoadjuvant metformin followed primary debulking surgery and adjuvant Metformin+chemotherapy, or neo-adjuvant metformin+chemotherapy, followed by interval debulking and adjuvant chemotherapy+Metformin. Patients were evaluated for side effects, PFS and overall survival (OS). Metformin treated tumors were evaluated for the presence of CSC via FACS and sphere assays. Results: Thirty-two patients (84%) completed at least six cycles of metformin+chemotherapy. Metformin was well tolerated with only one grade III/IV treatment-related adverse event (3%) noted. Common adverse effects were diarrhea (18%) and nausea (16%). Eighteen month PFS was 65.4% (95% confidence interval 47.9-78.3), Median PFS was 21.7 months (CI-17-26.7). Estimated three year OS was 73.5% (CI-54.7-84.3) with median OS not reached after a media follow-up of 33 months. Finally, tumors treated with metformin were noted to have a 3-fold decrease in ALDH+ CSC at baseline, increased sensitivity to Cisplatin in vitro, and a reduced ability to amplify ALDH+ CSC with passage in vitro. Conclusions: This is the first prospective study of Metformin in EOC patients. Translational studies confirm an impact of metformin on CSC. Metformin was well tolerated and outcome results were favorable, supporting the use of Metformin in phase-III studies. Clinical trial information: NCT01579812.
Loss of somatostatin receptor 2 expression and cellular metabolism and survival in small cell lung cancer.
Authors: Jonathan Lehman, Megan Hoeksema, Jun Qian, Heidi Chen, Chanjuan Shi, Rosana Eisenberg, Pierre P. Massion
Journal: Journal of Clinical Oncology (2016)

e20090 Background: Small cell lung cancer (SCLC) is a high grade poorly differentiated neuroendocrine carcinoma responsible for ~15% of diagnosed lung cancers and up to 25% of lung cancer deaths. Treatment paradigms are unchanged over the last 20 years. Advances in targeted therapies are sorely needed. Somatostatin receptors (SSTR) are neuroendocrine associated G protein-coupled receptors with effects on cell cycling, angiogenesis, apoptosis, and growth factors. They signal by inhibition of adenylate cyclase, calcium influx, and downstream kinases including MAPK and Akt. Methods: We evaluated existing CCLE and tumor RNA data for SSTR2 expression and evaluated IHC staining and western blotting of multiple neuroendocrine cell lines and tumor tissues including patient derived xenografts. We assessed SSTR2 expression and overall survival in a 98 patient SCLC cohort. We established multiple SCLC SSTR2 shRNA knockdown lines and evaluated cell viability, apoptosis,in vivo and in vitro growth, downstream phosphorylation, and metabolic characteristics via measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Results: SSTR2 is highly expressed in many SCLC tumors and cell lines by RNAseq, western blotting, and IHC. Low SSTR2 expression in our 52 limited stage patients was associated with improved survival with a hazard ratio of 0.45 with p < 0.05. SSTR2 knockdown led to up to 3 fold changes in cell viability in vitro in multiple cell culture lines, increased apoptosis, and strong selective pressure for SSTR2 expressing clones in vivo. Metabolic testing showed significant differences in mitochondrial activity in the SSTR2 knockdown cell lines with a slightly increased basal metabolic rate and a greater than 75% increase in maximal respiration compared to the control scrambled construct cell line. This matches array data showing decreased pAMPKa with a decrease in SSTR2 levels. Conclusions: Aberrant energy homeostasis may contribute to cell death in SCLC via neuroendocrine pathways. Collectively, this data brings new interest to SSTR2 signaling as a pathway target for therapy in a subset of SCLC and suggests future metabolic targets in SCLC.
Hepatocyte‐Specific β‐Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes
Authors: Jacquelyn O. Russell, Wei‐Yu Lu, Hirohisa Okabe, Marc Abrams, Michael Oertel, Minakshi Poddar, Sucha Singh, Stuart J. Forbes, Satdarshan P. Monga
Journal: Hepatology (2018)

