tbuckley/cabot-search huggingface dataset:
A Phase I/II trial of fruquintinib in combination with paclitaxel for second-line treatment in patients with advanced gastric cancer.
Authors: Rui-hua Xu, Dongsheng Zhang, Lin Shen, Jin LI, Jing Huang, Jifang Gong, Weijian Guo, Yang Zhang, Songhua Fan, Ke Li, Ye Hua, Weiguo Su
Journal: Journal of Clinical Oncology (2017)

128 Background: Advanced gastric cancer (AGC) is a major problem particularly in Asian countries. The treatment options are limited after standard first line chemotherapy. This phase I/II study aimed to evaluate the tolerability, pharmacokinetics and preliminary efficacy of fruquintinib, a selective oral VEGFR inhibitor, combined with paclitaxel as second-line therapy in Chinese patients with AGC. Methods: This open arm phase I/II trial (NCT02415023) consisted of dose finding and dose expansion stages. In the dose finding stage, 3 dose levels of fruquintinib (2, 3, 4 mg; once daily for 3 weeks) were evaluated in combination with standard 80 mg/m2 paclitaxel (once weekly on Days 1, 8 and 15) in a 28-day cycle until the maximum tolerated dose or recommended phase II dose (RP2D) was reached. Additional patients were enrolled at the RP2D to further assess the efficacy, safety and pharmacokinetic profile. Results: As of Sept. 10, 2016, a total of 32 patients were enrolled including 15 during dose escalation. The RP2D regimen was determined to be fruquintinib 4mg daily combined with paclitaxel 80mg/m2 weekly for 3 weeks followed by 1 week off in a 4 week cycle. Two patients at 4mg experienced dose-limiting toxicity, both with febrile neutropenia. The grade 3 or 4 treatment emergent adverse events were neutropenia (40.6%), leukopenia (28.1%), decreased hemoglobin (6.25%), hand-foot skin reaction (6.25%), neurophlegmon (6.25%), and hypertension (6.25%), more frequent in the 4mg cohort. At steady state, Fruquintinib AUC (AUC ss ) increased dose-proportionally and within the historic range as a single agent, while paclitaxel exposure, at the RP2D regimen, increased by approximately 30% compared to the AUC prior to fruqintinib dosing. Twenty-eight of 32 patients were evaluable for response, and of these, 10 patients had partial response (Objective Response Rate = 35.7%), 9 patients experienced stable disease for at least 8 weeks (Disease Control Rate = 67.9%). At RP2D, ≥ 16w-PFS = 50% and ≥ 7m-OS = 50%. Conclusions: Combination of fruquintinb and paclitaxel appeared to be generally well-tolerated with promising tumor response. Further evaluation in a controlled phase II study is warranted. Clinical trial information: NCT02415023.
GRASPA-AML 2012-01 study (NCT01810705): A multicenter, open, randomized phase 2b trial evaluating ERY001 (L-asparaginase encapsulated in red blood cells) plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive chemotherapy.
Authors: Xavier G. Thomas, Emmanuelle Tavernier Tardy, Romain Guieze, Patrice Chevallier, Jean pierre Marolleau, Frederique Orsini, Ian Hitchcock, Iman El-Hariry
Journal: Journal of Clinical Oncology (2015)

TPS7099 Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells and the most common malignant myeloid disorder in adults, with a median age of 65 years at diagnosis. There is unmet medical need for elderly patient with AML unfit for intensive chemotherapy. L-asparaginase (L-ASP) plays a key role in all treatment phases for Acute Lymphoblastic Leukemia (ALL). Some leukemic cells, with asparagine synthetase deficiency, need plasmatic L-asparagine for protein synthesis. L-ASP hydrolyses L-asparagine leading to depletion of this amino acid. Normal cells are resistant to L-asparaginase because they can synthesize asparagine using asparagine synthetase. Several clinical studies and case reports showed a potential benefit of L-ASP in certain AML cell lines or mixed lineage leukemia. ERY001 is a novel platform of RBC encapsulation of L-asparaginase. Antitumor activity of ERY001 as well as any L-ASP is based on depletion in plasmatic asparagine, which is an essential amino acid for cells survival in almost all lymphoblastic cells. Methods: GRASPA-AML 2012-01 is an international multicenter, open label, randomized, phase 2b trial evaluating clinical activity and tolerability of ERY001 plus low-dose cytarabine (LDAC) vs LDAC alone, in treatment of elderly patients (65-85 years), with newly diagnosed AML and who are unfit for intensive chemotherapy. The primary objective is progression free survival (PFS). The key secondary objectives are: response to treatment, event free survival, overall survival, quality of life, pharmacokinetic and pharmacodynamics profiles, and immunogenicity. Patients are randomized 2:1 to: Arm A: LDAC only (40 mg daily for 10 consecutive days, every 28 days); Arm B, ERY001 (100 IU/kg) in combination with subcutaneous LDAC, for up to 24 months. Patients are assessed every 4-5 days during each cycle. The study is currently in recruiting phase. Seventy-three patients were recruited to date. Clinical trial information: NCT01810705.
Hepatocellular carcinoma (HCC): Resection with adjuvant hepatic artery infusion chemotherapy (HAIC) versus resection alone—A systematic review and meta-analysis.
Authors: Alexandra Moran, Lorena Flor Ramos, Omar Picado, Heather Stuart, Vikas Dudeja, Fiorella Pendola, Danny Sleeman, Nipun B. Merchant, Danny Yakoub
Journal: Journal of Clinical Oncology (2017)

