tbuckley/cabot-search huggingface dataset:
The antidiarrheal efficacy of a proprietary amino acid mixture in neuroendocrine tumor (NET) patients.
Authors: Laura Luque, Aman Chauhan, Qian Yu, Rachel C Miller, Heidi Weiss, Fariha Siddiqui, Zackary Tarter, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2018)

218 Background: Gastroenteropancreatic neuroendocrine tumor (GEPNET) incidence has risen 6-fold over past 3 decades. North American Neuroendocrine Tumor Society estimates that over 100,000 GEPNET patients are currently living in the United States. One of the common quality of life limiting symptom seen in GEPNET patient is diarrhea. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. A novel amino acid based oral rehydration solution (enterade) is currently being evaluated in a Phase II clinical trial for antidiarrheal effects in post bone marrow transplant patients (NCT02919670). We conducted a pilot study of enterade in neuroendocrine tumor (NET's) patients with quality of life limiting diarrhea. Methods: Medical records of all the NET patients given enterade to alleviate symptomatic diarrhea were evaluated. Patients were treated at Markey Cancer Center between May 2017-June 2018. Results: Total 69 NETs patients were treated with enterade. Enterade was administered as 8 Oz bottle BID for 1 a week. Antidiarrheal efficacy data was available on 41 patients at the time of abstract submission. 15 patients had small bowel NETs, 5 had bronchial NETs, 1 had colorectal NETs, 3 had NETs of unknown primary, 3 had gastric NETS, 3 had pancreatic NETs and one had high grade neuroendocrine carcinoma of the prostate. Data regarding primary site was unavailable in 10/41 patients. 21 patients had history of prior bowel resection either for primary neuroendocrine tumor resection or debulking. 25 patients were on somatostatin analogs at the time of initiation of enterade. 31 out of 41 patients reported some reduction in diarrhea frequency. 21 out of these 41 patients reported at least a 50% reduction in diarrhea frequency. Conclusions: 75.6% (31/41) neuroendocrine tumor patients reported improvement in diarrhea frequency with enterade. 51.2% (21/41) reported more than 50% reduction in diarrhea frequency. A prospective Phase II study of enterade in neuroendocrine tumor patients with quality of life limiting diarrhea is currently planned.
Tracking tumor-specific mutations in plasma, saliva and para-carcinoma tissues from patients with head and neck squamous cell carcinomas.
Authors: Ping Wu, Yaoyun Tang, Yuhua Gong, Xuan Tao, Yanfang Guan, Ling Yang, Xuefeng Xia, Xin Yi, Chubo Xie
Journal: Journal of Clinical Oncology (2018)

6056 Background: In this study, tumor derived Cell-free DNA (cfDNA) is detected in plasma and saliva samples in head and neck squamous carcinomas (HNSCC), as well as genomic variants in para-carcinoma tissues (PCT). The utility of cfDNA and alterations in PCT to predict tumor relapse is evaluated. Methods: A cohort of 27 patients with HNSCC were enrolled, plasma and saliva samples collected pro and post surgery. Tumor samples and PCT were also taken at surgery for each patient. Targeted next generation sequencing with a panel of 1021 genes was performed on all samples. Results: Average number of somatic mutations in each tumor was 5.86 alterations (range, 1 to 13). Tumor-specific mutations were observed in 70% patients (n = 19) in plasma and 52% patients (n = 14) in saliva. At least one somatic mutation was identified in 73% (19 of 26) of PCT. TP53 was the most common mutated gene in all categories of sample. Tumor-specific DNA was detected in 94% of stage III-IV patients, comparing 67% of stage I-II. It is more likely to identified somatic mutations in plasma in hypopharyngeal carcinoma (90% in hypopharynx versus 50% in oral cavity and 64% in larynx). Approximately, they were more likely detected in saliva in oral cancer (83% in oral cavity versus 46% in larynx and 40% in hypopharynx). Disease free survival (DFS) was 50% in patients with detectable postoperative cfDNA in plasma and 86% in patients undetectable (HR = 8.09, P < 0.05). Similarly, patients (n = 7) with detectable postoperative cfDNA in saliva were significantly lower DFS than those patients undetectable (n = 20) (HR = 22.18, P < 0.01). Interestingly, patients whose PCT harbored more than one TP53 mutations or its frequency more than 5% have more tendency to relapse (P< 0.01). Conclusions: Tumor-specific mutations can be detected in cfDNA from plasma or saliva samples, including PCT, and tracking these mutations in cfDNA and in PCT can predict disease relapse after surgery in patients with HNSCC. Patients with cfDNA positive in post-surgery samples are at higher risk of relapse and are more likely to derive benefit from adjuvant treatment.
Preliminary clinical and pathologic characteristics of patients treated in second-line (2L) with 25 cycles (Cy) or more of FOLFIRI + Aflibercept (FA).
Authors: Carles Pericay, Nieves Purificacion Martinez, Monica Corral, Ismael Macias, Olga Donnay, Ignacio Juez, Beatriz García-Paredes, Jose Carlos Mendez, Diego Cacho, Beatriz Gonzalez Astorga, Ana Ruiz, Mayte Delgado, Nuria Rodriguez, Veronica Calderero, Elena Mata, Juan Antonio Barrera Ramirez
Journal: Journal of Clinical Oncology (2016)

