tbuckley/cabot-search huggingface dataset:
Plasma fibronectin levels in gastrointestinal cancer patients undergoing radiation therapy
Authors: R. G. Baluna, C. D. Fuller, T. Y. Eng, C. R. Thomas
Journal: Journal of Clinical Oncology (2005)

9679 Background: Fibronectin (Fn), a multifunctional protein with major adhesive and opsonic properties, functions in the maintenance of tissue integrity, hence is a candidate marker of ionizing radiation effect. The specific aim of the present study is to evaluate the levels of plasma Fn in gastrointestinal cancer patients (pts) undergoing radiation therapy (RT). Methods: Twenty-four pts treated with external beam RT were entered onto this study. Plasma Fn levels were determined before and following a course of RT in pts with gastric, ampullary, rectal or anal cancer. The RTOG criteria were used to determine the grade of RT toxicity. All pts provided IRB-approved informed consent. Plasma Fn levels were determined using duplicate serum samples in a commercial radial immunodiffusion assay (Binding Site, Birmingham, UK). Statistical analysis utilized the non-parametric Mann-Whitney U-test with an alpha of 0.05. Results: Pre-treatment Fn levels were significantly lower in gastrointestinal cancer pts (median±SE) (285.2 ± 62 μg/ml, p=0.05) as compared with lung cancer pts (507.5± 91 μg/ml). Interestingly, RT in pts with gastrointestinal cancer resulted in significant increases in plasma Fn levels at the end of therapy (424.2±71ug/ml, p=0.01) as compared with baseline levels (285.2 ± 62 μg/ml), while RT in lung cancer pts resulted in significant decreases in plasma Fn levels (361±58 μg/ml, p=0.04) compared with the baseline levels (507.5 ± 91 μg/ml). The effect of RT on Fn synthesis in endothelial cells and hepatocytes may, in part, explain differential responses in plasma Fn levels to RT to different anatomic sites. To determine the possible predictive value of Fn for the development of acute toxicity, the levels of plasma Fn in gastrointestinal cancer pts without toxicity (436.0± 34.0 μg/ml) were compared with levels of plasma Fn in pts with grade I-II RTOG acute toxicity (255.0 ± 74.7 μg/ml) and a significant difference was observed (p=0.03). Conclusions: Modulation of plasma Fn levels by ionizing radiation suggests a possible role of Fn in radiation effect. Studies are ongoing to further clarify the clinical significance of the changes in plasma Fn levels after RT and to elucidate the underlying mechanisms of interaction. No significant financial relationships to disclose.
Early response to platinum-based chemotherapy in non small cell lung cancer (NSCLC) predicts survival
Authors: B. Sirohi, A. Matakidou, S. Ashley, S. Popat, W. Saka, K. Priest, A. Norton, M. James, T. Benepal, T. Eisen, M. O’Brien
Journal: Journal of Clinical Oncology (2005)

7208 Background: Response rates to combination platinum based chemotherapy vary from 20–40% leaving a large number with either stable or progressive disease. Short courses (3–4) have been shown to be as effective as longer courses (6–8). We looked at our database to see if response after 2 courses correlated with final response and outcome. Methods: From a prospectively maintained database, 320 patients (202 men, 118 women, median age 60 years (range, 25–82) with stage 3–4 NSCLC (51% adeno-carcinoma, 33% squamous cell) were identified who received ≥ 4 courses of platinum-based chemotherapy as first line treatment attaining either stable disease (SD) or partial response (PR). Responses were assessed by CT scans after 2 and 4 courses. Results: After 2 courses, 115 (36%) patients attained PR and 205 SD. Of the 205 with SD, 51 went onto attain PR with 4 courses of treatment while 154 (48%) remained with SD; there was no difference in outcome of these two groups. After 2 courses, the 2-y survival for patients attaining PR (n=115) was 23% compared to 11% for those in SD (P=0.002). Attaining subsequent PR after 4 courses of same 1st line chemotherapy with prior SD after 2 courses did not have an impact on outcome. Cox regression analysis shows that after adjusting for other prognostic factors, response after 2 courses of chemotherapy remains an independently significant prognostic factor for survival (Table). Conclusion: These data suggest NSCLC patients with SD after 2 cycles of 1st line chemotherapy have poorer outcome than those in PR at this point. PET scan may have a role in better assessment and prediction of response. New approaches are needed to improve outcome in patients with SD after 2 courses. No significant financial relationships to disclose.
Cost-Effectiveness of Immune Checkpoint Inhibition in<i>BRAF</i>Wild-Type Advanced Melanoma
Authors: Christine G. Kohn, Simon B. Zeichner, Qiushi Chen, Alberto J. Montero, Daniel A. Goldstein, Christopher R. Flowers
Journal: Journal of Clinical Oncology (2017)

