bluuebunny/crossref_metadata_2025 huggingface dataset:
Second neoplasms in survivors of childhood acute lymphoblastic leukemia treated with both chemotherapy and radiotherapy.
Authors: Looi Wen Shen , Koh Jia Wen Janine Cynthia , Chin Francis , Teh Yi Hui Jonathan , Chan Mei Yoke , Tan Ah Moy
Published: February 2017

e293

Background: Second malignant neoplasms (SMNs) are a concern in survivors of childhood cancer. Chemotherapy forms the mainstay of treatment for acute lymphoblastic leukaemia, but radiotherapy is used in certain situations. As both chemotherapy and radiotherapy can be carcinogenic, patients treated with both modalities may be at a higher risk of SMNs. This study aims to investigate the incidence of SMNs in patients treated with both chemotherapy and radiotherapy. Methods: Children aged 16 years and below diagnosed with acute lymphoblastic leukaemia from 1993 to 2014 were identified in the Childhood Cancer Registry. Manual and electronic medical records were reviewed for information on demographics, management and SMNs. Results: A total of 64 patients treated with both chemotherapy and radiotherapy were identified. Seventeen (26.6%) were female and 47 (73.4%) were male. The median follow-up was 9.2 years (range, 1.1-22.0 years). The median age at diagnosis was 5.3 years, (range, 0.3-14.6 years). The median age at which radiotherapy was given was 6.6 years (range, 2.9-15.4 years). SMNs were noted in 3 of 64 (4.7%) patients. Two of 3 patients had a SMN within the radiation field (both cranial). The histological diagnoses were basal cell carcinoma and cerebral PNET. The remaining patient had an ovarian immature teratoma outside the radiation field. The latency period ranged from 8.3 years to 13.3 years (median 9.4 years) from date of diagnosis to development of SMN. The estimated 10-year cumulative incidence was 4.3%, 95% CI [0.01, 0.13] using a competing risks analysis. Radiotherapy data was available in 63 patients. Fifty-one of 63 (81.0%) received cranial irradiation, of which 3 (5.9%) also received spinal irradiation. Total body irradiation was performed in 20 of 63 (31.7%), and testicular irradiation in 17 of 63 (27.0%) patients. The orbit was targeted in 3 of 63 (4.8%) patients. Conclusions: Long term survivors of acute lymphoblastic leukaemia treated with both chemotherapy and radiotherapy may have a significant risk of second malignant neoplasms, which may occur years after the initial diagnosis.
Identifying lifestyle and genetic factors to prevent recurrence of non-muscle invasive bladder cancer in a prospective cohort study at Kaiser Permanente (the Be-Well study).
Authors: Kwan Marilyn L. , Kushi Lawrence H. , Quinn Virginia P. , Ghai Nirupa R. , Roh Janise M. , Becerra Tracy A. , Martinez Adriana A. , Cannavale Kimberly L. , Carruth Alexander S. , Lee Valerie S. , Ergas Isaac J. , Loo Ronald K. , Aaronson David S. , Zhang Yuesheng , Ambrosone Christine B. , Tang Li
Published: February 2017