Liver regeneration after injury is normally mediated by proliferation of hepatocytes, although recent studies have suggested biliary epithelial cells (BECs) can differentiate into hepatocytes during severe liver injury when hepatocyte proliferation is impaired. We investigated the effect of hepatocyte‐specific β‐catenin deletion in recovery from severe liver injury and BEC‐to‐hepatocyte differentiation. To induce liver injury, we administered choline‐deficient, ethionine‐supplemented (CDE) diet to three different mouse models, the first being mice with deletion of β‐catenin in both BECs and hepatocytes ( Albumin‐Cre; Ctnnb1flox/flox mice). In our second model, we performed hepatocyte lineage tracing by injecting Ctnnb1flox/flox ; Rosa‐stopflox/flox‐EYFP mice with the adeno‐associated virus serotype 8 encoding Cre recombinase under the control of the thyroid binding globulin promoter, a virus that infects only hepatocytes. Finally, we performed BEC lineage tracing via Krt19‐CreERT ; Rosa‐stopflox/flox‐tdTomato mice. To observe BEC‐to‐hepatocyte differentiation, mice were allowed to recover on normal diet following CDE diet–induced liver injury. Livers were collected from all mice and analyzed by quantitative real‐time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. We show that mice with lack of β‐catenin in hepatocytes placed on the CDE diet develop severe liver injury with impaired hepatocyte proliferation, creating a stimulus for BECs to differentiate into hepatocytes. In particular, we use both hepatocyte and BEC lineage tracing to show that BECs differentiate into hepatocytes, which go on to repopulate the liver during long‐term recovery. Conclusion : β‐catenin is important for liver regeneration after CDE diet–induced liver injury, and BEC‐derived hepatocytes can permanently incorporate into the liver parenchyma to mediate liver regeneration.
Obesity in metastatic colorectal cancer: Pooled analysis of FFCD trials.
Authors: Thomas Aparicio, Emilie Maillard, Michel Ducreux, Olivier Bouche, Philippe Rougier, Aimery De Gramont, Sylvain Manfredi, Thierry Lecomte, Pierre-Luc Etienne, Laurent Bedenne, Jaafar Bennouna, Jean Marc Phelip, Eric Francois, Pierre Michel, Jean-Louis Legoux, Mohamed Gasmi, Roger Faroux, Gilles Breysacher, Come Lepage, Jean Francois Seitz
Journal: Journal of Clinical Oncology (2016)

3532 Background: Previous studies showed that high and low body mass index (BMI) are associated with worst prognosis in early-stage colorectal cancer (CRC) and low BMI is associated with a worst prognostic in metastatic CRC (mCRC). We aimed to assess obesity according to time, efficacy outcomes according to BMI, dose reduction in obese patients (pts). Methods: A pooled analysis of individual data from 2085pts enrolled into 8 FFCD first line mCRC trials from 1991 to 2013 was performed. Obese pts (BMI ≥ 30) were compared to normal or overweight pts (BMI: 18.5-29). Skinny pts (BMI < 18.5) were compared to pts with BMI > 18.5. Analyses were stratified by trials, overall pooled hazard ratios (HR and 95% CI) were calculated using a fixed effect model. Cochrane Q tests were used to study heterogeneity between trials: for all analyses trials were homogenous. Medians of survivals were calculated with the Kaplan-Meier method. Interaction tests were performed between obese effect and sex, age (≤ 70 vs > 70 years) and chemotherapy with antiangiogenics. Results: Twelve percent of the enrolled pts were obese (7.7% for 1991-1999, 14.5% for 2000-2006, 13.6% for 2007-2013). Comparison of obese pts vs pts with BMI 18.5-29 revealed a median overall survival (OS) of 19.5 vs 16.9 months(m), HR = 1.15 [1.00-1.33] p = 0.06, a median progression free survival (PFS) of 7.9 vs 7.3m, HR = 1.06 [0.93-1.22] p = 0.36, and an objective response rate (RR) of 42% vs 38.5%, OR = 1.02 [0.77-1.37] p = 0.87. A significant OS and RR improvement were observed in pts with BMI > 25 compared to pts with BMI 18.5-24: 18.5 vs 16.3m, HR = 1.13 [1.02-1.25] p = 0.02, and 42% vs 36% OR = 1.23 [1.01-1.50] p = 0.04 respectively. Subgroup analysis revealed that obesity was associated with better OS and PFS in men (p = 0.03, 0.05 respectively). OS and PFS were significantly lower in skinny pts HR = 0.75 [0.60-0.94] p = 0.01, and HR = 0.75 [0.60-0.93] p = 0.01 respectively. Dose reduction at the first cycle was more frequent in pts with BMI ≥ 30 vs BMI 18.5-29: 34% vs 17% p < 0.001 (especially in obese pts with bsa > 2m2). Conclusions: Overweight and obesity are significantly associated with better OS compared to normal weight in mCRC, mainly observed in men. The pejorative prognostic of a BMI < 18.5 is confirmed. A dose reduction is frequent in obese pts.
Incidence and characteristics of adrenal insufficiency following immune checkpoint inhibitor therapy for melanoma.
Authors: Logan Rhea, Suraj S. Venna, Sekwon Jang
Journal: Journal of Clinical Oncology (2018)