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.
Metronomic (M), capecitabine (C), and oxaliplatin (O) plus bevacizumab (B) as treatment of advanced colorectal cancer (ACRC) in very elderly people (M-COB): Efficacy and safety (E&amp;S) evaluation—A 2-year monitoring.
Authors: I. U. Carreca, F. M. Bellomo, G. Pernice, M. Antista, R. Amelio, L. Balducci
Journal: Journal of Clinical Oncology (2011)

e14086 Background: A limit to delivery of cytotoxic chemotherapy in elderly people with cancer, is severe toxicity as principal side effect of treatment. We designed in 2009 a treatment schedule to evaluate E&S of combination of three drugs O, C plus B in ACRC very old patients in a metronomic mode (M-COB) Methods: 75 (37 f -38 m) very elderly patients with advanced colorectal cancer (median age:76; range: 70-82) were enrolled. Comprehensive Geriatric Assessment (CGA) was performed to all pts to assess eligibility for chemotherapy. Treatment schedule was: O (65 mg/m2) + B (7.5 mg/Kg) on day 1 (O doses was adjusted by Kintzel-Dorr formula). C (fixed dose of 1,000 mg bid) was delivered from day 2 to day 15 every 3 weeks for 12 cycles. Primary endpoints: toxicity profile (NCI-CTC v2.0) and QoL score (EORTC QLQ-C30). Secondary endpoints:. Clinical Response Rate (CRR) by WHO ‘s criteria. All patients were evaluated for main toxicity (Hemat, G.I., HFS, N&V) by ECOG Common Toxicity Criteria. Results: 76 patients were included into groups I Balducci's classification, for frailty assessement. A 50.1% tumor response rate(TRR) was observed both with a 86.7% Clinical Benefit (CB). No one pts experienced grade 4 toxicity. QoL score improvement was noted in all pts after treatment. Median PFS was 12.3 months with a 6 months PFS rate of 82%. Median OS was 23.5 months with a 12 months survival probability of 78.8%. Conclusions: We choose fixed dose of C in order to reduce main toxicity as shown in std treatment of aged pts with ACRC. Nevertheless this don’t impact on efficacy of treatment. Finally the high rate of clinical benefit encourage further enrollement of patients.In conclusion this schedule seem to be active and safe because improves tolerability without any decrease of efficacy in this kind of patients.
Prognostic significance of lymphadenectomy in patients with esophageal cancer receiving neoadjuvant chemoradiation.
Authors: Charmi Vijapura, Ravi Shridhar, Jill M. Weber, Sarah E. Hoffe, Jeremiah Lee Deneve, James S. Barthel, Richard C. Karl, Ken Meredith, Khaldoun Almhanna
Journal: Journal of Clinical Oncology (2012)