e296

Background: Bladder cancer is one of the top 10 incident cancers. Most cases (75%) are diagnosed as non-muscle invasive disease (NMID), yet NMID typically recurs (70%) and a subset (25%) progresses to muscle-invasive disease. Be-Well is a 5-year, NCI-funded prospective cohort study of NMID bladder cancer patients at Kaiser Permanente Northern (KPNC) and Southern California (KPSC). The goal is to examine diet and lifestyle factors and prognosis, with an emphasis on cruciferous vegetable (CV) intake and their unique isothiocyanate (ITC) content, the modifying effect of polymorphisms of ITC-metabolizing genes, and interactions with treatment. Our prior work suggests that dietary ITCs may prevent disease recurrence and progression in NMID patients. Methods: Newly-diagnosed patients with NMID (Ta, Tis, T1), who are English-speaking, KP members, and ≥ 21 years of age, are rapidly ascertained from electronic pathology reports and enrolled on average 2.6 months post-diagnosis. Baseline participation consists of a telephone interview including a food frequency questionnaire focused on CV intake, and providing blood and urine samples. Patients will be contacted for follow-up interviews and urine samples at 12 and 24 months. Smoking, medication use, occupational exposures, physical activity, quality of life, and urinary function are also queried. Biospecimens are processed and assayed at Roswell Park Cancer Institute. Strong support for Be-Well by KP urologists will promote dissemination of study results in patient care and recommendations. Results: Recruitment began in February 2015. To date, 159 patients have completed the baseline interview, representing 76% male and 24% female, and 80% White, 8% Black, 6% Hispanic, 3% Asian, and 3% Other. Urine specimens have been collected from 87% of consented patients. Blood specimens have been collected from 87% of KPNC patients, with collection at KPSC to begin in Fall 2015. Conclusions: The Be-Well Study is poised to be the largest and most comprehensive study to answer critical questions related to prognosis, quality of life, and care in patients diagnosed with early-stage bladder cancer.
Management of dysphagia in esophageal cancer (EC): A population-based study.
Authors: Mikhail Sameh , Hinton Alice , Wuthrick Evan John , Perry Kyle , Merritt Robert , Williams Terence Marques , Conwell Darwin , Bekaii-Saab Tanios S. , Krishna Somashekar
Published: February 2017

100

Background: Dysphagia is associated with significant morbidity in patients (pts) with EC. Our study is the first report of national trends in hospitalizations due to EC and dysphagia, with special emphasis on nutritional interventions and related outcomes. Methods: The analysis included all adult inpatients with EC and dysphagia in the Nationwide Inpatient Sample from 2002-2012. We examined temporal trends and performed multivariate analysis for key outcomes; controlling for demographics, hospital factors, comorbidities, and interventions. Results: Among 509,593 hospitalizations involving pts with EC, 12,205 were related to dysphagia. The percentage of all hospitalizations for EC (1.52 vs. 3.28%; p < 0.001) and EC with dysphagia (0.0025 vs. 0.0059%, p < 0.001) doubled over the study period. Among all pts with EC, inpatient mortality for EC with dysphagia was 4.39%. Mean length of stay (LOS) and cost of hospitalization were 8.1 days and $15,171, respectively. Feeding tube (FT) placement was performed in 27 % of pts, esophageal stenting in 13% and peripheral nutrition (TPN) was used in 11%. The incidence of stent placement was higher in urban teaching hospitals (33%) vs. urban non-teaching (21%) or rural nonteaching hospitals (17%). On multivariate analysis, placement of FT and stents was associated with comparable inpatient mortality and LOS, but TPN was associated with higher mortality (OR 2.25; 95% CI 1.93, 2.62) and prolonged LOS (+3.4 days, CI 2.79, 3.97). Compared to FT, stents (+ $3,042, CI 432, 5,652) and TPN (+ $10,573, CI 8,766, 12,380) resulted in higher cost of hospitalization. More pts developed sepsis on TPN (6.1%) compared to FT (2.5%) or stents (1.8%). Inpatient mortality associated with any nutritional intervention was lower in urban teaching compared to rural nonteaching hospitals (0.71; CI 0.65, 0.79). Conclusions: Hospitalizations for EC and dysphagia are increasing and mortality in such pts is high and multifactorial. TPN is associated with sepsis and mortality in this setting. Nutritional intervention practices and possibly outcomes vary significantly based on hospital type. This finding should be further explored to better define the most appropriate interventions and treatment setting for this patient population.
Results of Phase II trial of AUY922, a novel heat shock protein inhibitor in patients with metastatic gastrointestinal stromal tumor (GIST) and imatinib and sunitinib therapy.
Authors: Chiang Nai-Jung , Yeh Kun-Huei , Chiu Chang-Fang , Chen Jen-Shi , Yen Chueh-Chuan , Lee Kuan-Der , Lin Yu-Lin , Bai Li-Yuan , Chen Ming-Huang , Lin Jen-Shi , Yang Youngsen , Rau Kun-Ming , Hsiao Hui-Hua , Shan Yan-Shen , Chen Li-Tzong
Published: February 2017

