tbuckley/cabot-search huggingface dataset:
Evolution in the treatment of esophageal disease at a single institution: 2004-2013.
Authors: David V Pham, James P. Dolan, Brian S. Diggs, Erin W. Gilbert, Brett C. Sheppard, Brandon Tieu, Paul Schipper, Fernando M Giraud, Charles R. Thomas, John G. Hunter
Journal: Journal of Clinical Oncology (2015)

96 Background: The aim of this study was to analyze the evolution in the surgical management of esophageal disease at an academic medical center during the last decade. Methods: We reviewed a retrospective cohort of patients who underwent esophagectomy between 2004 and 2013 for benign and malignant esophageal disease. Patient, institutional and postoperative variables were abstracted and reviewed across the study period. Results: 317 patients were analyzed. The median age was 63.5 years and 80% were male. Malignancy accounted for 88% of esophagectomy patients in 2004 and 97% in 2013. Operations for high grade dysplasia (HGD) decreased 75% in the same period (p=0.008). In 2004, an Ivor Lewis esophagectomy was the most common surgical technique but the 3-Field technique has become the operation of choice in 2013 (54% vs.71%, p&lt;0.001). Likewise, a laparoscopic approach was used in 19% of cases in 2004 and 100% of cases in 2013 (p&lt;0.001). Median lymph node harvest increased from 7 to 18 nodes (p=0.001). Atrial fibrillation was the most common perioperative complication (24%) and anastomotic leaks ranged between 3 to 14% (p=0.18), occurring in 3% of patients in 2013. Hospital stay decreased from 15 to 8 days over the study period (p=0.001). In 2013, 89% of patients were discharge to home compared to 73% in 2004 (p=0.04). The average mortality rate for our cohort was 3.5%. Conclusions: Over the last decade, our treatment of esophageal disease has evolved from a predominant open Ivor Lewis to a laparoscopic 3-Field approach. Operations for malignancy have also increased dramatically. Postoperative complications and mortality has been consistently low during the latter years of the study.
Randomized phase I/II trial of two schedules of bortezomib and bevacizumab (BBmibmab) in metastatic renal cell cancer: USC trial 4K-05-1.
Authors: David I. Quinn, Denice Wei, Kristy Massopust, Charlean Ketchens, James Hu, Amir Goldkorn, Ana Aparicio, Sarmad Sadeghi, Jacek K. Pinski, Monica Averia, Susan G. Groshen, Tanya B. Dorff
Journal: Journal of Clinical Oncology (2016)

574 Background: VEGF agents are a mainstay of therapy in advanced RCC. Bev has activity in RCC but was licensed with interferon-α, which can produce side effects and reduced QoL. Based on non-overlapping side effect profiles, we studied bortezomib (Bmib), a proteasome inhibitor, with the VEGF ligand monoclonal antibody, bevacizumab (Bmab). Primary objective was to examine safety/toxicity of 2 dose schedules of Bmib with Bmab with secondary aims of efficacy (benchmarked to NCI data) and correlatives. Methods: From 2005 and 2014, 62 RCC patients with clear cell or papillary predominant histology treated with 0-4 prior therapies were screened: 10 screen failed, 4 were ineligible (2 treated, 2 not) leaving 48 eligible patients, of whom 46 were evaluable for safety and efficacy endpoints with 20 in each of the phase II dose schedules. Regimens were randomly allocated, stratified by MSKCC group. Results: Best tolerated doses of Bmib with Bmab 10mg/kg IV q3wks on each regimen were A: 1.3 mg/m 2 on D 1, 4, 8 and 11 q3wks &amp; B: 1.8 mg/m 2 on days 1 and 8 q3wks. MSKCC strata: low, intermediate, high risk in 43, 42%; 48, 49%; 9, 9% for schedules A and B, respectively; other baseline factors were not significantly different between A &amp; B. Overall: nephrectomy 90%; ECOG 0 73%; male 71%; median age 57 years; Caucasian 48%, Hispanic 33%, Black 8%, Asian 10%;. Median cycles both arms: 5. Best RECIST 1.0 response PR: 13%, 13%; SD 52%, 48%; PD 26%, 35%; Reason off therapy: PD 58, 67%; toxicity 25, 17% in arms A, B. Median OS: 33.4, 14.7 months (p=0.69), TTP 11.2, 9.4 months, PFS 7.3, 6.6 months (p=0.61) in arms A, B. Grade 3+ tox: A 14/24 vs. B 13/24, p=1.0. Arm A had numerically more skin toxicities and grade 2/3 hematological tox (Plats and WBCs) compared to arm B but this was not statistically significant. Conclusions: Randomized comparisons of novel agents are feasible in renal cell cancer using risk factor algorithms. This VEGFrTKI contemporaneous series of Bmab based therapy with 2 schedules of Bmib suggests potential better outcomes for schedule A with more frequent dosing of Bmib – further sensitivity analysis is ongoing to determine whether this is explained by histology or therapeutic sequencing or likely to suggest proteasome as a target in RCC. Clinical trial information: NCT00184015.
Impact of sarcopenia on long-term prognosis of patients with esophageal cancer after surgery.
Authors: Tsutomu Hayashi, Soji Ozawa, Kenichi Kamachi, Akihito Kazuno, Eisuke Ito, Osamu Chino, Hideo Shimada, Hiroyasu Makuuchi
Journal: Journal of Clinical Oncology (2014)