87 Background: The optimal number of lymph nodes that should be harvested in esophageal cancer patients remains to be defined, particularly in patients that receive neoadjuvant therapies. We investigated the impact of nodal resection and survival in esophageal cancer patients treated with neoadjuvant chemoradiation (NT). Methods: Using our comprehensive esophageal cancer database we identified patients treated with NT followed by esophagectomy between 2000-2011. Clinical and pathologic data were compared using Fisher’s exact and chi-square while, Kaplan Meier estimates were used for survival analysis. Overall (OS) and disease-free survival (DFS) were compared with varying numbers of lymph nodes resected &lt;10 and ≥10 (ST-1), &lt;12 and ≥12 (ST-2), and &lt;15 and ≥15 (ST-3). Multivariate analysis was analyzed by the Cox proportional hazard model. Results: We identified 358 patients treated with NT and esophagectomy with a median follow-up of 18.5 months (range, 0-116 months). There was no survival benefit demonstrated for patients with increased lymph nodes removed during their surgery (ST-1 OS p=0.400, DFS p=0.8727; ST-2 OS p=0.6833, DFS p=0.6092; ST-3 OS p=0.1798, DFS p=0.4028). Patients were further stratified by pathologic response to NT and nodal harvest. There were no differences in OS or DFS in patients with increased nodal harvest when analyzed by complete (pCR) (ST-1 OS p=0.7278, DFS p=0.3602; ST-2 OS p=0.6182, DFS p=0.3592; ST-3 OS p=0.4489, DFS p=0.6976), partial (pPR) (ST-1 OS p=0.3762, DFS p=0.5061; ST-2 OS p=0.8036, DFS p=0.6497; ST-3 OS p=0.0890, DFS p=0.3364), or non response (pNR) (ST-1 OS p=0.6825, DFS p=0.7161; ST-2 OS p=0.7084, DFS p=0.8351; ST-3 OS p=0.5002, DFS p=0.7314) to NT. Multivariate analysis demonstrated that age (p=0.028), t-stage (p=0.006), pPR (p=0.025), and pNR (p&lt;0.0005) to NT were all independent predictors of mortality. Conclusions: In our experience, the number of lymph nodes resected was not predictive for overall or disease free survival in esophageal cancer patients treated with NT. In addition, extended lymph node resection did not improve survival for those with residual disease.
Differential radiographic appearance of BRAF V600E mutant metastatic colorectal cancer (mCRC) in patients matched by primary tumor location.
Authors: Claire Greene, Chloe Evelyn Atreya, Ryan McWhirter, Nabia Ikram, Katherine Van Loon, Alan P. Venook, Benjamin M. Yeh, Spencer Behr
Journal: Journal of Clinical Oncology (2016)

554 Background: BRAF mutation status and location of CRC primary each correlate with pattern of metastatic spread. We sought to determine whether presence of a BRAF V600E (BRAF) mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: 40 patients with BRAF mutant mCRC were matched to 80 patients with BRAF wild-type CRC by location of primary tumor (right colon, left colon or rectum), sex, and age ( &lt; 50; 50+). CT scans were reviewed for disease characterization. BRAF mutation status, clinicopathological characteristics, and sites of metastatic disease were associated using proportion tests. Results: Of the 120 matched patients,60% were female. The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Median age at diagnosis was 57, range 20-88 yrs. Significantly higher frequencies of peritoneal metastases (p = 0.045) and ascites (p = 0.0038) occurred in patients with BRAF mutant tumors. Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. In patients with left colon primaries, BRAF mutations associated with less frequent liver metastases (42% vs. 79%, p = 0.024) and more frequent ascites (58% vs. 12%, p = 0.0038). Disease was not measurable by RECIST version 1.1 criteria in 20% of patients with BRAF mutations, most often with peritoneal metastases and ascites. Conclusions: Presence of a BRAF V600E mutation associated with a greater proportion of peritoneal metastases and ascites, even among patients matched for primary tumor location. Of 20 patients with BRAF mutant mCRC and peritoneal metastases plus ascites, 6 patients (30%) had disease that was not measurable by RECIST version 1.1. Radiographic characterization provides a window on BRAF mutant mCRC biology and also reveals a challenge for response evaluation on clinical trials. [Table: see text]
Is there a clinical benefit in testing for UGT1A1*28 prior to irinotecan therapy?
Authors: Bihani Yoshana Kularatne, Anthony Marinaki, Vasilis Karavasilis, James F. Spicer, Paul J. Ross, Dimitrios G. Pectasides, Thomas Makatsoris, George E. Pentheroudakis, George Fountzilas
Journal: Journal of Clinical Oncology (2012)