134

Background: Our preclinical studies showed that AUY922 treatment could induce downregulation of KIT protein and apoptosis in both imatinib-sensitive and -resistant GIST cells (Autophagy 2013). This prospective, phase II trial evaluated the efficacy and safety of AUY922 in patients with metastatic GISTs after failure or intolerance to imatinib and sunitinib in an Asian population. Methods: Based on the MTD defined in previous phase I study, infusion 70 mg/m2 of AUY922 was given once weekly, 4 weeks as a cycle. The primary endpoint was disease control rate (DCR, objective response + stable disease ≥ 16 weeks), assessed by computed tomography (CT) scan according to RECIST v1.1 every 8 weeks. Metabolic response was assessed by positron emission tomography (PET)-CT scans performed at baseline and after 4 weeks of treatment. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: Between 2011.10 and 2015.01, 25 evaluable patients were enrolled. DCR at 16 weeks was 20% but none had partial response. According to the EORTC-defined PET response criteria, ten patients (40%) had metabolic partial response ( > 25% decrease of SUV from baseline) at 4 weeks after AUY922 treatment. At a median follow-up time of 7.8 months (range, 2.0-33.4 months), median progression-free survival (PFS) was 2.4 months (95% confidence interval (CI), 1.6-3.2 months) and median overall survival was 9.6 months (95% CI, 0-21.1 months). Metabolic partial responders had a trend of better PFS (3.8 vs. 1.9 months in non-responders, P = 0.09). The common adverse events (AEs) were fatigue (82%), visual disturbances (70%), diarrhea (55%). Grade 3/4 AEs included visual field darkening (3.7%), blurred vision (7.4%) and diarrhea (7.4%). Treatment interruption and dose modification were frequently required (62%) in patients with more than 8 weeks of treatment because of grade 2-3 visual field darkening. Conclusions: AUY922 showed modest antitumor activity in heavily pretreated GIST patients. Clinical relevant ocular toxicity was unexpectedly high in current study cohort; its correlation with PK will be further explored. Clinical trial information: NCT 01389583.
Readmission after robotic Ivor Lewis esophagectomy: Earlier discharge, increased readmissions?
Authors: Salem Ahmed I. , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Meredith Kenneth
Published: February 2017

149

Background: Readmissions after esophagectomy are costly and incidence can be as high as 25%. The robotic assisted approach has potential benefits of earlier discharge compared to conventional techniques, however it is unclear what impact an earlier discharge will have on readmission rates. We sought to examine the impact of early discharge on readmission rates with robotic approaches. Methods: A retrospective review of all patients undergoing robotic assisted Ivor Lewis esophagectomy (RAIL) from 2009-2015 was conducted. Clinicopathologic factors and surgical outcomes were recorded and compared. We then compared outcomes to a historical cohort from the Surveillance, Epidemiology, and End Results-Medicare data (2002 to 2009). Length of stay, 30-day and 90-day readmissions, and mortality were determined. All statistical tests were two-sided and a p-value < 0.05 was considered statistically significant. Results: We identified 147 patients who underwent RAIL. There were 78.9% (116) male with an average age 66 ±10 years. Adenocarcinoma was the predominant histology in 86% (126) patients, 9.52% (14) patients had squamous cell histology, and 4.76% (7) patients had other histology. Neoadjuvant therapy was administered to 77.6% (114) patients. In the SEER database 1,744 patients with esophageal cancer underwent esophagectomy: 80% of patients (1,390) were male, with a mean age of 73 years; 71.8% of tumors (1,251) were adenocarcinomas, and 38% of patients (667) received neoadjuvant therapy. Median length of stay was 13 days, 30-day mortality was 8.8% (158 patients), and 90 day mortality was 17.9% (302) compared to median LOH of 9 days, 30-day mortality of 0.6% (1) and 90-day mortality of 1.4% (2)% in the robotic cohort, p < 0.0001, p = 0.007, and p < 0.0001. Readmission rates at 30 and 90 days were 18.6% (212) and 31.3% (356) in the SEER patients, and 3.4% (5) and 5.4% (8) in the robotic cohort p = 0.001 and p < 0.001. Conclusions: RAIL is a safe surgical technique that provides an alternative to conventional approaches to esophageal resection. Patients undergoing RAIL had lower mortality rates and LOH. Despite the lower LOH, RAIL was associated with lower 30 and 90-day readmissions.
Final overall survival (OS) analysis with modeling of crossover impact in the phase III GRID trial of regorafenib vs placebo in advanced gastrointestinal stromal tumors (GIST).
Authors: Demetri George D. , Reichardt Peter , Kang Yoon-Koo , Blay Jean-Yves , Joensuu Heikki , Schaefer Klaus , Wagner Andrea , Casali Paolo Giovanni , Kappeler Christian
Published: February 2017

