tbuckley/cabot-search huggingface dataset:
Small bowel adenocarcinoma treatment: A single centre experience.
Authors: Philip Bredin, Joseph J McKendrick, Prasad Cooray, Rachel Wong
Journal: Journal of Clinical Oncology (2017)

451 Background: Small bowel adenocarcinoma (SBA) has a high mortality. Randomised controlled trials are not feasible due to its rarity, therefore there is no gold standard treatment approach. Surgical resection for early stage disease is the only potentially curative option. Systemic therapeutic options are generally extrapolated from oesophagogastric and colorectal chemotherapy regimens. Methods: This is a retrospective review of treatment and outcomes for SBA patients who attended Eastern Health between 1 st January 2010 and 30 th June 2015. Approval was obtained from the Eastern Health Human Research and Ethics Committee. Results: Thirty-six patients with SBA were identified: 16 (44%) duodenal, 12 (33%) ampullary, 6 (17%) jejunal, 2 (6%) terminal ileum, 1 not specified. Median age was 72 and 25 (69%) were male. Stage at diagnosis was as follows: Stage 1 = 4 (11%), Stage 2 = 8 (22%), Stage 3 = 9 (25%) and Stage 4 = 10 (28%). Surgery with curative intent occurred in 19 patients (Whipple’s = 13, wide local excision = 6) of whom 6 received adjuvant (predominantly fluoropyrimidine-based) chemotherapy. One patient died from post-operative complications. At last follow-up, 8 patients remained in complete remission; 11 had relapsed; 3 were lost to follow-up. Three patients had died due to disease. Median relapse-free survival in the curative-intent group was 21.4 months. Median overall survival (OS) has not been reached. Sixteen patients were initially treated with palliative intent. Ten underwent palliative surgery (bypass = 7; resection = 3). Overall, 16 patients commenced palliative chemotherapy, including 8 from the curative-intent group post-relapse. The most commonly used regimen was oxaliplatin plus fluoropyrimidine. Best responses to chemotherapy were partial response = 5 (31%) and stable disease = 4 (25%). Six patients received second-line chemotherapy. Median progression-free survival on first-line chemotherapy was 4.8 months. Median OS was 9.4 months. Conclusions: SBA has a poor prognosis. Although 56% of advanced SBA patients had disease control using chemotherapy extrapolated from other gastrointestinal malignancies, responses were not durable.
Profiling exosomal mRNAs in patients undergoing immunotherapy for malignant melanoma.
Authors: James Hurley, Lan Hu, Graham Brock, Ian Sinclair, Ryan J. Sullivan, Vincent J. O'Neill, Johan Skog, Keith Flaherty
Journal: Journal of Clinical Oncology (2015)

e22159 Background: Traditionally, oncology biomarker discovery and development has required the use of material obtained from tissue biopsies. However, recent developments in the exosome field have allowed biomarker research in biofluids to evolve. Exosomes are highly stable microvesicles, approximately 30-200 nm in diameter, that are shed by cells into all biofluids, including blood, urine, and CSF, carrying a rich source of intact protein and RNA. RNA can be efficiently isolated and addressed using technologies such as RT-qPCR and NGS. Here we demonstrate the use of RNA extracted from these vesicles to monitor transcriptional changes in response to an immunotherapy treatment for malignant melanoma. Methods: Exosomes were isolated, using exoRNeasy columns, from plasma collected from malignant melanoma patients treated with Ipilimumab. Patients were split in two groups, based upon either a positive or negative response to the therapy (15 patients in total). Plasma was collected pre-treatment (baseline) and at 3 time-points post initial treatment (2 and 4 weeks, and 4 months). RNA was extracted using exoRNeasy kit. We screened the levels of 586 mRNAs associated with inflammation and 21 mRNA controls by RT-qPCR using the OpenArray technology Results: Over 450 genes were detected across all samples and time-points. A number of mRNA species showed differential expression in patients responding to the therapy compared to those that did not respond. These mRNAs have previously been linked to tumor progression or suppression; current candidate genes of interest include BMP2, PLCG1 and PDGFB. In addition, levels of a subset of mRNA were shown to continue changing as a response to the therapy. This indicates that the exosome RNA profile can be used for longitudinal monitoring of treatment response. Conclusions: RNA expression profiling from circulating exosomes offers the ability to monitor changes in immune pathway genes serially during immunotherapy. Initial data suggest expression signature changes occur early during therapy, offering the potential for predicting response.
Timing of adjuvant therapy in stage II-III colorectal cancer.
Authors: Lucas Vieira dos Santos, Thaissa Veiga Faria, Andre Bacellar Costa Lima, Kathia Cristina Abdalla, Vivian de Araújo Viana, Isabela R. Tavares, Eduardo Dias de Moraes, Armando Melani, Marcelo Rocha Cruz, Joao Paulo Lima
Journal: Journal of Clinical Oncology (2014)

