tbuckley/cabot-search huggingface dataset:
Renal effects of high dose celecoxib (C) during 2 phase II trials for hormone resistant prostate cancer (HRPC)
Authors: M. Yudd, B. Kasimis, S. Hwang, G. Stanislaus, S. McDowall, A. Haastrup, J. Penix, I. Boholli, Q. Xia, N. Nazha
Journal: Journal of Clinical Oncology (2005)

4751 Background It is unknown if high doses of Cox -2 inhibitors in cancer regimens have adverse renal effects. Concerns include acute renal failure (ARF), hyperkalemia (hyper K), proteinuria and hypertension. Methods 33 patients (pts) with HRPC and median (med) age of 74 years (56–95) were treated in 2 phase II trials (Kasimis and Zhong: Proc ASCO 2005 subm). All received high dose C 400 mg bid po for a med period of 4 months (M) (2–6); 25 received Docetaxel, and 8 received Epirubicin and Extramustine Phosphate. Chemistries, UA, and blood pressure (BP) were measured at baseline and every M. All ARF and hyper K episodes were evaluated by a nephrologist. Results Table shows that estimated glomerular filtration rate (e-GFR), creatinine (creat), K and BP did not change during C treatments at 1 and at the final M compared to baseline. Minor, clinically unimportant decreases in serum calcium and bicarbonate, and increases in chloride were noted. 7 mild and reversible episodes of ARF (>50% rise in creat) occurred in 6 pts during 142 Ms of treatment (1 episode/20 Ms) due to volume depletion in 3, obstruction in 2, sepsis in 1, and contrast in 1. C was not a major precipitating factor and 6 of 7 pts continued C after ARF without recurrences (1 pt withdrew after renal function improved). 3 pts had solitary episodes of mild hyper K (5.5–6.0 mmol/L); 1 pt with DM nephropathy receiving ACE had 3 episodes of hyper K, reaching 6.6 mmol/L. After ACE was stopped in 2 pts, hyper K never recurred. No pts developed increasing proteinuria. Conclusion High dose C was well tolerated. The incidence of ARF and hyper K was low, and causes were attributed to other factors. No differences in renal function (creat, e-GFR), K, and BP were noted during 142 Ms of C treatment compared to baseline, and no pts developed persistent proteinuria. No significant financial relationships to disclose.
Multivariate analysis of predictors of positive or close margins in breast-conserving therapy.
Authors: A. Chokechanachaisakul, C. A. Wesen, T. M. Hall, J. S. Falk
Journal: Journal of Clinical Oncology (2011)

105 Background: Local recurrence rates after breast-conserving therapy (BCT) are increased with positive or close margin lumpectomy. This group of patients usually requires a re-excision lumpectomy or a completion mastectomy, causing delays in systemic therapy, and a less desirable cosmetic outcome. The objectives of this study were to identify any predictive risk factors that might be associated with positive or close lumpectomy margins (&lt;1mm), and thus have implications for the planning of appropriate primary surgical excision. Methods: This was a retrospective cohort study of 195 consecutive patients from a prospectively collected, single-institution database. Patients who underwent primary lumpectomy for ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and invasive lobular carcinoma from October 2007 to July 2010 were reviewed. Statistical analysis of the data was performed using Chi-squared analyses, multivariate logistic regression and Student’s t-test to identify significant predictors of a close or positive margin following lumpectomy. Results: In this study, 53.8% had positive or close margins. Ninety-two percent of this group underwent re-excision (86.5%) and total mastectomy (13.5%). We also observed that 53.1% of patients who underwent second operation had no residual disease. Factors significantly associated with positive or close margins include a family history of breast cancer (OR=2.3, p=0.01), a non-palpable mass (OR=2.4, p=0.01), or an excisional biopsy (OR=6.02, p=0.022). Age, race, use of hormone replacement therapy, menopausal status, use of preoperative MRI or US, BIRAD, use of neoadjuvant chemotherapy, tumor size, staging, waiting time, histology, receptor status, and axillary status were not significantly correlated with positive or close margins. Conclusions: For patients who were recommended to have a lumpectomy, an increased risk of a positive or close margin was significantly associated with a family history of breast cancer, a nonpalpable mass, or an excisional biopsy. These predictors should be weighed in the decision for attempting lumpectomy with the goal of a negative margin versus the ability to obtain a satisfactory cosmetic outcome.
Survival prediction in carcinoma of unknown primary (CUP) based on the metastatic site
Authors: S. R. Veach, M. A. Saeed, J. Beschloss, R. Barrera
Journal: Journal of Clinical Oncology (2004)