156

Background: GRID showed that regorafenib (REG) improves progression-free survival (PFS; primary endpoint) vs placebo (PBO) in patients (pts) with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p < 0.0001). An interim OS analysis at the time of the primary PFS analysis showed a positive trend (HR 0.77; p = 0.199) despite 85% of PBO pts crossing over to REG. An exploratory analysis modeling the impact of crossover on OS suggested a benefit for REG. We present exploratory analyses of OS comparing crossover correction results at different times, including at the planned final OS analysis. Methods: Data cut-off dates for OS analyses were 26 Jan 2012 (final PFS analysis), 31 Jan 2014, and 8 Jun 2015 (final OS analysis). The impact of crossover on OS was modeled using 2 randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE), both considered best choice among correction analytics. Hazard ratios (HRs) and 95% CIs were derived using the Cox model. Results: Pts were randomized (2:1) to REG (n = 133) or PBO (n = 66). Data maturity in terms of deaths of randomized pts was 23%, 70%, and 81%. At data cut-off for the final OS analysis, a total of 162 deaths occurred: REG 109 (82%) and PBO 53 (80%); 7 pts remained on treatment. Compared to the 2012 OS analysis, continued crossover treatment further diluted the treatment effect, evidenced by the increasing HR in the ITT analysis at later times (Table). Conclusions: IPE correction provides more stable estimated median times and HRs than RPSFT. These exploratory analyses modeling the impact of crossover to active drug suggest that REG has a greater OS benefit than noted in the ITT analysis. Such sensitivity analytics are needed to understand fully the benefits of active drugs in crossover trials. Clinical trial information: NCT01271712. [Table: see text]
Survival and prognosticators of gastric cancer patients with only positive peritoneal lavage cytology.
Authors: Kano Kazuki , Sato Tsutomu , Maezawa Yukio , Segami Kenki , Nakajima Tetsushi , Ikeda Kousuke , Aoyama Toru , Hayashi Tsutomu , Yamada Takanobu , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Ogata Takashi , Cho Haruhiko , Yoshikawa Takaki
Published: February 2017

16

Background: Treatment strategies for only positive peritoneal lavage cytology findings have not yet been established. The objective of this retrospective study was to clarify the survival and prognosticators in these patients. Methods: Overall survival (OS) rates were examined in 39 patients with gastric cancer who underwent a curative resection and had positive peritoneal cytology in the absence of overt peritoneal metastases between January 2000 and June 2015. Univariate and multivariate analyses were performed to identify risk factors using a Cox proportional hazards model. Results: A total of 39 patients were evaluated. The median overall survival was significantly longer in the 34 patients who received chemotherapy after surgery than that in the 5 who did not (19.1 vs 5.9 months, p < 0.01). Among the patients who received chemotherapy after surgery, univariate and multivariate analyses showed that pN3b was an independent significant prognosticator (hazard ratio of 4.169 with 95% CI: 1.108-15.684, p = 0.035). The median OS was 15.8 months when the patients diagnosed with N3b was 33.1 months when the patients diagnosed with N3a or lower. Conclusions: The prognosis of gastric carcinoma with positive peritoneal lavage cytology without peritoneal metastasis is still poor and need more aggressive treatment. The lymph node metastasis was a significant prognosticator in these patients.
Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in Japanese patients with advanced gastric or gastroesophageal junction cancer.
Authors: Nishina Tomohiro , Shitara Kohei , Iwasa Satoru , Hironaka Shuichi , Muro Kei , Esaki Taito , Satoh Taroh , Yamaguchi Kensei , Machida Nozomu , von Heydebreck Anja , Watanabe Morihiro , Doi Toshihiko
Published: February 2017