3614 Background: Delay in commencing adjuvant therapy for colorectal cancer seems to impair survival in some retrospective studies. This is a large, bi-institutional retrospective study evaluating the impact of chemotherapy delay in survival. Methods: The interval between the primary surgery and the start of adjuvant chemotherapy was calculated. Survival was estimated using Kaplan-Meier method and the impact of multiple prognostic factors on survival by Cox Regression. Results: By the end of 2012, 2143 colorectal patients treated by surgery were identified from a retrospective database in two Brazilian institutions. Only stage II and III colorectal patients were selected, comprising 1963 patients, and 1318 patients received adjuvant chemotherapy (46% of patients started adjuvant chemotherapy within 6 weeks of surgery). The median follow up were 36 months. Patients starting chemotherapy within 6 weeks of surgery (vs. after 6 weeks) had longer overall survival (median not reached, HR 0.742, 95%CI 0.59-0.93, p=0.011). In the multivariate analysis, age, place of origin, stage, histological grade, emergency surgery, pre-operative therapy and radiotherapy were independent prognostic factors, but the interval between surgery and start of adjuvant therapy was not (HR 0.909, 95%CI 0.717-1.154, p=0.435). Sensitivity analysis using showed similar results. Conclusions: In this large retrospective study, the classic prognostic factors impacted on survival, and the timing of adjuvant therapy did not. Patients with delayed chemotherapy may harbor worst prognostic factors. Further investigation is warranted.
ALK-immunohistochemistry (IHC) standardization with D5F3 antibody in non-small cell lung carcinoma (NSCLC): An international consensus study.
Authors: Fred R. Hirsch, Yasushi Yatabe, Manfred Dietel, Lynette M. Sholl, Ming Sound Tsao, Ed Schuuring, Raymond R. Tubbs
Journal: Journal of Clinical Oncology (2013)

e22042 Background: The outcome of patients with advanced NSCLC with ALK fusions detected by ALK FISH has improved significantly when treated with crizotinib. ALK IHC*, which is a relatively inexpensive assay, correlates well with ALK FISH. An international ALK IHC project was initiated to formulate scoring standardization and assess reproducibility of an ALK IHC assay. Methods: Using ALK FISH status (Abbott, Des Plaines, IL) as the enrollment criteria, formalin-fixed paraffin-embedded tumors from 103 NSCLC patients from 6 different institutes were stained and analyzed for ALK protein expression using a recently developed fully automated ALK IHC assay (Ventana, Tucson, AZ). Seven international observers blindly assessed the specimens as “positive” or “negative” after two training sessions and the use of an assessment manual. Results: The agreement between ALK IHC and ALK FISH for evaluable cases where 4/7 or 6/7 readers agreed on ALK status was 92/98 cases (93.9%, 95%CI 87.3-97.2) and 90/96 cases (93.8%, 95%CI 87.0-97.1) overall; positive IHC agreement was 39/43 cases (90.7%, 95%CI 78.4-96.3) for both methods; negative IHC agreement was 53/55 cases (96.4%, 95%CI 87.7-99.0) and 51/53 cases (96.2%, 95%CI 87.2-99.0), respectively. Average inter-observer agreement was 1987/2032 reads (97.8%, 95%CI 95.9-99.1) overall; average positive agreement was 1,710/1,755 reads (97.4%, 95%CI 95.0-99.1); average negative agreement was 2,264/2,309 reads (98.1%, 95%CI 96.4-99.3). Of the 6 discrepant cases, 4 were unanimously scored as ALK IHC negative with ALK FISH being positive. Two were confirmed by chromogenic ISH to be ALK rearranged, one was unevaluable, and one was genomically heterogeneous. The remaining 2 discrepant cases were discordant among scorers relating to ALK IHC cellular compartment staining in one case and a minute sample size showing ALK IHC staining in the other. Conclusions: ALK IHC standardized assessment achieved high inter-observer reproducibility among an international panel of participants and high correlation with ALK FISH. A screening strategy using ALK IHC should be considered.*ALK IHC has not been approved for use in the US as a diagnostic for crizotinib.
Patient-reported KPS and other measures as predictors of survival in patients with advanced cancer.
Authors: Victor T Chang, Charles B. Scott, Melanie L. Gonzalez, Houling Yan, Jan Einhorn, Barbara Crump, Basil Kasimis
Journal: Journal of Clinical Oncology (2012)