4159 Background: The diagnosis and management of Carcinoma of Unknown Primary remains difficult. Survival is markedly influenced by factors such as histology of tumor and site of metastasis. Methods: Eligibility criteria for the study are tumour diagnosed only as CUP despite extensive laboratory and imaging studies with single metastatic site at presentation. Analysis of single institution database was carried out for the purpose of the study from year1997 to 2002. Kaplan-Meier curve is used to calculate survival and results are statistically significant when p<0.05. Results: Of 458 patients who were investigated, 200 patients had no primary site suspected and thus were eligible for analysis. 105 female and 95 male with mean age of 60 years were found. 84% (168) of tumors were poorly differentiated carcinoma and 2% (3) were well differentiated carcinoma. There were 27% (54) squamous cell carcinomas with mean survival of 50 months, 45% (89) adenocarcinoma with mean survival of 31 months and 14% (27) neuroendocrine carcinoma with 39 month mean survival. The mean survival data for liver 20% (40) was 28m, lymph nodes 37% (74) was 50m, bone 14%(28) was 30m, peritoneum8%(16) was 37m, lung13%(26) was 26m, brain 3%(6) was 22m, retroperitoneum 6%(5) was 11m and pelvic mass6%(5) was 27m. Conclusions: CUP from all sites results historically in a mean survival of 5 to 11 months. In this retrospective study the survival clearly was influenced by the site of first presentation and the histological characterization of the tumour. The diagnosis of squamous cell carcinoma carries a superior survival at 50 m. Lymph node presentation likewise carried the best survival statistics at 50m. The future chemotherapeutic trials of carcinoma of unknown primary should be designed utilizing the specific histology and site of presentation. No significant financial relationships to disclose.
Iron Toxicity Impairs Autophagy and Promotes ER Stress in Obesity and Alcohol-Induced Fibrosing Steatohepatitis
Authors: Terrence C. Tan, Darrell H. Crawford, Lesley Jaskowski, Nishreen Santrampurwala, V. Nathan Subramaniam, Andrew D. Clouston, Denis I. Crane, Gregory J. Anderson, Linda M. Fletcher
Journal: Hepatology (2012)
Tumor response and progression-free survival (PFS) as potential surrogate endpoints for overall survival (OS) in extensive-stage small cell lung cancer (ES-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials.
Authors: N. R. Foster, Y. Qi, Q. Shi, J. E. Krook, J. W. Kugler, J. R. Jett, J. R. Molina, S. E. Schild, A. A. Adjei, S. J. Mandrekar
Journal: Journal of Clinical Oncology (2010)