168

Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report safety and clinical activity from this phase Ib dose expansion JAVELIN study (NCT01943461) of avelumab in Japanese patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJ) based on level of PD-L1 expression. Methods: GC/GEJ pts (ECOG performance status 0-1 at trial entry) received avelumab 10 mg/kg Q2W by IV infusion until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Best overall response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression on fresh tissue samples collected up to 6 mos prior to trial was assessed by immunohistochemistry using various cutoff criteria. Results: As of Mar 11 2015, 20 pts (18 GC, 2 GEJ) were treated with a median follow-up of 6 mos. Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 18/20 pts (90%); one patient (5%) reported a grade 3 TR-TEAE (alanine aminotransferase increase). There were no treatment-related deaths. Confirmed ORR was 15.0% based on 3 partial responses (PR) and the disease control rate (PR + stable disease) was 65.0%. PD-L1 expression was evaluable in 19 pts. Pts with PD-L1+ samples (n = 5 [26.3%]; ≥ 1% cutoff) showed a 40.0% ORR compared with 7.1% ORR in pts with PD-L1− samples (n = 14 [73.7%]; p= 0.155). Median PFS was 12.3 wks (95% CI: 3.1, ne) for PD-L1+ and 11.1 wks (6.0, 12.1) for PD-L1− ( ≥ 1% cutoff). PFS rate at 12 wks was 60.0% (95% CI: 12.6, 88.2) and 32.1% (10.2, 56.9) for PD-L1+ and PD-L1− pts, respectively. Conclusions: Single agent avelumab showed an acceptable safety profile and clinical activity in GC/GEJ pts. A trend of higher ORR and higher PFS rate was observed in PD-L1+ pts compared with PD-L1− in this small cohort. Further analysis is ongoing and expansion of this cohort to 40 pts is underway. *Proposed INN. Clinical trial information: NCT01943461.
Circulating biomarkers exploratory study in loco-regional gastroesophageal adenocarcinoma patients.
Authors: Longo Federico , Earl Julie , Martinez-Avila Jose Carlos , Guerrero Carme , Pachon Vanesa , Rodríguez Garrote Mercedes , Ferreiro REYES , Gómez Rueda Ana , Molina Javier , Villamayor Delgado Maria , Martinez Saez Olga , Salgado Alfonso Cortes , Muñoz del Toro Jacobo , Cortez Castedo Silvia Patricia , Olmedo Garcia Maria Eugenia , Lopez Hervas Pedro , Priego Pablo , Galindo Julio , Guillén Ponce Carmen , Carrato Alfredo
Published: February 2017