e15023 Background: Studies in 2L metastatic colorectal cancer (mCRC) have survival ranging around 10-14 months (m). No study has averaged over 10cy. In daily practice, there is a subset of patients (pt) treated with FA with unknown characteristics receiving a number of cy higher than the average numbers of cy from the clinical trials. Chau et al. identified best-responders as those with ECOG0 with any metastatic site (MS) and those with ECOG1 with only one MS, but the number of cy received is unknown. Materials and Methods: Retrospective analysis based on the clinical records of Spanish mCRC pt receiving ≥ 25cy in 2L with FA to identify clinical and pathological features. Analyses were performed with SPSS (Statistical Package for the Social Science) for the progression-free survival (PFS) and overall survival (OS) curves. Results: Eighteen patients (male/female 9/9) were identified. Median age: 56years (39-68). All tumors were located in left colon: rectum 10pt, sigma 6pt, left 2pt. Histologic grade was well or moderately differenciate in 12pt. 7 pts had perineural or vascular invasion. RAS was mutated in 13pt and wild type in 5pt. Disease characteristics in 1L: MS at first diagnostic: 1 in 9pt (liver only 7pt, liver+other 7pt, lung only 1pt, lung+other 2pt). Oxaliplatin based CT was the treatment in 1L. Objective response rate (ORR) 77,8%. Bevacizumab was given in 12pt, anti-EGFR in 4pt. 1L PFS was 16.03m (15.14-16.91). 8 pts were resected from their metastases. Starting 2L: ECOG0 13pt; ECOG1 5pt (all with more than 1 MS). Number of MS: 1 in 6pt. (lung only 4pt, lung+other 8pt, liver+other 4pt). ORR was 61,1%. Median cy administred: CT 30 (12-50), Aflibercept 34 (25-50). Doses modification: CT 14pt, Aflibercept 4pt. OS 2L with 14 pt ongoing: 28.74m (25.85-31.64). Global OS since diagnosis: 46,67m (42,99-50,36). Conclusions: Long treatment duration can be achieved with FA, independently of the ECOG or the number of MS. In this series, all patients had a left-sided tumor and were mostly RAS mutant. The safety is in line with the VELOUR trial. Tumor location should be evaluated as a potential predictive factor. Funded by sanofi
Cost-effectiveness of nivolumab vs. ipilimumab/nivolumab vs. trifluridine/tipiracil or mFOLFOX6/cetuximab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer.
Authors: Jacqueline N. Chu, Jin G. Choi, Sassan Ostvar, James Anthony Torchia, Kerry Lynn Reynolds, Justin F. Gainor, Daniel C. Chung, Jeffrey W. Clark, Chin Hur
Journal: Journal of Clinical Oncology (2018)

