tbuckley/cabot-search huggingface dataset:
Prognostic factor of distal bile duct cancer (DBDC) and ampullary cancer (AC) after pancreatoduodenectomy.
Authors: Shinjiro Tomiyasu, Keita Sakamoto, Mitsuhiro Inoue, Masayoshi Iizaka, Nobuyuki Ozaki, Kei Horino, Hiroshi Takamori, Masahiko Hirota, Hideo Baba
Journal: Journal of Clinical Oncology (2017)

333 Background: Ampullay cancer (AC) is relatively good prognosis in the biliary tract cancer. Such as LN metastasis, pancreatic invasion is a prognostic factor in AC. On the other hand, Distal bile duct cancer (DBDC) is somewhat good prognosis in the biliary tract cancer. Such as ductal resection margin positive is a prognostic factor in DBDC. There are few papers considered to both difference. Therefore, we conducted this study to examine the difference of AC and DBDC. Methods: To evaluate Cancer-Specific Survival (CaSS), Recurrence-Free Survival (RFS) and prognostic factors after pancreatoduodenectomy (including pylorus-preserving pancreatoduodenectomy: PPPD, subtotal stomach-preserving pancreatoduodenectomy: SSPPD) based on a series of 80 patients of AC and 36 patients of DBDC from 1996 to 2015. We reviewed and analyzed the clinicopathologic data, recurrence and survival. Results: Five years CaSS and RFS of AC were 72.3% and 72.5%. In univariate analysis, pancreatic invasion, R1or R2 resection, duodenal invasion and lymph node metastasis are significantly poor prognosis. In multivariate analysis, pancreatic invasion and R1or R2 resection are poor prognostic factors (pancreatic invasion, p = 0.0012, hazard ratio (HR) 5.65 [confidence interval (CI) 1.92-19.5 95%], R1or R2 resection, p = 0.0043, HR 6.22 [CI 1.68-40.2 95%]). On the other hand, five years CaSS and RFS of DBDC were 35.8% and 46.8%. In univariate analysis, pancreatic invasion (+) ≥ 5 mm in depth, and duodenal invasion are significantly poor prognosis. In multivariate analysis, duodenal invasion is the only poor prognostic factors (p = 0.0227, HR 2.90 [CI 1.16-7.39 95%]). Conclusions: DBDC is considerable poor prognosis compared with AC. Lymph node metastasis is not prognostic factor depends on D2 LN dissection in AC, than pancreatic invasion. Cancer cells invaded pancreatic parenchyma in AC; pancreatic invasion may be the most important prognostic factor by biology-like pancreatic cancer. Duodenal invasion in DBDC was prognostic factor reflects the degree of development of the cancer beyond pancreatic parenchyma. Further clinicopathological and biological studies are needed to confirm our findings.
The role of the microbiome in human health and disease: an introduction for clinicians
Authors: Vincent B Young
Journal: BMJ (2017)

Research into the microbiome—the indigenous microbial communities (microbiota) and the host environment that they inhabit—has changed clinicians' ideas about microbes in human health and disease. Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes. Thus disease can result from a loss of beneficial functions or the introduction of maladaptive functions by invading microbes. This review will show how an understanding of the dynamics and function of the indigenous microbiota has altered our view of microbes in maintaining homeostasis and causing disease. It will discuss how disruption of the beneficial functions of the microbiota can lead to disease. Methods for studying the microbiota will be introduced as part of a conceptual framework for using these methods to delineate novel roles for microbes in health. Key associations between specific changes in the microbiome and disease will be discussed. This will lead to an explanation of how the intentional manipulation of the microbiota, either by restoring missing functions or eliminating harmful functions, may lead to novel methods to prevent or treat a variety of diseases. With the explosion of studies relating the microbiome to health and disease, this review aims to provide a foundation for clinicians to follow this developing area of biomedical research.
Clinical significance of AR mRNA quantification from circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (Abi) or enzalutamide (Enza).
Authors: John Silberstein, Brandon Luber, Hao Wang, Changxue Lu, Yan Chen, Yezi Zhu, Maritza N. Taylor, Michael Anthony Carducci, Mario A. Eisenberger, Jun Luo, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2017)