357 Background: HCC have a recurrence rate of up to 70% in 5 years after resection detrimentally lowering survival. The role of adjuvant HAIC in management of HCC in patients who are not candidates for transplantation is controversial. We aimed to evaluate overall and disease free survival in these patients. Methods: A comprehensive online search of MEDLINE, EMBASE, PubMed, SCOPUS and the Cochrane database was conducted (Jan 1994 - August 2016). Comparative studies including patients with HCC, who are not transplant candidates, undergoing surgical resection and adjuvant HAIC vs surgical resection alone were reviewed. Study quality was assessed using STROBE checklist. Pooled risk ratios and 95% confidence intervals (CI) for overall and disease-free survival at 1, 3 and 5 years were calculated. Results: Overall, 10 studies with 595 HCC patients were included; 283 underwent resection followed by HAIC and 312 underwent resection alone. Mean age was 61 ± 10.1 years with a male/female ratio of 6/1. Meta-analysis of all included studies showed better overall survival in patients undergoing resection followed by HAIC compared with resection alone at 1-YR (Average 90.1% vs 79.5%, RR:1.15, CI:1.07 – 1.24, p=0.095, NS), 3-YR (Average 72.1% vs 49.4%, RR:1.57, CI:1.34 – 1.77, p&lt;0.01) and 5-YR (Average 51% vs 30.2%, RR:1.71, CI:1.33 – 2.20, p&lt;0.01). Median survival time for the resection with HAIC group was 54.94 months compared to 31.5 months for the resection alone group. In addition, disease-free survival was better with HAIC at 1-YR (RR:1.36, CI:1.21 – 1.54, p&lt;0.01), 3-YR (RR:1.59, CI:1.27 – 1.98, p&lt;0.01) and 5-YR (RR:1.85, CI:132. – 2.61, p=0.011). The median disease-free survival time for the resection with HAIC group was 17.5 months compared to 7.35 months for the resection alone group. Subgroup analysis showed that this survival advantage was more significant in patients with tumors ≥7cm (p&lt;0.05). Conclusions: Combination of HCC resection with HAIC improve overall and disease-free survival of patients with HCC who are not candidates for transplantation, especially in tumors ≥ 7cm.
Minimally invasive hepatectomy conversions: An analysis of outcomes.
Authors: Jack P Silva, Nicholas G Berger, Susan Tsai, Kathleen K. Christians, Callisia Clarke, Harveshp Mogal, T. Clark Gamblin
Journal: Journal of Clinical Oncology (2017)

430 Background: Surgical approach has been described as a factor influencing morbidity in patients undergoing hepatectomy. Minimally invasive surgery (MIS) converted to open has previously been included in an open hepatectomy cohort of the National Surgical Quality Improvement Program (NSQIP) dataset for analysis. This study sought to compare MIS conversion to open hepatectomy cases and analyze factors leading to conversion. Methods: The NSQIP data set was queried for patients undergoing hepatectomy for liver disease between January 1, 2014 and December 31, 2014. Cases were divided into three cohorts: completely MIS (laparoscopic or robotic), open, or planned MIS converted to open approach according to the dataset definitions. Demographic, clinical-pathologic, and perioperative variables were described and short-term postoperative outcomes were compared between groups. Results: A total of 2,884 patients were identified. Open approach was performed most commonly (80.96%, n = 2,335), followed by minimally invasive (15.05%, n = 434) and MIS converted to open (3.99%, n = 115). Patients undergoing conversion were more likely to have higher BMI, hypertension, and hepatocellular carcinoma. Conversion patients suffered from significantly higher morbidity (p &lt; 0.001) compared to MIS, but had comparable outcomes to open procedures. Conclusions: MIS hepatectomy has been shown to have lower morbidity but similar mortality to open hepatectomy. Conversion procedures appear to have similar outcomes to open procedures, with greater morbidity compared to MIS. Differences in morbidity from previous studies may be partially attributed to the inclusion of conversions in the open hepatectomy cohort.
Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer
Authors: K. Y. Chung, B. Minsky, D. Schrag, E. O’Reilly, D. D’Adamo, E. Hollywood, M. Quinones, L. Saltz
Journal: Journal of Clinical Oncology (2006)