e15134 Background: We use a decision analytic model to project the effectiveness and cost burden of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) treatment in the era of immunotherapy. Methods: We simulated the treatment of hypothetical patients with MSI-H/dMMR mCRC in two scenarios: patients refractory to two lines of chemotherapy, or untreated. We compared nivolumab, ipilimumab/nivolumab, trifluridine/tipiracil (third-line) and mFOLFOX6/cetuximab (first-line) based on the CheckMate 142, RECOURSE, and CALGB/SWOG 80405 trials. Results: Ipilimumab/nivolumab was the most effective strategy in both third- and first-line settings, and both checkpoint inhibitor therapies were more effective than chemotherapy (Table 1). However, neither checkpoint inhibitor therapy was cost-effective compared to chemotherapy in the base case due to maintenance nivolumab drug cost. Ipilimumab/nivolumab could be the most cost-effective strategy in both settings if treatment duration were limited to two years. Conclusions: Checkpoint blockade is significantly more effective for MSI-H/dMMR mCRC compared to third- and first-line chemotherapy, but is not cost-effective in either setting due to drug costs. Decreases in duration of maintenance nivolumab could make ipilimumab/nivolumab cost-effective. THERAPY COST, US$| UNADJ.LYs| QALYs| ICER, US$/QALY Third-line therapy Base case Trifluridine/tipiracil 90,700 0.74 0.07 Nivolumab 1,113,400 8.21 6.76 153,000 Ipilimumab/nivolumab 1,519,200 10.69 9.25 162,700 Treatment limited to two years Trifluridine/tipiracil 90,700 0.74 0.07 Nivolumab 264,000 8.21 6.76 Weakly dominated Ipilimumab/nivolumab 298,900 10.69 9.25 22,700 First-line therapy Base case mFOLFOX6/cetuximab 388,400 2.72 1.63 Nivolumab 1,196,600 8.21 7.00 150,700 Ipilimumab/nivolumab 1,583,900 10.69 9.44 158,700 Treatment limited to 2 years mFOLFOX6/cetuximab 388,400 2.72 1.63 Strongly dominated Nivolumab 347,170 8.21 7.00 Ipilimumab/nivolumab 363,700 10.69 9.44 6,800 LY = life-years
The validity of algorithms using health administrative data in identifying cancer-related events in adolescents and young adults: A population-based study using the IMPACT cohort.
Authors: Jason D Pole, Paul C. Nathan, Nancy N. Baxter, Cindy Lau, Corinne Daly, Aileen Cullen, Sumit Gupta
Journal: Journal of Clinical Oncology (2017)

e18168 Background: Despite the importance of estimating population level cancer outcomes, most registries do not collect critical events such as relapse and progression. Attempts to use health administrative data to identify these events have focused on older adults and have been mostly unsuccessful. We developed and tested administrative data-based algorithms in a population-based cohort of adolescents and young adults (AYA) with cancer. Methods: We identified all Ontario AYA 15-21 years of age diagnosed with leukemia, lymphoma, sarcoma, or testicular cancer between 1992 and 2012. Chart abstraction was used to determine the end of initial treatment (EOIT) date and subsequent cancer-related events (progression, relapse, second cancer). Linkage to population-based administrative databases identified fee and procedure codes indicating cancer treatment or palliative care. Algorithms that determined EOIT based a time interval free of treatment-associated codes, and new cancer-related events based on billing codes, were compared to chart abstracted data. Results: The cohort comprised 1,404 patients. Time periods free of treatment-associated codes did not validly identify EOIT dates; using subsequent codes to identify new cancer events was thus associated with low sensitivity (56.2%). However, using administrative data codes that occurred after the EOIT date based on chart abstraction, the first cancer-related event was identified with excellent validity (sensitivity 87.0%, specificity 93.3%, PPV 81.5%, negative predictive value 95.5%). Conclusions: While administrative data alone did not validly identify cancer-related events, using administrative data in combination with chart collected EOIT dates was associated with excellent validity. The collection of EOIT dates by cancer registries would significantly expand the potential of administrative data linkage to assess cancer outcomes.
Breast Implant Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL): The French Lymphoma Study Association (LYSA) registry data.
Authors: Corinne Haioun, Camille Laurent, Fabien Le Bras, Thu Ha Dao, Emmanuel Itti, Caroline Malhaire, Jocelyne Chopier, Raphael Sinna, Youlia Kirova, Emmanuel Bachy, Borhane Slama, Jean Marc Schiano, Marie Bannier, Alexandra Traverse-Glehen, Romain Bosc, Luc Xerri, Fabien Reyal, Herve Tilly, Philippe Gaulard
Journal: Journal of Clinical Oncology (2018)