118 Background: Emerging evidence suggests that sarcopenia might have an adverse impact on the survival of patients with cancer. We herein investigated the impact of sarcopenia on the long-term outcome of patients with esophageal cancer after curative surgery by analyzing the muscle cross-sectional area using computed tomography (CT). Methods: Sarcopenia was assessed in 204 patients undergoing a macroscopic curative esophagectomy for the resection of esophageal cancer between January 2005, and December 2008 at Tokai University Hospital by measuring the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on CT images obtained before surgery. The measured total psoas area (TPA) was normalized according to the patient’s height. Sarcopenia was defined as a TPA of ≤525 mm/m 2 for men, and ≤375 mm/m 2 for women. The impact of sarcopenia was assessed after controlling for clinical factors using multivariate modeling. Results: The median follow-up period was 60 months. The median patient age was 64 years; 184 (90%) patients were male and 20 (10%) were female. The median TPA was 580 mm/m 2 for the men and 386 mm/m 2 for the women. Sixty-nine (34%) patients had sarcopenia (TPA ≤525 mm/m 2 for men, 375 mm/m 2 for women ). The overall five-year survival rates were 33% for the patients with sarcopenia, and 66% for those without sarcopenia. In a multivariate analysis, a low body mass index (BMI ≤ 18.5 kg/m 2 ; hazard ratio [HR], 1.87 [P = 0.028]), pathological stage of disease (HR for stage I, 1.587 in stage II [P = 0.219], 4.146 in stage III [P &lt; 0.001], and 6.712 in stage IV [P &lt; 0.001]), tumor location (HR of upper thoracic for middle and lower thoracic, 2.350 [P = 0.002]), and sarcopenia (HR, 1.858 [P= 0.006]) were independently associated with the overall mortality. Conclusions: Sarcopenia is associated with an increased risk of overall mortality in esophageal cancer after curative surgery independent of tumor-specific factors and the BMI. The development of effective interventions for sarcopenia warrants further study to improve the prognosis of patients with esophageal cancer.
Regulation of HDM2 E3-ubiquitin ligase in esophageal adenocarcinoma cells by AURKA.
Authors: Vikas Sehdev, Abbes Belkhiri, Mohammed Soutto, Ahmed M. Katsha, Wael El-Rifai
Journal: Journal of Clinical Oncology (2013)

35 Background: Esophageal adenocarcinomas (EAC) exhibit intrinsic resistance against chemotherapy. AURKA regulates cell cycle progression and its overexpression is associated with oncogenic transformation. We have recently reported that AURKA is significantly overexpressed in about 70% of human EAC tissue samples and EAC cell lines. We have previously shown that AURKA inhibits p53- and p73-mediated apoptotic pathways in GI adenocarcinomas. HDM2 is an E3-ubiquitin ligase which is closely involved in regulating p53 and p73 protein stability and activity. In this study we demonstrate that AURKA directly interacts with HDM2 and regulates HDM2 protein expression and phosphorylation in both FLO-1 and OE33 EAC cells. Methods and Results: Western blot analyses were done following AURKA overexpression with adenovirus, knockdown with si-RNA or inhibition with MLN 8237 (0.5µM) in FLO-1 and OE33 EAC cell lines. The data indicated that overexpression of AURKA induced both total and phospho-HDM2-(Ser166) protein levels. Knockdown or inhibition of AURKA significantly decreased expression of both total and phospho-HDM2-(Ser166) protein levels in FLO-1 and OE33 EAC cells. Additionally, following adenovirus mediated overexpression of AURKA, co-immunoprecipitaion (Co-IP) was done for AURKA and HDM2 in FLO-1 and OE33 EAC cells. The two-way Co-IP data indicated the presence of HDM2 in a complex associated with AURKA and vice-versa. The data from in vitro protein kinase assay indicated that recombinant AURKA directly phosphorylates recombinant HDM2 at Ser166 site. To confirm direct interaction between recombinant AURKA and HDM2 proteins we performed IP following the in vitro kinase assay. The in vitro kinase IP data indicates that kinase intact recombinant AURKA directly interacts and phosphorylates recombinant HDM2 protein. Conclusions: Our data indicate that AURKA regulates HDM2 expression and phosphorylation in both FLO-1 and OE33 EAC cells. Additionally, we also report for the first time that AURKA directly interacts with HDM2 and phosphorylates it at Ser166 site. Therefore, our study suggests that AURKA-mediated regulation of HDM2 could be the major underlying mechanism for induction of apoptosis in p53-negative EAC.
Predictor factors of response to neoadjuvant chemoirradiation for patients with locally advanced rectal cancer.
Authors: N. M. Abd El-Bary, M. Balbaa
Journal: Journal of Clinical Oncology (2011)