7637 Background: We investigated the putative surrogate endpoints (PSEs) of best response (BR), confirmed response (CoR), and PFS for association with OS, and as possible surrogate endpoints for OS. Methods: Individual patient (pt) data for 870 untreated ES-SCLC pts from 6 single-arm (274 pts) and 3 randomized trials (596 pts from 32 participating centers) containing platinum or paclitaxel-based regimens were pooled. Patient-level associations between the PSEs and OS were assessed by Cox models using a landmark analyses at 2, 4, and 6 months post-study entry. Model discrimination was evaluated using the concordance (c) index. Trial-level surrogacy of PSEs was assessed by the association of the treatment effects on OS and individual PSEs. Treatment effects were estimated through log hazard ratios and log odds ratios. Trial-level surrogacy measures included: R2 from a weighted least squares regression model (R2 WLS), Spearman rank correlation coefficient (Spearman), and R2 from a bivariate survival model (R2 Copula). Results: The median OS and PFS were 9.6 and 5.5 months, respectively; the BR and CoR rates were 44% and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (HR=0.42 [95% CI: 0.35, 0.51]; c-index = 0.63; p < 0.01), with 6-month PFS being the strongest (HR=0.41 [95% CI: 0.35, 0.49]; c-index = 0.66; p < 0.01). At the trial level, PFS showed the highest level of surrogacy for OS (R2 WLS = 0.79; R2 Copula = 0.80), which indicates that PFS explained 79% of the variance in OS and is a good surrogacy measure (see Table). Conclusions: PFS was strongly associated with OS, where PFS status as early as 4 months was a strong predictor of subsequent survival. PFS also shows promise as a potential surrogate for OS, and needs further validation using data from a larger number of randomized phase III trials. This data, if substantiated, will allow faster yet valid evaluation of drugs for ES- SCLC. Trial-level surrogacy measures Endpoint R2 WLS R2 Copula Spearman PFS 0.79 0.80 (95% CI: 0.67, 0.93) 0.75 BR 0.21 NA 0.52 CoR 0.40 NA 0.60 No significant financial relationships to disclose.
High-Dose Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation in Adulthood Histiocytocytic Disorders.
Authors: Nathalie Gaspar, Pascaline Boudou, Julien Haroche, Bertrand Wechsler, Eric Van Den Nest, Khe Huang-Xuan, Jean-Charles Piette, Veronique Leblond
Journal: Blood (2005)
Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): Preliminary efficacy analysis of a randomized phase III trial
Authors: J. Polikoff, E. P. Mitchell, S. Badarinath, C. D. Graham, A. Jennis, T.-T. Chen, T. N. Gustafson, C. Langer
Journal: Journal of Clinical Oncology (2005)

3574 Background: The EXPLORE study was designed as a randomized phase III study in patients (pts) with metastatic EGFR-positive colorectal cancer (CRC) who had received irinotecan in 1st-line. Pts were to receive either cetuximab (Erbitux) plus FOLFOX4 (5-FU, leucovorin, oxaliplatin), or FOLFOX4. The primary endpoint of the study was to be survival with secondary endpoints including response rate and time-to-progression. Although the study was designed to accrue 1100 pts, due to recent changes in clinical practice resulting in the replacement of irinotecan with oxaliplatin in the 1st-line setting, accrual to the current trial was stopped. An analysis of safety on the first 40 pts randomized to the study was reported at ASCO 2004 (Abstr# 3531). Methods: Pts with metastatic EGFR-positive CRC who had progressed on prior 1st-line irinotecan therapy with an ECOG performance status ≤ 2 received either Cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly dose and FOLFOX4 d1,d2 q 2 weeks (Arm A) or FOLFOX4 q 2 weeks (Arm B). Results: 102 pts were randomized from March 2003 through October 2004. Dosing information is available on 90 pts: 41 women and 49 men with a median age of 59 years (range 29–08). Forty-three pts treated on Arm A received a total of 407 cycles with a median of 8 cycles per patient (range 1–36). Forty-seven pts on Arm B received a total of 304 cycles with a median of 6 cycles per patient (range 1–20). Tumor measurements are available for 43 pts on Arm A and for 42 pts on Arm B pts. In Arm A, 9 pts had partial responses (PR), 20 pts had stable disease (SD) (including 2 unconfirmed PRs (uPR)), and 6 pts had progressive disease (PD). It was too early to report a response in an additional 8 pts. In Arm B, 4 pts had PRs, 26 had SDs (including 2 uPRs), and 9 had PDs. It was too early to determine a response in an additional 3 pts. Of the pts assessed for efficacy, 7 pts on Arm A and 5 pts on Arm B remain on study. The study is closed to accrual and final data on all pts will be presented at the meeting. Conclusions: The combination of FOLFOX4 and Cetuximab is active in pts with metastatic CRC previously treated with irinotecan. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab in combination with escalating doses of oral cediranib for patients with advanced malignancies
Authors: D. W. Davis, W. Liu, R. Kurzrock, A. Naing, J. Wheler, L. W. Ricks, S. Ivy, D. Hong
Journal: Journal of Clinical Oncology (2009)