e19606 Background: Understanding determinants of survival remains a challenge in patients(pts) with advanced cancer. Prognostic factors of interest include pts rating of their own performance status, and patient responses from the EQ-5D. Methods: This prospective study was approved by the VA New Jersey HCS IRB. Pts with metastatic cancer whose cancer had already been treated with standard or experimental chemotherapy with KPS &lt; 80%, or who did not wish to receive systemic chemotherapy, were recruited in a specified manner. At entry, Karnofsky performance status (KPS) was estimated, pts rated their own KPS, and answered a modified version of the EQ-5D. Cox regression survival analyses were performed. Results: Of 242 pts enrolled, 237 pts were analyzable. Median (M) age was 67 years (range 44-88), with 56% white, 41% black and 3% other; lung (26%) and prostate (18%) were the 2 most common primary sites and M KPS was 60% (range 30-100%). The majority (97%) of pts have died, with M survival of 95 days, range 4-2032 days. Higher KPS is associated with decreased risk of death (p&lt;.0001). Both patient KPS (p&lt;0.0319) and physician rated KPS were predictive of survival (p&lt;0.004). Discrepancy between physician and pt KPS was noted, with upstaging by pts 48%, same for 27%, and downstaging in 25%, with no effect on survival. Physician KPS was a better predictor than pt KPS at each level. The EQ-5D pain item showed an increased risk of death with increasing pain (p&lt;0.0001). The pain item was associated with KPS: pts with no pain had average KPS 75; moderate pain average KPS 63; extreme pain average KPS 48. The patient’s EQ-5D health rating was positively correlated with survival (p=0.0054), and with KPS (r=0.36). The other items in the EQ-5D did not predict survival. When all the factors (physician KPS, pt KPS, pain, health) were incorporated into a Cox model, only physician KPS was statistically significant (p=0.0033). Conclusions: Pts ratings of health and pain are significantly associated with KPS. Pts have a more positive outlook on their performance status. Physician KPS may be a better predictor because physicians have a wider frame of reference. Physician KPS can contribute to determination of hospice eligibility. Supported by VA HSRD IIR 2-103
Efficacy and Safety of Frontline Therapy with "FCR" Regimen for Chronic Lymphocytic Leukemia Outside Clinical Trials: Israeli CLL Study Group Experience
Authors: Yair Herishanu, Neta Goldschmidt, Osnat Bairey, Rosa Ruchlemer, Riva Fineman, Naomi Rahimi-Levene, Lev Shvidel, Tamar Tadmor, Ariel Aviv, Andrei Braester, Erel Joffe, Aaron Polliack
Journal: Blood (2014)
Cancer survivors’ perspectives on the U.S. generic drug shortage.
Authors: Stephanie Nutt, Ruth Rechis, Lawrence N. Shulman, Brandon M. Hayes-Lattin
Journal: Journal of Clinical Oncology (2012)

e19503 Background: Approximately 1.6 million new cancer cases are expected to be diagnosed in 2012 in the United States, making the need for generic cancer treatment drugs widespread. Methods: In late 2011, LIVESTRONG fielded the Drug Shortage Survey, which mirrored the questions from the American Hospital Association drug shortage survey for providers reworded for a patient audience. The primary goals of the brief survey were to 1) assess if survivors were aware of a generic drug shortage in the U.S. and 2) gauge the impact that the drug shortage has had on people affected by cancer. Individuals were asked to participate in this online survey through a number of means (including the LIVESTRONG Blog). Results: Between October 31, 2011 and January 30, 2012, 114 individuals completed the drug shortage survey, including 54 individuals who have been personally diagnosed with cancer. A little under half of the respondents (47%) felt they or a loved one had been impacted by the drug shortage, while an additional 30% were not sure if they had been impacted. Of the individuals impacted, the most commonly reported adverse effects of the drug shortage were not receiving medications needed for cancer treatment (40%) and receiving different medications (36%). The table highlights the reported effects. Conclusions: Results from this survey indicate that for cancer survivors who chose to participate in this survey who had been impacted by the drug shortage, the impact has been very significant. Additionally, results indicate that more information may need to be disseminated to the patient population about the drug shortage. [Table: see text]
20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G <sub>q</sub> ) to Affect Vascular Function and Trigger Hypertension
Authors: Victor Garcia, Ankit Gilani, Brian Shkolnik, Varunkumar Pandey, Frank Fan Zhang, Rambabu Dakarapu, Shyam K. Gandham, N. Rami Reddy, Joan P. Graves, Artiom Gruzdev, Darryl C. Zeldin, Jorge H. Capdevila, John R. Falck, Michal Laniado Schwartzman
Journal: Circulation Research (2017)