e14153 Background: General consensus has been reached regarding the role and effectiveness of preoperative chemo-radiotherapy (CRT) in downstaging of locally advanced rectal cancer with higher rates of sphincter preservation and R0 resections. However, no tumor regression has been found in a high percentage of patients. Aim: To identify predictor factors associated with poor tumor response to neoadjuvant CRT in locally advanced rectal cancer. Methods: This study included 28 patients diagnosed to have locally advanced rectal cancer. All patients were subjected to neoadjuvant capecetabine 850 mg/m2/12 hours daily during external pelvic irradiation of 45 Gys/over 5 weeks. According to the downstaging achieved; the patients were categorized into two groups: responders and non responders. Univariate and multivariate analysis were done to evaluate the influence of patient gender, tumor size, distance from the anal verge, lymph node metastases, presence of mucinous features, grade of the tumor and its circumferential extent as well as pretreatment carcinoembryonic antigen (CEA), albumin and hemoglobin levels on tumor downstaging. Results: Univariate analysis revealed that (T4; P=0.027), more than half of the rectal circumference involvement (P=0.009), high tumor grade (P=0.001), and CEA more than 2.5 ng/mL (P=0.022) were significantly associated with lower downstaging rates. Multivariate analysis revealed that tumor involvement of more than half of the rectal circumference (P=0.044) and CEA more than 2.5 ng/mL (P=0.038) are independent predictor factors of limited response to neoadjuvant CRT. Conclusions: Identification of predictor factors of limited tumor response to preoperative CRT may influence patient selection to preoperative treatment decisions.
Addressing resource allocation for advance care planning discussions in hospital.
Authors: Aaron Kee Yee Wong
Journal: Journal of Clinical Oncology (2016)

16 Background: Advance care planning (ACP) is fundamental in quality palliative care. There is no data detailing the demand for ACP discussions in hospitals, nor any standard objective criteria to decide urgency of such discussions. This cross-sectional study addresses this by comparing the ability of two commonly used instruments to detect palliative patients, and to predict death in the current admission. Methods: All inpatients were censored from the largest tertiary hospital in the state on a single inpatient day. 475 patients were followed for 3 months or until discharge or death, whichever earlier. Quan-modified Charlson score (QCS) and the Palliative Prognostic Score (PaP) was identified for each patient. These instruments were chosen based on external validity and ease of scoring. Results: See Table. 134 patients were identified as palliative (using Gold Standards Framework Indicators). 40 patients died. Both instruments were highly specific in detecting palliative patients and deaths but not sensitive, meaning they predicted patients who were palliative or died that admission. PaP&gt;5.6 was most sensitive test to detect death in current admission. Conclusions: Despite poor sensitivity, the most sensitive instrument (QCS) detected many patients requiring ACP discussion on a single day in hospital, highlighting the demand for ACP-trained staff. Secondly, streamlined usage of these instruments may assist in prioritising resource allocation. The QCS could identify patients needing ACP discussions (despite poor sensitivity, still identified many patients), whereas the PaP &gt; 5.6 could refine the prioritisation of such discussions. This strategy could assist in reaching as many patients as possible using current staffing levels. [Table: see text]
Analysis of the outcome of treatment for squamous cell carcinoma of the oral cavity: Retrospective study of 180 patients.
Authors: K. A. AL Saleh, R. Safwat, A. Gaber, O. Hattab
Journal: Journal of Clinical Oncology (2011)