e22077 Background: Immune checkpoint inhibitors (ICI) have been approved for various malignancies including melanoma. Adrenal insufficiency (AI) is a rare but potentially life-threatening adverse event related to ICI. This can be either primary adrenal gland destruction or interference with corticotrophin (ACTH) secretion by the pituitary gland (secondary). We conducted a retrospective single center study to better understand the incidence, characteristics and outcomes of AI associated with ICI. Methods: We reviewed the medical records of patients with melanoma who received pembrolizumab, nivolumab, ipilimumab or the combination of ipilimumab and nivolumab at Inova Schar Cancer Institute between October 2014 and December 2017. Patients were identified to have AI if they had low morning serum cortisol. AI was classified as either primary (high ACTH) or secondary (low-normal ACTH) AI. Patients with secondary AI were evaluated for isolated ACTH deficiency or panhypopituitarism. Results: A total of 119 patients with melanoma received ICI. Fourteen patients (12%) were diagnosed with AI (median age of 65, 8 were male). All cases were found to be secondary AI. The median onset of AI from the first dose of ICI was 15 weeks (range: 7 ~33). The assessment of serum cortisol was prompted in patients who complained of new onset fatigue, nausea, headache, fever and/or dizziness. One patient was diagnosed during hospitalization for sepsis-like symptoms. All of the patients had rapid resolution of symptoms after hydrocortisone replacement. Ten patients had concurrent secondary hypothyroidism suggestive of panhypopituitarism whereas 4 patients had isolated ACTH deficiency. Among 12 patients alive as of February 2018, all remain on hydrocortisone replacement therapy at median follow up of 12.5 months (range: 1 ~34) from the onset of AI. Conclusions: ICI-associated AI developed in 12% of patients requiring ongoing hydrocortisone replacement therapy among survivors. With the increasing use of ICI therapy in advanced cancers and resultant durable responses, we expect the incidence of AI to also increase. Clinicians should be aware of the irreversible nature of ICI-induced AI to properly counsel patients.
Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework
Authors: Cristina Giuliani, Paolo Garagnani, Claudio Franceschi
Journal: Circulation Research (2018)

Human longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequences for biomedicine. The genetics of human longevity is still poorly understood despite several investigations that used different strategies and protocols. Here, we argue that such rather disappointing harvest is largely because of the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan seems to be the result of an intriguing mixture of gene-environment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological, and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status, and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as genome-wide association study and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as apolipoprotein E, Forkhead box O3, interleukin 6, insulin-like growth factor-1, chromosome 9p21, 5q33.3, and somatic mutations among others. The major results of this approach suggest that (1) the genetics of longevity is highly population specific; (2) small-effect alleles, pleiotropy, and the complex allele timing likely play a major role; (3) genetic risk factors are age specific and need to be integrated in the light of the geroscience perspective; (4) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the 3 genetics of human body, that is, nuclear, mitochondrial, and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.