17

Background: Patients diagnosed with gastroesophageal adenocarcinoma (GEA) have a poor prognosis despite curative attempts with multimodal treatment including surgery, chemotherapy (CT) and radiotherapy (RT). VEGF, EpCAM, MUC1, CK19 and CK20 and CD133 have shown to provide additional prognostic information in advanced GEA patients. Methods: Circulating mRNA of total VEGF (and 2 VEGF isoforms 121 and 165), EpCAM, MUC1 and CD133 were determined in 36 loco-regional GEA patients (pts). Blood samples were collected before surgery or, when indicated, before the preoperative chemotherapy treatment, within a 7 days window. Additionally, 14 healthy volunteers and 7 advanced GEA pts were included to comparative analyses. The Wilcoxon test was used to assess differences in expression among the groups. Results: Pre-surgery CT was administered in 30 pts (79%). ECF or its modifications were administered in 22 pts, and FOLFOX in 7 pts. Type of resection achieved was R0 (19 pts, 59%), R1(7 pts, 22%) and R2 (6 pts, 10%). Post-surgery CT was administered in 22 pts (73%) including ECF or its modifications (10 pts), FOLFOX (7 pts) and CT-RT (4 pts). PFS occurred in 19 pts (61%) and 34 patients remained alive at the time of this analysis. Patients diagnosed with loco-regional GEA exhibited over expression as compared to healthy volunteers of VEGFi121 in 17 pts (47%) by 33-fold median change (IQR 5-43, %, p = 0.0008); VEGFi165 in 17 pts (47%) by 15-fold (IQR 5-36, p = 0.002); total VEGF in 19 pts (53%) by 15 fold (IQR 8-59, p = 0.01); EpCAM in 8 pts (22%) by 3-fold (IQR 0.5-3, NS); MUC1 in 19 pts (53%) by 23-fold (IQR7-59, p = 0.0008); and CD133 in 2 pts (6%) by 55-fold (IQR 28-83, NS). CK20 expression was not detected in healthy controls but was detected in 3 patients. Conclusions: VEGF and its isoforms VEGF121 and VEGF165 and MUC1 are potential diagnostic biomarkers in GEA. Due to the short follow-up of patients we cannot yet evaluate their role as prognostic biomarkers.
Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study.
Authors: Van Cutsem Eric , Lenz Heinz-Josef , Furuse Junji , Tabernero Josep , Heinemann Volker , Ioka Tatsuya , Bazin Igor , Ueno Makoto , Csõszi Tibor , Wasan Harpreet , Melichar Bohuslav , Karasek Petr , Macarulla Teresa , Guillén Ponce Carmen , Kalinka-Warzocha Ewa , Horvath Zsolt , Prenen Hans , Schlichting Michael , Mehdi Fazal , Bendell Johanna C.
Published: February 2017

193

Background: Pancreatic ductal adenocarcinoma (PDAC) is invariably diagnosed at an advanced stage and has poor clinical outcome. Hypoxia is a significant prognostic factor in PDAC progression and is associated with poor prognosis. Evofosfamide (Evo, previously known as TH-302) is a hypoxia-activated prodrug of bromo-isophosphoramide mustard (Br-IPM) that is preferentially activated under hypoxic conditions. The addition of Evo to gemcitabine (Gem) significantly improved progression-free survival (PFS) in a randomized phase II trial in advanced PDAC (NCT01144455). Methods: MAESTRO is an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo/Gem in patients (pts) with measurable, locally advanced unresectable or metastatic PDAC (NCT01746979). Evo and Gem were administered intravenously at a dose of 340 mg/m2 and 1,000 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Treatment continued until disease progression. Key eligibility criteria included ECOG PS 0/1 and no neoadjuvant or adjuvant chemotherapy <6 months prior to entry. The primary endpoint was overall survival (OS) with the study designed to detect a HR of 0.75 with 90% power. Secondary endpoints included PFS and objective response rate (ORR), employing a hierarchical testing procedure with a 2-sided α=0.05 at each level. Results: A total of 693 pts were randomized to treatment with Evo/Gem (n=xxx) or Placebo/Gem (n=yyy). Baseline pt characteristics were similar between treatment arms. The OS HR was X.XX (95% CI: Y.YY, Z.ZZ; p=A.AAA). Median OS was AA.A months (m) for Evo/Gem vs BB.B m for Placebo/Gem. Median PFS was C.C m and D.D m, respectively (HR E.EE [95% CI: F.FF, G.GG; p = H.HHH). ORR was JJ.J% with Evo/Gem vs KK.K% with Placebo/Gem (p = L.LLL). Grade ≥3 adverse events (AEs) occurring in >5% of pts in treated with Evo/Gem were: TBC. Conclusions: The data from the MAESTRO trial will make an important contribution to our understanding of PDAC treatment. Clinical trial information: NCT01746979.
A western validation of a novel gastric cancer prognostic model using American data.
Authors: Goldner Bryan S. , Song Ki Jun , Son Taeil , Kim Hyoung-Il , Melstrom Laleh , Singh Gagandeep , Noh Sung Hoon , Fong Yuman , Woo Yanghee , Hyung Woo Jin
Published: February 2017