3525 Background: Rare circulating tumor cells (CTCs) and endothelial cells (CECs) offer a feasible approach for studying the pharmacodynamic effects of investigational agents. We investigated the effects of bevacizumab (B) and cediranib (C) on inhibition of the VEGFR pathway and correlated these changes with dose and clinical response. Methods: Peripheral blood was obtained at baseline, 24hrs and at C2D26–30 post-treatment from patients (n=14) undergoing dose escalation of intravenous B and oral C. CTCs and CECs (CD31+ or CD105+) were isolated and immunofluorescently stained. Laser scanning cytometry (LSC) was used to quantify phosphorylated and total-VEGFR2 (pVEGFR2/VEGFR2), pERK/ERK, and apoptosis in each phenotype. Changes in each biomarker were correlated with partial response (PR) or stable disease and progression &gt; 2 months, evaluated using RECIST. Results: Overall, immature CECs (CD105+) enumerated by CellSearch™ revealed a dose-dependent significant decrease (p=0.0001). A 3-fold induction in apoptosis was observed at 24 hrs compared to baseline in the CD105+ CECs. Mature CD31+ cells assessed for VEGFR2 activity revealed an 83% and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low (B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the non-responders, mature CECs revealed a dose-dependent significant increase (-6.8% to 63%;p=0.031) in pERK/ERK expression levels. No significant changes were observed in CTC enumeration by CellSearch™. LSC-mediated CTC enumeration revealed a 4.77 % and 2.33% increase in CTCs following treatment in the non- responders and responder (p=0.809), respectively. Analysis of pVEGFR2 in CTCs revealed a 58% inhibition in the responder versus a 163% increase in expression in the non-responders (p=0.63). Conclusions: Inhibition of pVEGFR2 and induction of apoptosis in CECs confirmed the target therapy. An increase in CD105+ CECs is consistent with the hypothesis that anti-angiogenic efficacy induces endothelial cell shedding. Assessment of CECs indicates that B and C are more biologically active at lower doses, and resistance may be attributed to ERK activity. Support: UO1 CA062461 (RK) No significant financial relationships to disclose.
High-grade neuroendocrine carcinomas of the gastrointestinal tract: The Memorial Sloan - Kettering Cancer Center experience of 143 cases
Authors: B. Brenner, J. Shia, D. S. Klimstra, M. Gonen, M. A. Shah, G. D. Leonard, D. P. Kelsen
Journal: Journal of Clinical Oncology (2004)

4123 Background: High grade neuroendocrine carcinoma (HGNEC) of the gastrointestinal tract (GIT) is a very rare and aggressive malignancy. To better define its clinicopathological features, a retrospective single institution analysis was performed. Methods: The records of all patients with histologically proven HGNEC of the GIT seen at Memorial Sloan Kettering Cancer Center between 1980 and 2003 were reviewed. Results: One-hundred forty-three patients were identified, 73 with small cell carcinoma (SmCC) and 70 with large cell neuroendocrine carcinoma (LCNEC). The most common primary tumor location was in the large bowel. Thirty-eight percent of tumors had non-HGNEC components and 46% presented with extensive disease (ED), according to the VALSG staging system used in pulmonary SmCC. In limited disease (LD), surgery and chemoradiation resulted in a small group of long-term survivors, while chemotherapy was essentially palliative. Using chemotherapy, most commonly platinum and etoposide, a 50% response rate was observed. The median survival for the entire group was 13 months and the 3-year survival rate was 14%. Performance status (p<0.01) and weight loss (p=0.01) were found to predict outcome. No significant differences in patient and tumor characteristics nor in outcome were noted between SmCC and LCNEC. Tumors from different locations shared most of their clinicopathological features, although those arising at the upper GIT were found at an earlier stage and tended to have better prognosis. Conclusions: HGNEC from various sites within the GIT can be viewed as one clinical entity. SmCC and LCNEC have similar prevalence and clinicopathological characteristics. Mixed tumor histology is common and may affect therapy. Surgery and chemoradiation for LD may result in long-term survival. Response rate to chemotherapy appears lower than expected from the perceived similarity to SmCC of the lung. No significant financial relationships to disclose.
Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizamab for patients with unresectable colorectal liver-limited metastasis.
Authors: Robert C. G. Martin, Charles R. Scoggins, William S. Rilling, Marshall T. Schreeder, John S. Kauh, Steven M. Strasberg, Todd S. Crocenzi, Rebecca Redman, Vivek R. Sharma
Journal: Journal of Clinical Oncology (2014)