3560 Background: Cetuximab, a chimeric anti-EGFR monoclonal antibody, has clinical activity in colorectal cancer with demonstrated safety, efficacy and additive synergy with radiation in solid tumors (head &amp; neck, lung). A pilot trial was therefore designed to investigate the safety of cetuximab in combination with standard neoadjuvant protracted infusion 5-FU and radiation therapy in ultrasound T3–4 (uT3–4) or clinical T4 (cT4) or locally recurrent rectal adenocarcinoma. Secondary objectives of clinical activity were assessed by R 0 resection and pathologic complete response (CR) rates. Methods: uT3–4 or cT4 or locally recurrent rectal adenocarcinoma patients received cetuximab 400mg/m 2 day 1 (250mg/m 2 weekly thereafter) and 5-FU IVCI (225mg/m 2 ) over 5.5 weeks with concurrent pelvic radiation (5040cGy), and cetuximab (250mg/m 2 Qweek) for 4 additional weeks, followed by surgical resection 1–3 weeks later. Results: Total Treated: 20 patients (ages 27 - 72), 19 uT3 patients, 1 Local Recurrence patient. Cetuximab Therapy (10 planned treatments): Too early 2 pts, ≥ 8 doses 12 pts, 5 - 8 doses 2 pts, &lt; 5 total doses 4pts* (*cetuximab not given due to: 1 pt - acute cholecystitis from cholelithiasis; 1 pt - Grade 3 radiation perineal toxicity; 2 pts - treatment non-compliance). Radiation Therapy - 18 pts completed, 2 pts too early. Grade 3/4 Toxicities: Diarrhea 10%, Acneiform Rash (outside RT field) 15%, Stomatitis 5%, Radiation Field Dermatitis 5%, Transaminitis 5%. Surgical Outcomes: (17 pts completed surgery): R 0 Resection 100%, Pathologic CR 12%. Conclusions: Cetuximab in combination with protracted infusion 5-FU and concurrent radiation is feasible without synergistic or unexpected toxicities. Further randomized investigation of this regimen in the neoadjuvant setting for rectal cancer is warranted. No significant financial relationships to disclose.
Utility of bortezomib retreatment among patients with refractory multiple myeloma
Authors: J. L. Wolf, A. L. Leblanc MT, D. S. Battleman, B. Davis, J. R. Lyandres, I. B. Walters
Journal: Journal of Clinical Oncology (2006)

17549 Background: Bortezomib (VELCADE; Vc) has emerged as the standard of care for patients with relapsed or refractory multiple myeloma (MM). However, following initial Vc therapy, its utility in recurrent disease is unclear. This retrospective case series provides preliminary evidence of the safety and efficacy of Vc in the retreatment of patients with recurrent MM. Methods: An observational case series was developed based on a medical records review of all patients (N = 10) who completed Vc retreatment following completion of initial Vc therapy. Best response was measured as the greatest mean % reduction in the treatment response measure: serum/urine M-protein or plasma cells. Differences between initial treatment and retreatment efficacy and Vc-related hospitalizations were assessed using descriptive statistics. Results: During initial treatment 44% of patients responded to Vc (≥50% M-protein (3/9) or plasme cell reduction (1/9, 1 pt NA). At retreatment 50% of patients responded (5/10). Following initial Vc therapy, the median treatment-free interval was just over 13 months (56.6 weeks). One patient experienced a dose reduction due to peripheral neuropathy (grade 2) during retreatment, compared to two patients with neuropathy (grade 3) during initial treatment. Termination of therapy due to any unmanageable toxicity was much lower during retreatment (14.3% vs 62.5%). Finally, none of the patients were hospitalized for Vc-related events during retreatment, compared with two patients during initial treatment. Conclusions: Vc retreatment appears to be as effective as initial treatment in terms of response, and may actually yield less toxicity and hospitalizations. Even though this small sample size precluded statistical testing, the observed patterns are instructive and additional prospective trials are currently ongoing. However, based on these preliminary data, prolonged disease control may be achieved with repeated use. [Table: see text]
Inhibition of BRAF activity by the Raf kinase inhibitor BAY 43-9006 inhibits melanoma tumor development
Authors: Nishit R. Trivedi, Arati Sharma, Melissa Zimmerman, Charles D. Smith, Dave Tuveson, Gavin P. Robertson
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