e16019 Background: To assess the results of curative treatment of patients with squamous cell carcinoma of the oral cavity and to evaluate the factors predictive for recurrence and survival. Methods: This is a retrospective analysis of 180 patients with primary squamous cell carcinomas of the oral cavity seen between 1984 and 2005 in Kuwait cancer centre. All patients treated with curative intent with surgery +_ postoperative radiotherapy. (Analysis, March 2010). Results: At a minimum follow-up period of 5 years the local control rate was 61.1% and disease-free survival was 85% for the whole series. The LCR by treatment modality was 74% for local resection, 63% for composite resection and 81.2% for surgery plus radiotherapy. The actuarial control rate according to the stage of the disease was 83.8% and 49.1% for early and advanced stage respectively. The actuarial control rate for patients with positive and/or close and negative margins who received postoperative radiotherapy was 75% and 95% respectively. This difference is statistically significant. Extracapsular nodal extension was reported in patients 20.7%, twenty of them received post operative RT, with LCR of 60% for patients treated with surgery plus postoperative radiotherapy vs 3/10 (30%) for who did not receive postoperative radiotherapy. The actuarial LCR was 82.5% for patients with well and moderately differentiated carcinoma and 50% for high grade tumors. Conclusions: We conclude that prognosis ultimately depends on the stage of disease at presentation, margin status and extracapsular nodal extension. Patients positive margin of resection and/or extracapsular nodal extension treated by postoperative radiotherapy have significantly longer disease-free survival in comparison to patients treated by surgery alone. Concomitant chemotherapy and hyperfractionation for patients with advanced stage significantly improved locoregional control rates and consequently DFS but the toxicity rates were high. Future strategies must be directed at further improving these results.
Reducing unwarranted variability in care in radiation oncology through clinical pathways.
Authors: Kathleen Lokay, Dwight Earl Heron
Journal: Journal of Clinical Oncology (2014)

171 Background: UPMC CancerCenter (UPMC) includes 37 academic and community based sites in western Pennsylvania. Consistency and quality of care are critical to such a diverse network. To meet these challenges, UPMC developed clinical pathways for medical and radiation oncology (Via Pathways). The program has served UPMC well for almost ten years and is now a key foundation for UPMC’s overall strategy to move from volume to value. Methods: Radiation treatment pathways for over 90% of cancers were developed by committees of academic and community radiation oncologists from UPMC as well as other cancer centers across the country. The committees meet semi-annually to interpret the literature and define the most efficacious and least toxic treatments for highly-specific disease presentations (e.g., oropharynx, Stage III-IV, primary chemoradiation). Guidance for simulation contouring, planning and treatment delivery are provided along with applicable citations. A web-based portal presents the pathways on a patient specific basis using the physician’s daily clinic schedule (through an interface with the EMR). The UPMC radiation oncologists also utilize a feature of the pathways that allows for peer review of Off Pathway decisions by disease experts within the UPMC Radiation Oncology department. Results: Thirty-one (31) radiation oncologists at UPMC use pathways in their daily practice. For the 12 months ended May 31, 2014, UPMC physicians confirmed a pathways status for 98% of their patient consults (n=10,178) and achieved an On-Pathway rate of 95% for their 6,239 treatment decisions. All Off-Pathway treatment decisions were approved prior to treatment by a designated peer review radiation oncologist within UPMC, typically within 24 hours of request. Reasons for going Off-Pathway were recorded as well as what alternative approach to care was chosen. Conclusions: When appropriately developed and implemented, clinical pathways are a solution to standardizing care across multiple sites and physicians with the potential to improve the quality and cost effectiveness of cancer care.
Relationship of ERCC1 genotype variant with mRNA expression and ERCC1 protein levels in advanced urothelial carcinoma (UC).
Authors: Elizabeth A. Guancial, Lillian Werner, Joaquim Bellmunt, Nikitas Nikitas, Edward C. Stack, Rosina Lis, Sabina Signoretti, Massimo Loda, Meredith M. Regan, Rachel S. Park, Robert O'Brien, David M. Berman, Aristotelis Bamias, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2013)