174 Background: Reports have demonstrated the activity of combining both Irinotecan and Oxaliplatin into a FOLFOXIRI therapy. An option to gain similar benefits and less toxicity to FOLFOXIRI would be to administer the irinotecan through an hepatic arterial apporach. The aim of this study was to assess the maximal response and adverse event rates of Irinotecan Drug Eluting Beads (DEBIRI) with FOLFOX and Bevacizumab (Bev) as a first line treatment for unresectable colorectal liver metastasis (CLMs). Methods: Metachronous and Synchronous CLMs were randomly assigned to mFOLFOX6/Bev or mFOLFOX6, Bev and DEBIRI (FOLFOXDEBIRI). Primary end point was optimal response rates and adverse events. Secondary endpoints were patients (pts) converted to resection and survival. Results: The intention-to-treat population comprised 70 pts, 40 pts randomly assigned to the FOLFOXDEBIRI arm and 30 pts to FOLFOX/Bev arm. Both were similar with synchronous disease (50% vs. 36%), extent liver involvement (35% vs. 31%), but greater percentage in the FOLFOXDEBIRI arm of ECOG 1/2 (57% vs. 31%), p=0.04) and extra-hepatic disease (51% vs. 36%, p=0.02). Median number of chemotherapy cycles was similar in both arms of 8, with a similar Grade 3/4 adverse event rate of 54% FOLFOXDEBIRI and 46% FOLFOX/Bev arm. The overall response rate was significantly greater in the FOLFOXDEBIRI arm vs. FOLFOX/BEV at 2 mons (78% vs. 54%), 4 mons (95% vs. 70%) and 6 mons (76% vs. 60%, p=0.03). Significantly greater downsizing to resection in the FOLFOXDEBIRI arm vs. FOLFOX/Bev (35% vs. 16%, p=0.05), with an improved median progression free survival (15.3 mons vs. 7.6 mons). Overall improvement in hepatic specific progression free survival was seen in the treatment arm (12.8 mons vs. 10.5 mons). Conclusions: Simultaneous mFOLFOX6 with bevacizumab and hepatic arterial irinotecan drug eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity. Simultaneous FOLFOXDEBIRI leads to improved overall response rates, improved hepatic progression free survival, and more durable overall progression free survival in patients downsized to resection. Clinical trial information: NCT00932438.
Risk of brain metastases in HER2/neu-positive breast cancer
Authors: R. Altaha, E. Crowell, B. Ducatman, G. Higa, J. Abraham
Journal: Journal of Clinical Oncology (2004)

682 Background: Preliminary data indicate HER2/neu over-expression correlates with more aggressive disease, increased metastatic potential, and a poorer prognosis in patients with breast cancer. We conducted a retrospective study to evaluate whether patients with HER2/neu-positive breast cancer have an increased risk of developing brain metastases. Material and Methods: The pathology reports of 405 breast cancer patients diagnosed between April 1998 and January 2003 were reviewed. Based upon immunohistochemistry (IHC 3+) or FISH positivity, all HER2/neu-positive cases were identified and their medical charts reviewed for disease course and sites of metastases. Results: One hundred ten of the 405 patients (27%) were HER2/neu positive; sufficient oncologic history was available for 67 patients (24 premenopausal; 43 postmenopausal). Eighteen patients (27%) developed distant metastases (CI 95%: 0.177, 0.385) during follow-up lasting a median of 57 months. Brain metastases developed in 33.3% (6 out of 18)(CI 95%: 0.163, 0.562) of patients, five of who were <50 years of age; the sixth was 53 years old. The median time from diagnosis of breast cancer to development of brain metastases was 24 months (range 8 months –30 months) among the five patients <50 years old. The sixth patient found to have innumerable brain metastases in hemispheres, cerebellum and brain stem, 48 months after breast cancer diagnosis. There was a significant association (p=0.0485) between age of the patients and development of brain metastases in HER2/neu-positive breast cancer. Discussion: This small retrospective study shows that younger women with HER/2-neu-positive breast cancer may have a higher risk than reported for general metastatic breast cancer population, of developing brain metastases. This finding, if validated in larger studies, may alter treatment strategies for premenopausal patients with HER/2-neu-positive disease. No significant financial relationships to disclose.