478 Background: Irinotecan is used in the treatment of colorectal cancer, with severe neutropenia and diarrhoea being the main dose limiting toxicities. UGT1A1 variants have been shown to predict irinotecan associated toxicity. Despite an FDA warning in 2005, few centres have undertaken UGT1A1 testing prior to the commencement of therapy. The reason for this has been the lack of consistent data supporting its use as a marker of either neutropenia or diarrhoea. Where significance has been shown, sample sizes have been small and confidence intervals wide. Methods: We retrospectively correlated the presence of UGT1A1*28 polymorphism with severe neutropenia or diarrhoea in Greek patients receiving irinotecan-based chemotherapy for metastatic colorectal cancer. Severe (grade 3 or 4) neutropenia or diarrhoea (Common Terminology Criteria version 4) for cycles 1-4 were recorded for all patients using electronic case notes. Patients were genotyped for UGT1A1*28 polymorphism. Results: Of the 362 patients evaluated, 205 (56.6%) received irinotecan (180-255 mg/m 2 , 3 weekly) in combination with capecitabine and 155 (42.8%) received irinotecan (160-200 mg/m 2 , 2 weekly) in combination with 5-FU. Forty four (12%) patients experienced severe diarrhoea and 19 (5%) severe neutropenia. Clinical response data was unavailable in 162 (45%) patients. A favourable radiological response (stable disease, partial or complete response) was seen in 170/200 (85%) patients. A homozygous UGT1A1*28 genotype was detected in 38/362 patients. Of these, three (8%) experienced grade 3 or 4 diarrhoea during cycles 1-4 and three (8%) experienced severe neutropenia. There was no statistically significant correlation between genotype and toxicity in this patient group. Conclusions: Our study of a Caucasian group of Greek patients, the largest study to date, failed to show any correlation with UGT1A1*28 polymorphism and the occurrence of grade 3 or 4 neutropenia or diarrhoea. The results of this study suggest that testing for the UGT1A1*28 mutation prior to the start of irinotecan therapy may not be clinically useful.
DNMT3A R882H Overexpression Acts in a Dominant Negative Manner to Cause DNA Hypomethylation and Increased Susceptibility to Hematopoietic Malignancies in Transgenic Mice
Authors: Angela M. Verdoni, Christopher B Cole, Shamika Ketkar-Kulkarni, Tamara Lamprecht, Nichole Havey, David H. Spencer, Timothy J. Ley
Journal: Blood (2014)
Bother following stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Onita Bhattasali, Leonard Chen, Jee-Won Park, Joy S. Kim, Thomas M. Yung, Brian Timothy Collins, Simeng Suy, John Lynch, Anatoly Dritschilo, Sean P. Collins
Journal: Journal of Clinical Oncology (2014)

195 Background: Stereotactic body radiation therapy (SBRT) delivers high doses of radiation while minimizing radiation to adjacent normal tissues. Large fraction sizes may increase the risk of functional decrements. However, treatment-related bother may be more important to a patient than treatment-related dysfunction. Methods: Between August 2007 and July 2011, 228 hormone-naïve patients with clinically localized prostate cancer were treated with 35-36.25 Gy SBRT delivered using the CyberKnife Radiosurgical System (Accuray) in five fractions. Patients completed the validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire at baseline, one month post-treatment, every three months the first year, then every six months. EPIC scores for bother range from 0 to 100 with lower values representing increased interference or annoyance caused by limitations in function. Results: Two hundred twenty eight patients at a median age of 69 (range, age 44 to 90) received SBRT with a minimum follow-up of 24 months. Urinary bother increased transiently first at one month and again at 12 months before returning to pre-treatment scores at two years: 80.2 (baseline); 68.2 (one month); 79.8 (three months); 78.3 (six months); 74.5 (nine months); 71.1 (12 months); 75.8 (18 months); 78.3 (24 months). Bowel bother followed a similar pattern but with a more protracted late-stage decline: 91.4 (baseline); 76.0 (one month); 87.8 (three months); 88.4 (six months); 85.8 (nine months); 85.7 (12 months); 87.8 (18 months); 90.1 (24 months). Sexual bother progressively worsened over two years: 65.9 (baseline); 64.8 (three months); 63.0 (six months); 63.2 (12 months); 59.0 (18 months); 58.4 (24 months). Conclusions: SBRT for clinically localized prostate cancer was well tolerated. Treatment-related bother was comparable to conventionally fractionated radiation therapy and brachytherapy. Transient late increases in urinary and bowel bother were observed at one year. Sexual bother steadily increased during the first two years following treatment.
Identification of mutations of the SWI/SNF complex gene PBRM1 by exome sequencing in renal carcinoma.
Authors: B. T. Teh, I. Varela, P. Tarpey, K. Raine, D. Huang, C. K. Ong, K. A. Furge, P. J. Campbell, M. R. Stratton, P. A. Futreal
Journal: Journal of Clinical Oncology (2011)