3846 

Activating mutations of the BRaf gene are found in >60% of human melanomas. Approximately 90% of these mutations occur in the activation segment of the kinase domain as a single base substitution. This change converts a valine to glutamic acid at codon 599 (V599E) in exon 15. This mutation leads to activation of the kinase, and is suspected of activating downstream effectors of the MAP kinase-signaling cascade leading to melanoma tumor development. In this study, we evaluated the role that the V599E BRaf mutation plays in melanoma tumor development by determining whether inhibition of V599E BRaf activity prevented melanoma tumor development. We used siRNA targeted against BRaf or a Raf kinase inhibitor (BAY 43-9006) to reduce expression or activity in our melanoma xenograft tumor model. SiRNA targeting of BRaf in melanoma cells expressing V599E BRaf, reduced activity of the MAP kinase-signaling cascade in culture and inhibited tumor development in animals. In contrast, siRNA against CRaf or laminin had a negligible effect on tumor development. Furthermore, treatment with BAY 43-9006 also inhibited tumor development in a dose-dependent manner. The effects of BAY 43-9006 were measured on cellular proliferation, apoptosis and vascular development in temporally and spatially matched tumors using BRDU staining, a TUNEL assay and CD31 staining, respectively. Compared to controls, tumors in mice treated with BAY 43-9006 showed a significant decrease in vascular development and an increase in apoptosis. To confirm this mechanism of action of BAY 43-9006 we analyzed the tumors at several sequential time points after administration of the drug and the results strongly suggest that the increase in apoptotic rates was a consequence of inhibition of angiogenesis. Thus, BRaf is a vital therapeutic target in melanoma tumor development and BAY 43-9006 may be a useful therapeutic drug for the treatment of this cancer.
Effect of obesity on overall survival in patients diagnosed with chronic myelomonocytic leukemia (CMML).
Authors: Dima Alfakara, Amer Swedeh, Gregory Kaufman, Mrinal M. Patnaik, Sharukh Hashmi, William J. Hogan, Michelle A. Elliott, Alexandra P. Wolanskyj, Shujun Liu, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2013)

7064 Background: Obesity is a growing medical challenge that has strong association with many comorbid diseases. Body mass index (BMI) is used as one indicator for obesity. A few papers have linked hematological cancers with a worse prognosis if obesity was present. Aim: to study the influence of obesity clinical outcome in patients (pts) with CMML. Methods: A retrospective chart review of pts with CMML at Mayo Clinic Rochester between 1994–2011 was done. BMI was calculated at diagnosis or first time visit. Overweight was defined as BMI ≥25, while obesity as BMI &gt;30. IRB approval was obtained. Comparison between medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier estimates via JMP software v.9. Results: We found227 pts with a median follow-up of 311 days, 68% of which weremales. Median age was 71 years, hemoglobin 11 gm/dL, white blood cells (WBC) 12x 10 9 /L, and platelets 90x 10 9 /L. Obese pts had a median age of 68 (p=0.0058), hemoglobin 11 gm/dL (p=0.0018), WBC 13.5 x 10 9 /L, platelets 115x10 9 /L (p=0.012), PB blasts 0, bone marrow (BM) blasts 3.5% compared to non-obese pts (73, 10, 11, 78, 0, 3%, respectively). Diploid cytogenetics were similar in both groups (68% vs 64%, respectively, p=0.54). Leukemic transformation into acute myeloid leukemia (LT) was found in 13% vs 10% (p=0.83). Overall response (OR) was 24% and 23%, respectively (p=0.2), when limited to hypomethylating agents OR was 33% vs 27%, respectively (p=0.62). Median OS was found to be similar (571 day vs 569 days, respectively, p=0.56). When compared, overweight pts had similar outcome to non-overweight. Median LT was 11% vs 15% respectively, OR was 21% vs 28% respectively (p=0.5), and OS was 571 days vs 549 days respectively (p=0.21). On a multivariate analysis age, hemoglobin, platelets, BM blasts%, gender, and obesity (p=0.048) were of a significant value for OS. Conclusions: When compared, both obesity and overweight did not affect demographic characteristics, overall response, or transformation into AML. When comparing median overall survival, obesity was not a significant factor, possibly due to short follow-up. However, on multivariate analysis obesity did have a negative impact on overall survival.
Systemic chemotherapy (CT) as salvage treatment for locally advanced rectal cancer (LARC) patients (pts) who fail to respond to neoadjuvant chemoradiotherapy (CRT).
Authors: Francesco Sclafani, Gina Brown, David Cunningham, Sheela Rao, Paris P Tekkis, Diana M. Tait, Federica Morano, Chiara Baratelli, Eleftheria Kalaitzaki, Shahnawaz Rasheed, David J. Watkins, Naureen Starling, Andrew Wotherspoon, Ian Chau
Journal: Journal of Clinical Oncology (2017)