132 Background: AR-targeting agents remain the backbone of mCRPC therapy. We previously reported an association between AR-V7 mRNA detection in CTCs and resistance to Abi/Enza (NEJM 2014). Here, we report the prognostic significance of full-length androgen receptor (AR-FL) mRNA quantification from CTCs in pts starting Abi or Enza. Methods: We prospectively enrolled mCRPC pts starting Abi or Enza, and examined the prognostic value of AR-FL detection using a CTC-based mRNA assay (modified AdnaTest, Qiagen). We examined PSA 50 responses, PSA progression free survival (PSA-PFS), clinical/radiologic PFS (PFS), and overall survival (OS). We constructed multivariable (MVA) Cox regression models adjusting for AR-V7 status, PSA level, Gleason sum, number of prior therapies, prior Abi/Enza use, prior taxane use, presence of visceral disease, and ECOG score. Results: We enrolled 202 pts (median f/u 12.9 mo). AR-FL status was negative in 97/202 pts (48%), &lt; median in 52/202 (26%) and &gt; median in 53/202 (26%). Higher AR-FL levels correlated with positive AR-V7 detection (35.5 copies [range: 2.5–1209] in AR-V7+ vs 1.4 copies [range: 0–172.5] in AR-V7–, P&lt; .001), as well as lower PSA 50 responses (55.4 copies in nonresponders vs 6.7 copies in responders, P&lt; .001). In Kaplan-Meier analysis, PSA-PFS, PFS and OS differed significantly between AR-FL negative, AR-FL &lt; median, and AR-FL &gt; median (Table). In MVA models, AR-FL level (as a continuous variable) was prognostic for PSA-PFS (HR 1.06, 95%CI 1.00–1.12, P= .04) and trended with prognosis for PFS (HR 1.04, 95%CI 0.99–1.11, P= .13) and OS (HR 1.07, 95%CI 1.00–1.15, P= .06). AR-V7 status was also independently prognostic for all outcomes in MVA analyses. Conclusions: This study demonstrates CTC-derived AR-FL copy number is prognostic for clinical outcomes in Abi/Enza-treated mCRPC pts. In addition to AR-V7 status, AR-FL quantification could serve as another molecular biomarker of Abi/Enza sensitivity after analytical validation/standardization. [Table: see text]
Mutation profile in non-small cell lung cancer: Analysis of a Brazilian population.
Authors: Jessica Ribeiro Gomes, Marcus Paulo Fernandes Amarante, Renata D'Alpino D'Alpino, Raphael Brandao Moreira, Tercia Tarciane Soares de Sousa, Aline Da Rocha Lino, Marcelo Rocha S Cruz, Marcos André Costa, Fabio Schutz, Carolina Kawamura Haddad, Rafael Schmerling, Fernando C. Maluf, Antonio C. Buzaid
Journal: Journal of Clinical Oncology (2015)

e19115 Background: Non-small cell lung cancer (NSCLC) is known to harbor molecular mutations or rearrangements predictive to a variety of targeted therapies, which have been increasing the overall survival (OS) in recent years. There is a lack of studies evaluating the prevalence of those molecular alterations in NSCLC patients in Brazil. Methods: This was a retrospective analysis of patients diagnosed with lung adenocarcinoma who were treated at Antonio Ermirio de Moraes Oncology Center (Brazil) from January 2011 to December 2014. Status of EGFR (epidermal growth factor receptor) mutation, ALK (anaplastic lymphoma kinase) translocation, KRAS (kirsten rat sarcoma) mutation, HER2 (human epidermal receptor-2) ampification, and ROS1 (c-ros oncogene 1) rearrangement status was evaluated. Results: A total of 290 patients with lung adenocarcinoma were included in the analysis. Median age was 65 years (range 30-89), 51.7% were male and 67.9% were smokers or previously smokers. At diagnosis, 57.6% were metastatic and 4.8% were stage IIIB according to AJCC 2010. The analysis of EGFR status was performed in 162 patients (55.9%). The prevalence of EGFR mutation was 32.7%: 23 patients at exon 19, 21 at exon 21; 6 at exon 20; and 1 at exon 18. The prevalence of ALK translocation was 4.0% (3/75 patients). KRAS mutation was detected in 20% (3/15), BRAF mutation in 11.8% (2/17), HER2 amplification in 14.3% (2/14), and ROS1 mutation in 9% (1/11). Conclusions: Despite being a retrospective analysis, a high prevalence of EGFR mutation (32.7%) and ALK translocation (4.0%) was detected in a brazilian population with NSCLC, which offers further clinical benefit.
A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report.
Authors: Jack M. Su, Patrick Andrew Thompson, Adekunle Adesina, Xiao-Nan Li, Lindsay Baker Kilburn, Arzu Onar-Thomas, Mehmet Kocak, Brenda Chyla, Evelyn Mary McKeegan, Katherine E. Warren, Stewart Goldman, Ian Pollack, Maryam Fouladi, Alice Chen, Malcolm A. Smith, Vincent L. Giranda, James M. Boyett, Susan Blaney, Larry E. Kun
Journal: Journal of Clinical Oncology (2013)