7554 Background: BIA-ALCL is recognized as a distinct entity. In the French Lymphopath network with 59,356 lymphomas registered since 2010, 55 peripheral T-cell lymphomas (PTCL) out of 526 breast lymphomas were reviewed, that included 46 cases of BIA-ALCL. Methods: since 2016, a WebEx national multidisciplinary meeting has been implemented by the French Cancer Agency in order to define therapeutic strategies for newly diagnosed cases. BIA-ALCL registry funded by LYSA is collecting patient clinical data including reasons for breast implantation (breast augmentation, reconstruction), implant manufacturer, treatments and outcome. Results: 29 BIA-ALCLs have been analyzed so far. Median age was 62 y (29-77). In 15 out of 29 patients (pts) the first implant followed a mastectomy for breast cancer. Ten pts were implanted twice and 6 pts 3 times or more. Most implants were silicone-filled and textured. The median time between the first and last implant surgery and BIA-ALCL diagnosis were 10y [4-37] and 4y [0.2-8] respectively. The two clinical presentations i.e. effusion (n = 22) and breast tumor mass (n = 7) correlated with the 2 distinct histological subtypes (in situ or infiltrative). The majority of pts (84%) were stage IE (n = 21) or II (n = 1), whereas 7 pts were stage IV. Implant removal with capsulectomy was performed in 26 out of 29 patients with additional treatment based mostly on CHOP or CHOP-like chemotherapy regimens in 12 pts. After 2 years of median follow-up, 25 pts are alive and free of disease. Four pts with tumor mass presentation have died, either from lymphoma progression alone (n = 3) or with concomitant active breast cancer (n = 1). Conclusions: In situ BIA-ALCLs have an indolent clinical course and remain in complete remission mainly after implant removal. Infiltrative BIA-ALCLs have a more aggressive clinical course. Multiple implants and/or a past history of breast cancer could favor the occurrence of BIA-ALCL. New insights into the biology of BIA-ALCL might translate into more targeted and effective therapies.
Interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer: An analysis of institutional and public data.
Authors: Ali Jalali, Jing Wang, Won-Chul Lee, Jianhua Zhang, Chia Chin Wu, Don Lynn Gibbons, XiMing Tang, Neda Kalhor, Julie Izzo, Carmen Behrens, Frank V. Fossella, Anne S. Tsao, J. Jack Lee, Stephen Swisher, John Heymach, Andrew Futreal, Ignacio Ivan Wistuba, Roy S. Herbst, Vassiliki Papadimitrakopoulou, Jianjun Zhang
Journal: Journal of Clinical Oncology (2017)

8538 Background: In many types of cancer, infiltration of tumor by immune cells, as a reflection of the immune response against the tumor, is thought to play a critical role in clinical outcome. Tumors, however, tend to evade the immune response as they progress. In this study, we characterize the interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer (NSCLC). Methods: We performed histologic immune profiling and microarray expression analysis on primary tumor specimens from 275 NSCLC patients (PR: PROSPECT trial) as well as RNA-Seq expression analysis on biopsy specimens from 50 patients with advanced NSCLC (B2: BATTLE-2 trial). RNA-Seq data from the TCGA lung cancer project was also analyzed. Immune Infiltration Score (IIS) was computed from the expression data using the Estimate package in R. Immune Suppression Score (ISS) was defined as the difference between the mean of CD3, CD4, CD8, FOXP3, and PD1 counts in the periphery and core of the tumor. Results: Tumor IIS is correlated (all p &lt; 0.0005) with tumor immune infiltration as measured by inflammatory cell count on frozen tumor or several immune marker counts in tumor core. IIS is positively associated with survival (p = 0.04) independently of age (p = 0.008) and stage (p = 8e-10). IIS in the top half is associated with higher median survival vs. bottom half (10.2 vs 2.2 months, p &lt; 0.0001) in B2. In TCGA lung adenocarcinoma samples, IIS is higher in stage I/II disease vs stage III/IV (p = 0.003). For all immune markers in PR samples, periphery of the tumor on average has higher counts vs tumor core (p &lt; 0.0011), and this difference (suppression score) is higher in stage III/IV samples vs stage I/II for CD3, CD4, and CD8 (all p &lt; 0.04) and for FOXP3 and PD1 (p &lt; 0.1). ISS is negatively associated with survival (p = 0.02) independently of age (p = 0.06) and stage (p &lt; 0.0001). Conclusions: As NSCLC tumors progress, immune infiltration in the periphery of the tumor increases while infiltration in the core decreases, reflecting increasing immune suppression. Tumor immune infiltration and suppression, as measured by IIS and ISS, are significant predictors of survival, independently of age and stage.
Long-term efficacy and safety of dasatinib in patients with chronic myeloid leukemia in accelerated phase who are resistant to or intolerant of imatinib
Authors: Oliver Ottmann, Giuseppe Saglio, Jane F. Apperley, Christopher Arthur, Eduardo Bullorsky, Aude Charbonnier, John F. Dipersio, Hagop Kantarjian, Hanna Jean Khoury, Dong-Wook Kim, Diane Healey, Lewis Strauss, Jorge E. Cortes
Journal: Blood Cancer Journal (2018)