Rationale: 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration, and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction, and vascular diseases. Objective: To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists. The present study was undertaken to identify a receptor to which 20-HETE binds and through which it activates a signaling cascade that culminates in many of the functional outcomes attributed to 20-HETE in vitro and in vivo. Methods and Results: Using crosslinking analogs, click chemistry, binding assays, and functional assays, we identified G-protein receptor 75 (GPR75), currently an orphan G-protein–coupled receptor (GPCR), as a specific target of 20-HETE. In cultured human endothelial cells, 20-HETE binding to GPR75 stimulated Gα q/11 protein dissociation and increased inositol phosphate accumulation and GPCR-kinase interacting protein-1-GPR75 binding, which further facilitated the c-Src–mediated transactivation of epidermal growth factor receptor. This results in downstream signaling pathways that induce angiotensin-converting enzyme expression and endothelial dysfunction. Knockdown of GPR75 or GPCR-kinase interacting protein-1 prevented 20-HETE–mediated endothelial growth factor receptor phosphorylation and angiotensin-converting enzyme induction. In vascular smooth muscle cells, GPR75–20-HETE pairing is associated with Gα q/11 - and GPCR-kinase interacting protein-1–mediated protein kinase C–stimulated phosphorylation of MaxiKβ, linking GPR75 activation to 20-HETE–mediated vasoconstriction. GPR75 knockdown in a mouse model of 20-HETE–dependent hypertension prevented blood pressure elevation and 20-HETE–mediated increases in angiotensin-converting enzyme expression, endothelial dysfunction, smooth muscle contractility, and vascular remodeling. Conclusions: This is the first report to identify a GPCR target for an eicosanoid of this class. The discovery of 20-HETE–GPR75 pairing presented here provides the molecular basis for the signaling and pathophysiological functions mediated by 20-HETE in hypertension and cardiovascular diseases.
Validation of rano criteria: Contribution of T2/FLAIR assessment in patients with recurrent glioblastoma treated with bevacizumab.
Authors: Raymond Yi-kun Huang, Rifaquat Rahman, Whitney B. Pope, Benjamin M. Ellingson, S. Keith Anderson, Sara J Felten, Karla V. Ballman, Wenting Wu, Lakshmi Nayak, Eudocia Quant Lee, Lauren E. Abrey, Evanthia Galanis, David A. Reardon, Timothy Francis Cloughesy, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2014)

2007 Background: Since its introduction, the RANO criteria have been widely adopted in clinical trials for evaluating treatment response in high-grade gliomas. To date, the criteria have not been validated using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma treated with bevacizumab from the randomized phase II BRAIN trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation in the RANO criteria on measurements of objective response rates (ORR) and progression free survival (PFS). Methods: The imaging data of 163 patients with recurrent glioblastoma from the BRAIN trial were evaluated by 6 readers blinded to clinical information. The ORR and median PFS were determined using the RANO criteria and compared to those obtained without evaluating the T2/FLAIR abnormality (Macdonald criteria). Landmark analyses were performed at 2, 4 and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival. Results: The ORRs were 0.433 (95% CI: 0.373 - 0.494) and 0.451 (95% CI: 0.391 – 0.513) by RANO and Macdonald criteria, respectively (p = 0.78). The median PFS was 4.21 months (95% CI: 3.68-5.49) using RANO criteria, compared to 5.52 months (95% CI: 4.27-6.83) as determined by Macdonald criteria (p=0.04). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by RANO criteria were predictive of overall survival (OS) (hazard ratios for 4-month landmark; OR HR= 2.12, p = 0.0003, PFS HR=4.08, p<0.0001). Conclusions: The inclusion of T2/FLAIR assessment in the RANO criteria results in a small difference in median PFS but no significant difference in ORR. The associations of OR and PFS with survival using the RANO criteria at 6 months and earlier time points following therapy potentially support their possible roles as surrogates for OS.
The utility of serum lactate dehydrogenase (LDH) in the follow-up of patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Navneeth Rao Bongu, Basem M. William, Martin Bast, Gregory Bociek, Philip Jay Bierman, Julie Vose, James O. Armitage
Journal: Journal of Clinical Oncology (2012)