2

Background: A novel prediction model, the Yonsei University Gastric Cancer Prediction Tool was developed by an international collaborative group (G6+) for accurate determination of 5-year overall survival of gastric cancer patients. This prediction model was created using a prospectively maintained single institution database of 12,399 patients and included clinically relevant factors not accounted for in the TNM staging system. This prediction model was validated using external data sets from Asia; its’ applicability in the American population has yet to be determined through a validated data set. Methods: Using the SEER dataset, 2014 release, all patients with gastric adenocarcinoma diagnosed between the years 2002 –2012 who underwent resection were selected. The following characteristics were selected for analysis: age, sex, gender, depth of tumor invasion, number of positive lymph nodes, total lymph nodes retrieved, presence of distant metastasis, extent of resection, and histology. These data were processed through a recently published prognostic nomogram to obtain concordance index (C-statistic) using the bootstrap method and calibration was assessed. This was compared to the current prognostic index, the TNM staging system. Results: A total of 26,019 possible patients were identified from the SEER database, years 2002-2012. Of these, 11,765 had complete datasets. Validation of the prognostication model revealed a C-statistic of 0.762 (95% CI 0.754-0.769). This is compared to the 7thTNM staging model, C-statistic 0.683 (95% CI 0.677-0.689). The new nomogram was found to be significantly more accurate with a p-value of < 0.001. Conclusions: Our study validates a novel prediction model for gastric cancer in the American patient population. Using this model, superior accuracy in prognosticating the 5-year survival of gastric cancer patients was confirmed in the western cohort strongly supporting its global applicability. This model also allows for inclusion of those who did not undergo adequate lymphadenectomy or who underwent a non-curative resection and can be a useful prediction tool for an increasing number of gastric cancer patients world-wide.
Obesity and mortality in patients with esophageal cancer: A systematic review and meta-analysis.
Authors: Gupta Arjun , Majumder Kaustav , Arora Nivedita , Singh Preet Paul , Singh Siddharth
Published: February 2017

20

Background: Obesity influences incidence of esophageal cancer (EC) with contrasting impact on esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESC). However, it is unclear whether it influences mortality in patients with EC. We performed a systematic review and meta-analysis to assess the association between obesity and EC mortality. Methods: Through a systematic search of major databases and conference proceedings, up to June 2015, we identified observational studies reporting the association between obesity (premorbid body mass index [BMI] ≥ 30 kg/m2) and all-cause mortality in patients with EC. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CI), comparing highest BMI category with reference category in each study using random effects model; heterogeneity was measured using the inconsistency index (I2). Results: We identified 8 studies (including 1 pooled cohort study) with 2,784,027 people, of whom 18% were obese. On meta-analysis, compared with EC patients with reference BMI, obese EC patients had aHR for mortality of 0.97 (95% CI, 0.66-1.43), with high heterogeneity (I2 = 88%) after pooling maximally adjusted HRs. On analyzing patients with EAC alone (3 studies), mortality aHR was 1.10 (95% CI, 0.43-2.82), with high heterogeneity (I2 = 95%). Data to separately analyze ESC or to perform subgroup analysis in males vs females, smokers vs never smokers and Asia Pacific vs Western populations was limited. Conclusions: Based on meta-analysis, obesity does not appear to be associated with mortality in patients with EC. However, high heterogeneity and limited data for subgroup analysis limits the interpretation of this analysis. Further prospective studies evaluating mortality in patients with established EC are needed to answer this question. [Table: see text]
Risk factor of thrombosis and impact on prognosis in patients with pancreatic cancer receiving chemotherapy.
Authors: Ishigaki Kazunaga , Nakai Yousuke , Isayama Hiroyuki , Hamada Tsuyoshi , Takahara Naminatsu , Mizuno Suguru , Mohri Dai , Kogure Hirofumi , Matsubara Saburo , Yamamoto Natsuyo , Tada Minoru , Koike Kazuhiko
Published: February 2017