Treatment with a frontline BCR-ABL1 tyrosine kinase inhibitor (TKI; e.g., imatinib, dasatinib, and nilotinib) allows patients with chronic myeloid leukemia (CML) in chronic phase (CP) to achieve a near normal life expectancy1, whereas treatment for CML in accelerated phase (AP) is more problematic. While reports describe outcomes for patients with CML-AP at initial diagnosis2,3, outcomes have been historically worse once CP disease has progressed to AP. Approximately 50% of patients with CML-AP who receive imatinib as initial treatment develop imatinib resistance4 and experience disease progression5. Second-generation TKIs are indicated for patients with CML-CP or advanced CML resistant to/intolerant of prior therapy (including imatinib)6. After initial approval of dasatinib twice a day (BID) for the treatment of patients with CML resistant to/intolerant of imatinib in all stages, this phase 3 CA180-035 study (NCT00123487) was developed to investigate once (QD) or twice (BID) a day dasatinib treatment in patients with CML-AP, CML in blast phase, or Ph+ acute lymphoblastic leukemia resistant to/intolerant of imatinib.
Quantitation of DNA methylation and copy number variations by targeted sequencing of retrotransposon.
Authors: Jeffrey Buis, Tom Goodman, Julie Kim, Adele Kruger, Brendan Tarrier, Jie Ma, Jay Stoerker
Journal: Journal of Clinical Oncology (2016)

e23139 Background: Copy number variations and genome-wide DNA hypomethylation represent two characteristics of cancer genome for a variety of cancers. Retrotransposons account for more than 45% of human genome, and provide an opportunity for the widespread detection of genetic and epigenetic alterations in DNA samples. A sequencing-based test was developed for simultaneous quantitation of DNA methylation and copy number variations in biological specimens, such as plasma cell-free DNA. Methods: Cellular DNA and plasma cell-free DNA were selectively targeted for retrotransposons, processed on next-generation sequencing platform. Methylation status was determined for millions of CpG sites within retrotransposons and a genome-wide methylation index was calculated. Meanwhile, human genome was divided into 3,100 bins. Changes in DNA copy number were examined at one million base pair resolution for all genomic segments, with ~93% genome coverage accomplished using a single target capture probe. Results: DNA methylation was stable in control subjects, with genome-wide methylation indices ranging from 85.6% to 87.2% for non-malignant solid tissues or blood cells (n = 15). Hypomethylated DNA was detected in cancer cells, with methylation indices ranging from 65.4% to 70.7%. Methylation indices for plasma cell-free DNA varied from 82.8% to 84.2% in control subjects (n = 4), consistent with observations in cellular DNA. Moreover, methylation index for plasma cell-free DNA can be determined without whole genome amplification, representing a technical advancement in a liquid biopsy test. Compared to control samples, copy number analysis for individual retrotransposons identified multiple sub-chromosomal amplifications or deletions in cancer cells. Control samples admixed with graduated amounts of tumor DNA showed decreased levels of DNA methylation. The methylation index correlated with the percentage of tumor DNA in the sample. Conclusions: The presence of hypomethylated DNA or sub-chromosomal copy number variations can be detected by targeted sequencing of retrotransposons. Simultaneous quantitation of these two biomarkers for tumor cells provides a novel approach in cancer screening and diagnosis.
TCT-1 Optimal Duration of Dual Antiplatelet Therapy After Left Main Coronary Stenting With Everolimus-Eluting Stents: Analysis From the EXCEL Trial
Authors: Sorin Brener, Patrick Serruys, Martin Leon, Marie-Claude Morice, David Kandzari, Roxana Mehran, A. Pieter Kappetein, Joseph Sabik, Yangbo Liu, Ovidiu Dressler, Ori Ben-Yehuda, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Melatonin as a Hormone: New Physiological and Clinical Insights
Authors: José Cipolla-Neto, Fernanda Gaspar do Amaral
Journal: Endocrine Reviews (2018)

Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain–acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.