8047 Background: The prognostic significance of high serum LDH is well established for both indolent and aggressive lymphomas at diagnosis. The performance characteristics of LDH in predicting relapse after treatment in patients (pts) with DLBCL has not been well studied. The determination of utility of LDH monitoring in pts with DLBCL would have widespread practice implications. Methods: We searched the Nebraska Lymphoma Study Group database to identify pts with DLBCL who were treated with a rituximab-based regimen, from 2000 to 2010, and sustained a complete response (CR). For the pts who relapsed (RP), after sustaining a CR, we collected the LDH level at relapse and the LDH level 3 months prior (considered baseline). For pts who never relapsed (NR), we collected the last 2 LDH levels at follow-up; levels had to be at least 3 months apart. The relative increase of LDH was compared, to baseline, among RP vs. NR. Results: We identified 129 pts, 15 pts were excluded from the analysis as their LDH results were not available, 27 relapsed and 87 didn’t. Median age of pts was 57 years. Only 9/27 RP (33%) had increase in LDH above upper limit of normal (ULN) at relapse. The mean increase in LDH at relapse was 1.2 fold above the ULN for RP vs. 0.83 for NR (p=0.59). The mean increase in LDH, from baseline, was 1.1 fold in NR vs. 1.3 in RP (p=0.3). The likelihood ratio (LR) of relapse was 4.65 for pts who had 1.5 fold increase in LDH above baseline (1.5xLDH) vs. those who didn’t (p=0.03). The sensitivity, specificity, positive and negative predictive values of 1.5xLDH for detecting relapse, compared to clinical and imaging findings were 0.18, 0.95, 0.55, and 0.79 respectively. Also, 1.5xLDH at relapse was significantly associated with the presence of fever (LR=5.74; p=0.03) but not with other symptoms including drenching night sweats, anemia, or new/progressive lymphadenopathy. Conclusions: A 1.5 fold increase in LDH, over a period of 3 months, is associated with increased likelihood of relapse from DLBCL. Modest elevations in LDH (&lt;1.5 fold of baseline) doesn’t seem to be associated with relapse. LDH, when elevated at least 1.5 fold of baseline, is a specific (i.e. 56%), but not a sensitive (i.e. 19%) marker, for relapse of DLBCL.
Association of high BIM mRNA levels with longer survival in advanced gastric cancer.
Authors: Nandie Wu, Jia Wei, Lixia Yu, Ana Gimenez Capitan, Jose Javier Sanchez, Rafael Rosell, Baorui Liu
Journal: Journal of Clinical Oncology (2015)

e15075 Background: 5-fluorouracil,oxaliplatin, and docetaxel chemotherapy are commonly used in the treatment for gastric cancer (GC). Apoptosis relevant genes might be associated with drug resistance.Approximately half of the patients could be the candidates for second-line treatment at the time of failure to first-line chemotherapy. Docetaxel is among the most frequently used agents for gastric second-line treatment. Methods: We investigated mRNA expression levels of BIM, AEG-1 and AXL in 131advanced gastric cancer samples and correlated gene levels with patients’ overall survival.All 131 patients received first-line FOLFOX chemotherapy, in which 56 patients were further treated with second-line docetaxel-based chemotherapy. Results: Correlation between BIM mRNA expression and AEG-1 mRNA expression was observed(rs = 0.30, P= 0.002). There is no association betweenmRNAexpression levels of any of the individual genes and overall survival in patients only receiving first-line FOLFOXchemotherapy.In a subgroup of patients receiving docetaxel-based second-line chemotherapy, those with high or intermediate levels of BIM obtained a median overall survival of 18.2 months (95% CI = 12.8-23.6), compared with 9.6 months (95% CI = 8.9-10.3) in patients with low BIM levels (P= 0.008). However, there was no correlation between AEG-1, AXL mRNA expression and overall survival. The risk of mortality was higher in patients withlow BIM mRNA levels compared with high or intermediate levels (HR = 2.61, 95% CI = 1.21-5.62, P= 0.01). Conclusions: BIM could be considered as a biomarker to identify whether patients can benefit from docetaxel-based second-line chemotherapy in gastric cancer.