2036 Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m 2 /dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m 2 BID, and TMZ, 135 mg/m 2 /day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD &gt; 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m 2 . PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.
Circulating DNA as a Prognostic Marker in Sickle Cell Disease.
Authors: Pinar Ulug, Nisha Vasavda, Stephan Menzel, Karthik Ramasamy, Taku Sugai, Gordon Cheung, Sheila Kondaveeti, Moji Awogbade, Sybil Bannister, Juliette Cunningham, David Rees, Swee Lay Thein
Journal: Blood (2006)
Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a novel pan-HER inhibitor continuously given in patients with advanced solid tumors.
Authors: YuJung Kim, Jisu Oh, Tae Min Kim, Sae-Won Han, Keun Wook Lee, Jee Hyun Kim, Seock-Ah Im, Kyun-Seop Bae, Yook-Hwan Noh, Hyun-Jin Nam, Kyung-Mi Park, Jeewoong Son, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

2565 Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on, 1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F=13:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated(≥4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance &lt;80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile duct cancer], and the duration of response were 32, 40+, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUC last values, whereas C max values were lower in fed condition than in fasted condition. Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information: NCT01455584.
Dietary intake and metabolic syndrome in adult survivors of childhood cancer.
Authors: Webb A Smith, Chenghong Li, Kerri Nottage, Deokumar Srivastava, Jennifer Lanctot, Daniel M. Green, Vikki G Nolan, Joseph H. Laver, James G. Gurney, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2012)

9526 Background: Childhood cancer survivors (CCS) are at increased risk for metabolic syndrome (MetSyn) and increased morbidity and mortality from cardiovascular disease. Following a heart healthy diet may decrease this risk. The purpose of this investigation was to characterize dietary patterns and to evaluate the association between diet and MetSyn among CCS. Methods: CCS who were 10+ year survivors of childhood cancer, who were older than 18 years of age, and participating in the St. Jude Lifetime Cohort Study (SJLIFE). They completed a medical assessment based on Children’s Oncology Group screening guidelines, and a food frequency questionnaire (FFQ). Laboratory and physical measures were obtained to determine MetSyn status using the NCEP-ATPIII criteria. Participants were classified as having MetSyn if they met the criteria for ≥3 components of MetSyn. Data from the FFQ were used to score dietary patterns according to WCRF/AICR recommendations. Those who met ≥4 of the 7 recommendations were classified as following a “healthy diet.” A stratified analysis by sex using log-binomial regression models was undertaken to evaluate associations between diet and MetSyn, adjusted for age, age at diagnosis, cranial radiation, education, household income, and smoking status. Results: Among 1421 participating CCS (49.3% male, median age 33.0 years, range, 18.9-60.0 years), 31.5% met the criteria for MetSyn and 25.8 % followed a healthy diet according to the WCRF/AICR recommendations. In multiple regression models stratified by sex, females who followed a “healthy diet” were 2.1 (95% CI 1.5-2.9) times less likely and males who followed a “healthy diet” were 2.2 (95% CI 1.5-3.1) times less likely to have MetSyn than those who reported following a “healthy diet”. Conclusions: Heart healthy diets in CCS are associated with decreased risk for MetSyn. Dietary interventions may be warranted in CCS with MetSyn.
The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF-mutant colorectal cancer cell lines.
Authors: Basak Celtikci, Robert Carson, Patrick G. Johnston, Sandra Van Schaeybroeck
Journal: Journal of Clinical Oncology (2014)

3594 Background: Oncogenic mutations in BRAF occur in 8% of patients with advanced colorectal cancer (CRC) and have been shown to correlate with poor prognosis. In contrast to BRAF mutant (MT) melanoma, where the BRAF inhibitor Vemurafenib (PLX4032) has shown significant increases in response rates and overall survival, only minor responses to Vemurafenib treatment have been reported in BRAFMT CRC. Clear understanding of the vulnerabilities of BRAFMT CRC is important, and identification of druggable targets uniquely required by BRAFMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel resistance mechanisms to MEK inhibition in BRAFMT CRC. Methods: Paired BRAFMT/WT RKO and VACO432 CRC cells and non-isogenic BRAFMT LIM2405, WiDR, HT-29 and COLO205 CRC cells were used. Changes in protein expression/activity were assessed by Western Blotting. Interactions between MEK1/2 and JAK1/2 or c-MET inhibition were assessed using the MTT cell viability assays and Flow Cytometry. Apoptosis was measured using Western Blotting for PARP, cleaved caspase 3, 8 and 9, and caspase 3/7 and 8 activity assays. Results: Treatment with MEK1/2 inhibitors AZD6244, trametinib, UO126 and PD98059 resulted in acute increases in STAT3 activity in the BRAFMT RKO and VACO432 cells but not in their BRAFWT clones and this was associated with increases in JAK2 activity. Inhibition of JAK/STAT3 activation using gene specific siRNA or small molecule inhibitors TG101348 or AZD1480, abrogated this survival response and resulted in synergy and significant increases in cell death when combined with MEK1/2 inhibitors AZD6244 or trametinib in BRAFMT CRC cells. The RTK c-MET is activated upstream of STAT3 following MEK1/2 inhibition. Inhibition of c-MET and MEK1/2, using pharmacological inhibitors (crizotinib and AZD6244), results in synergy and increased cell death in BRAFMT CRC cells. Conclusions: We have identified JAK/STAT3 activation as an important escape mechanism for BRAFMT CRC following MEK1/2 inhibition in vitro. Combinations of JAK/MEKi or MET/MEKi can be a potential novel treatment strategy for poor prognostic BRAFMT advanced CRC patients.
Phase I study of definitive chemoradiation with gemcitabine and the WEE1 inhibitor AZD1775 in unresectable pancreatic cancer.
Authors: Kyle Clifford Cuneo, Meredith Morgan, Matthew J Schipper, Jonathan Maybaum, Mahmoud Al-Hawary, Diane M. Simeone, Vaibhav Sahai, Mark Zalupski, Theodore Steven Lawrence
Journal: Journal of Clinical Oncology (2017)