260 Background: DNA repair factors may be predictive for response to chemotherapies that produce DNA damage. While low ERCC1 protein and mRNA levels have been reported as associated with improved outcomes in metastatic UC patients treated with platinum-based chemotherapy, the relationship between genotype, mRNA expression, and protein level is unknown. The ERCC1 germline 19007C&gt;T single-nucleotide polymorphism (SNP) is functionally associated with reduced translation of ERCC1 mRNA. We investigated the relationship between ERCC1 germline SNP, ERCC1 tumor mRNA and protein expression, in a cohort of patients with advanced UC who received first-line, platinum-based chemotherapy. Methods: A cohort of clinically annotated, uniformly-treated advanced UC patients with FFPE primary tumor tissue available was identified through the Hellenic cooperative Oncology Group (HECOG) (N=93). Genomic DNA extraction, nested PCR, and restriction fragment length polymorphism techniques for the 19007C&gt;T SNP were performed to identify C/C, C/T and T/T genotypes. ERCC1 mRNA expression was interrogated using Nanostring nCounter profiling. IHC analysis was performed on tissue arrays using an ERCC1 antibody. Percent of positive nuclear staining was categorized as quartiles using previously identified cut-points. Results: ERCC1 C/T genotype was identified in 30/61 samples (49%) and T/T in 14/61 samples (23%). In 54 patients with both SNP and mRNA data available, T/T genotype was associated with the highest level of mRNA expression, followed by the C/T genotype (p=0.04). Neither ERCC1 genotype (N=44) nor ERCC1 mRNA expression (N=54) was associated with ERCC1 protein expression as measured by IHC (p=0.52 and p=0.13, respectively). Conclusions: ERCC1 19007C&gt;T is associated with increased ERCC1 mRNA expression. However, neither genotype nor mRNA are surrogates for ERCC1 protein detected by IHC in advanced UC tumors. This suggests that while genotype influences mRNA expression of ERCC1, the use of the nucleotide excision repair pathway as a predictive biomarker of platinum-sensitivity may be more complex than previously appreciated and require the integrative use of proteomics, genomics and epigenomics.
Bortezomib (BZB)-associated adverse events (AE) in patients with multiple myeloma (MM).
Authors: L. Katragadda, N. Sanathkumar, M. Veeraputhiran, A. Restrepo, S. Haider, J. Muzaffar, B. Barlogie, E. J. Anaissie
Journal: Journal of Clinical Oncology (2011)

e18565 Background: In patients (pts) with MM, BZB therapy causes AE, some of which may be related to autonomic nervous system (ANS) dysfunction. Methods: We conducted a retrospective case control study of 5 pts, with pts serving as their own control. Each pt received 2 cycles of BZB-containing regimens (BZB with Dexamethasone and either Thalidomide or Lenalidomide). One of the two treatment courses used high-dose (HD) BZB (1.6 mg/m2, higher than the standard 1 to 1.3 mg/m2), while low-standard (LD) dose (0.7, 1.0 or 1.3 mg/m2) was applied during the other cycle. The medical records of these pts were reviewed, including for AE that are typically associated with ANS dysfunction like orthostatic hypotension, pyrexia (≥ 1020), severe diarrhea and severe constipation. Orthostatic hypotension was used as a measurable toxicity parameter with statistical comparison of its incidence (Pearson Chi Square test) between three groups: 1) pre-BZB therapy (control); 2) LD and 3) HD BZB cycles. Results: Cycles of LD BZB were well tolerated in all 5 patients in contrast to poor toleration in 4 of the 5 HD BZB cycles which required aggressive medical management for severe dizziness (1 pt) and hospitalization in 3 pts: 1) severe constipation and pyrexia(≥ 1020); 2) severe diarrhea, orthostatic hypotension and dizziness and 3) severe orthostatic hypotension. A specific etiology for these AE could not be identified despite a comprehensive work-up. The AE normalized by day 0 of the second cycle. Orthostatic hypotension was observed in 3 of 5 and 5 of 5 of LD and HD BZB cycles respectively versus 0 of 5 in the control group. A significant incidence of orthostatic hypotension was observed with HD BZB vs. control (α = 0.0079; α<0.05 is significant) and with both BZB groups combined vs. control (α= 0.0093). Conclusions: HD BZB therapy is associated with otherwise unexplained, but transient orthostatic hypotension, pyrexia, and severe diarrhea and constipation. These findings are classically observed in ANS disorders, suggesting that some of BZB-related AE may be caused by transient ANS dysfunction.
Efficacy and Feasibility of Nelarabine Savage Therapy In Adult Relapsed or Refractory T Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (T-LBL) Strongly Indicates the Introduction of a Nelarabine-Based First Line Regimen
Authors: Cristina Papayannidis, Ilaria Iacobucci, Mariachiara Abbenante, Stefania Paolini, Sarah Parisi, Annalisa Lonetti, Viviana Guadagnuolo, Anna Ferrari, Emanuela Ottaviani, Nicoletta Testoni, Antonio Curti, Cristina Clissa, Michele Baccarani, Giovanni Martinelli
Journal: Blood (2010)