4571 Background: The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. Methods: A recent large-scale screen of ~3500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (KDM6A), JARID1C (KDM5C)and SETD2. These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Results: Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodeling complex gene PBRM1 as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. Conclusions: These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
A phase II study of docetaxel (D) followed by flavopiridol (F) in advanced, gemcitabine-refractory pancreatic cancer (PC)
Authors: R. D. Carvajal, M. A. Shah, A. Tse, R. Lefkowitz, D. P. Kelsen, G. K. Schwartz, E. M. O'Reilly
Journal: Journal of Clinical Oncology (2008)

15558 Background: PC harbors frequent alterations of p16, a cyclin-dependent kinase inhibitor (CDKI), resulting in cell cycle dysregulation. In a phase I study of docetaxel (D) → flavopiridol (F), a CDKI that potentiates chemo-induced apoptosis in PC cell lines, 10 patients (pts) with PC were treated: 1 had a complete response (CR) lasting >2 yrs, 1 had a partial response (PR), and 4 had stable disease (SD) (Fornier et al, Clin Cancer Res, 2007). We thus designed a National Cancer Institute sponsored phase II study of D → F in pts with gemcitabine-refractory PC. Methods: Pts with stage IV PC and measurable disease by RECIST, who progressed on one prior gemcitabine-based therapy in the adjuvant, locally advanced, or metastatic setting, were eligible. Pts received D 35mg/m2 followed 4–6 hours later by F 80mg/m2 on days 1, 8 and 15 q28 days (1 cycle). Response was assessed every 2 cycles. A Simon two-stage design was used to evaluate the primary endpoint of response (RECIST), with a projected response of 5% for D alone and 25% for D → F. If <1 response was seen in the first 9 pts treated, the study was to be terminated. If ≥4 responses were seen in 30 patients, then the study was to be considered positive. Results: 10 pts were enrolled; 9 were evaluable for response. Median age: 64 yrs (range, 49–81); 4 male/6 female; median KPS: 80 (range, 70–90). No response was seen and the study was closed after the 1st stage. 6 pts (67%) had progression as their best response following 2 cycles of therapy. 3 pts achieved SD (33%), with 1 achieving a 20% minor response; all 3 progressed clinically before completion of the 3rd cycle. Toxicity was significant, with 7 pts (78%) requiring ≥1 dose reduction for transaminitis (n=1, 11%), grade (gr) 4 neutropenia (n=3, 33%), gr 3 fatigue (n=4, 44%), and gr 3 diarrhea (n=2, 22%) Conclusions: D → F has minimal activity and significant toxicity in pts previously treated for PC. The different outcomes in the phase I and II studies may be due to pt selection: the phase I pts were younger (56.5 vs 64.0 yrs) with a higher KPS (90 vs 80). Those who achieved CR/PR/SD on the phase I study were less heavily treated. The toxicities observed reflect the challenges of treating pts with PC in a 2nd-line setting where the risk/benefit equation is tightly balanced. Supported by R01CA67819 (GS). No significant financial relationships to disclose.