TPS512 Background: Targeting cell cycle checkpoints has the potential to enhance the efficacy of chemoradiation therapy. Tumor cells commonly have an abnormal G1 checkpoint due to mutations in the p53 pathway making them reliant on the G2 checkpoint to repair DNA damage. In our preclinical studies, WEE1 inhibition with AZD1775 abrogates the G2 checkpoint and sensitizes pancreatic cancer cell lines and xenografts to chemoradiation. Additionally, AZD1775 attenuates homologous recombination repair and promotes replication stress in cancer cells. Given our preclinical findings, we designed a phase I dose escalation study of the WEE1 inhibitor AZD1775 with gemcitabine and radiation in patients with unresectable pancreatic cancer (NCT02037230). Methods: The primary objective of our phase I study is to determine the MTD (maximum tolerated dose) of AZD1775 when combined with gemcitabine and radiation in patients with locally advanced pancreatic cancer. Our secondary objectives are to estimate the efficacy of this regimen at the target dose and to determine if WEE1 is inhibited by AZD1775 at or below its target dose in surrogate tissues (hair follicles). Patients with unresectable, non-metastatic pancreatic cancer are eligible for the study. Protocol therapy consists of the administration of AZD1775 and gemcitabine at the assigned dose levels in accordance with a Time-to-Event Continual Reassessment Method. All patients on the study are treated with four cycles of therapy consisting of AZD1775 given orally on days 1, 2 and 8, 9 of a 21 day cycle with gemcitabine given intravenously over 30 minutes on day 1 and day 8. Cycles 2 and 3 are administered with concurrent radiation therapy, 52.5 Gy in 25 fractions to the primary pancreatic tumor. The MTD will be determined by the development of dose limiting toxicities (DLT) within the first 4 cycles of therapy with a target DLT rate of 25%. Blood samples obtained at baseline and after cycles 1, 2, and 4 will be used for correlative studies on circulating tumor cells and tumor derived exosomes. Our estimated accrual is 36 patients. To date we have enrolled 21 patients. Supported by P50 CA130810, R01 CA163895, Cancer Center Core grant P30 CA46592, and the Taubman Institute. Clinical trial information: NCT02037230.
Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma: A report from the Children’s Oncology Group.
Authors: Pooja Hingorani, Edoardo Missiaglia, Janet Shipley, James Robert Anderson, Timothy J. Triche, Mauro Delorenzi, Julie M Gastier-Foster, Michele Wing, Douglas S. Hawkins, Stephen Skapek
Journal: Journal of Clinical Oncology (2015)

10510 Background: Pediatric rhabdomyosarcoma has two common histological subtypes: embryonal (ERMS) and alveolar (ARMS). PAX/FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology while fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion-gene negative RMS (FN-RMS) patients but this has not been independently validated. The goal of the current study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in an unrelated cohort of patients with FN-RMS. Methods: A series of cases were taken from the Children’s Oncology Group (COG) D9803 study of children with intermediate-risk RMS and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathological characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinical-pathological variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR 7.3 95%CI[1.9-27.0], p = 0.003) and failure-free survival (N = 57; HR 6.1 95%CI[1.9-19.7], p = 0.002). Conclusions: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in a future, prospective clinical trial.
High Mobility Group A1/2 Chromatin Remodeling Proteins Associate with Polycythemia Vera Transformation to Acute Leukemia in Humans and a JAK2 V617F Transgenic Mouse Model
Authors: Linda Resar, Donna Marie Williams, Zhizhuang Joe Zhao, Ophelia Rogers, Lingling Xian, Jerry L. Spivak, Alison R Moliterno
Journal: Blood (2016)