709 Background: International guidelines suggest that RT dose escalation, intraoperative RT or brachytherapy could be considered for LARC pts with positive resection margins, pT4 or unresectable tumours after standard neoadjuvant CRT. However, data to support these approaches are scarce. The potential of systemic CT as salvage treatment after failure of neoadjuvant CRT for LARC has never been explored. We conducted a single-centre, retrospective analysis to address this question. Methods: Pts with newly diagnosed rectal adenocarcinoma who were deemed inoperable or candidates for extensive (i.e. beyond total mesorectal excision, TME) surgery after completion of long-course RT and received salvage systemic CT were included. The primary objective was to estimate the proportion of pts who became potentially suitable for TME after CT. Secondary objectives included the proportion of pts who ultimately underwent TME and survival outcomes. Results: 45 pts (2001-2015) met the study inclusion criteria (39 candidates for extensive surgery and 6 with unresectable tumours). Previous RT was given concurrently with CT in 43 cases (median dose: 54.0 Gy; range: 34.0-55.8). Salvage oxaliplatin-based and irinotecan-based CT was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. 8 pts (17.8%) became suitable for TME based on the MRI after CT, 10 (22.2%) ultimately underwent TME with clear margins and 2 (4.4%) were managed with a watch &amp; wait approach following radiological clinical complete response. Additionally, 13 pts had a beyond-TME surgery with curative intent. 3-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% CI: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and watch &amp; wait pts these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Conclusions: Systemic CT may be an effective salvage strategy for LARC pts who fail to respond to long-course CRT and are inoperable or candidates for beyond-TME surgery. According to our study, 1 out of 4 pts may become resectable or being spared from an extensive surgery after systemic CT.
Molecular profiling of ER weakly-positive breast cancer.
Authors: Brandon S. Sheffield, Zuzana Kos, Xiuqing Wang, Christine Chow, Sherman Lau, Robert Wolber, Cyril Blake Gilks, Nickolas Myles, Thomas A. Thomson, Malcolm M. Hayes, Rakesh Rachamadugu, Inge J. Stijleman, Philip B. Bernard, Torsten O. Nielsen, Stephen K. L. Chia
Journal: Journal of Clinical Oncology (2015)

525 Background: The estrogen receptor (ER) is a key predictive biomarker in the treatment of breast cancer. Luminal subtypes of breast cancer express ESR1, and are eligible for hormonal therapy. Standard laboratory assessment of ER status is currently immunohistochemistry (IHC)-based. Since the introduction of ER IHC, the threshold for positivity has decreased from 10% to ≥ 1% of tumor cells whilst methodological advances have increased the sensitivity of IHC detection. These trends have led to considerable uncertainty regarding the use of hormonal therapy in the setting of ER weakly-positive tumors. We report intrinsic subtype classification on a cohort of ER weakly-positive early stage cancers and discuss the implications on clinical treatment. Methods: Consecutive cases of untreated, surgically resected primary breast cancer were retrospectively identified from 4 tertiary care centres in British Columbia, Canada. All participating centres engage in routine external proficiency testing for breast biomarkers. Based upon the semiquantitative Allred score, combining staining intensity and percentage of tumor cells, ER-negative (Allred 0 and 2) and ER weakly-positive (Allred 3-5) cases were included. Gene expression profiling was performed using qRT-PCR. Intrinsic subtype prediction was made based upon the PAM50 gene expression signature. Results: 153 cases were included in the series; 62 cases originally diagnosed as ER weakly-positive and 91 ER-negative. Weak ER signal by IHC correlated poorly with ESR1 gene expression by qRT-PCR (R2 =0.2 [0.1-0.3, 95% CI]). Of the 62 cases originally assessed as ER weakly-positive, only 6 (10%) were confirmed as luminal subtype by gene expression profiling with the remaining cases showing basal-like or HER2-enriched subtypes (90%). In this highly enriched ER weakly-positive cohort, the positive predictive value of low-level ER staining for luminal subtype was extremely poor (8% [3%-18%, 95% CI]). Conclusions: Weak ER expression by IHC is a poor correlate of both luminal subtype and ESR1 expression in breast cancer. In the setting of highly sensitive and robust IHC methodology, cutoffs for ER status determination and subsequent systemic therapy may need to be revisited.