218

Background: Thromboembolism (TE) is common in cancer patients, and pancreatic cancer is reported to be highly associated with TE. The aim of this analysis is to clarify risk factors for TE and its clinical impact in pancreatic cancer patients. Methods: Data on consecutive pancreatic cancer patients receiving systemic chemotherapy between August 1999 and July 2015 were retrospectively studied. The diagnosis of TE was made on CT scan either performed for suspicious symptoms of TE or for evaluation of chemotherapy response, and TE was classified into two groups: arterial events including coronary artery disease (CAD), cerebrovascular disease and other artery thrombosis, and venous events including deep vein thrombosis/pulmonary embolism (DVT/PE), portal vein thrombosis (PVT) and IVC thrombosis. Overall survival and time to TE (TTE) were calculated by Kaplan-Meier analysis. Risk factors for TE development were analyzed using a Cox proportional hazards model. To evaluate the impact of TE on survival, multivariate analyses were performed using a time-dependent covariate multiple Cox model. Results: A total of 475 patients (195 female, a median age of 67 years) were analyzed. TE was identified in 57 patients (12%). Venous TE were 45 (79%) including DVT/PE 24(42%), IVC thrombosis 2 (4%), PVT 19 (33%). Arterial TE were 12 (21%) including cerebrovascular infarction 9 (16%), CAD 2 (4%) respectively. The median TTE was 169 days (95% CI, 75-203). Liver metastasis was the only significant risk factor for TE in the multivariate analysis (OR 2.01, 95%CI 1.12-3.47, P = 0.012). The median survival from TE development was 57 days (95% CI, 37-65) and TE was significantly associated with poor prognosis (HR 3.31, 95%CI 2.72-5.27, P< 0.01) in the time-dependent covariate analysis. Conclusions: TE was not uncommon in pancreatic cancer patients receiving chemotherapy and was associated with poor prognosis. Whether the prophylaxis for TE can improve survival should be further investigated, especially in high risk patients such as patients with liver metastasis.
Pancreatic squamous cell carcinoma: Epidemiology, clinicopathologic characteristics, and outcomes.
Authors: Makarova-Rusher Oxana V. , Ulahannan Susanna Varkey , Greten Tim F. , Duffy Austin G.
Published: February 2017

220

Background: Although squamous metaplasia is commonly detected in pancreatic parenchyma, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. Methods: Using SEER-18 database primary code C25 in conjunction with histology codes for SCC (8052-8053, 8070-8078, 8083-8084) and for adenocarcinoma (AC) (8052-8053, 807-8078, 8083-8084), we identified cases diagnosed from 2000 to 2012. Age-adjusted incidence rates and trends over time were calculated. Patients with SCC were compared with AC by clinical features (TNM categories and histological differentiation), and 1-year and 2-year relative survival (RS) outcomes. Chi-square tests for categorical variables and t-tests for continuous variables were conducted. Kaplan-Meier method was used to estimate RS and Z-test was used to compare RS rates. SEERStat and GraphPad were used for analysis. Results: We identified 214 patients with microscopically confirmed SCC and 72,860 patients with AC. SCC constituted less than 1% of all cases of primary pancreatic cancer; however, age-adjusted incidence rates for this subtype tripled between 2000 and 2012. The annual percent increase of SCC incidence rate was 5.5%. Significant differences were observed by age, gender and race: older age groups, blacks and males had higher SCC incidence rates. Compared to AC, a greater proportion of patients with SCC had poorly differentiated histology (15.8% vs. 30.4%, p < 0.01). Similar to AC, the majority of patients with SCC had stage IV disease at diagnosis, 54.3% for AC vs. 56.4% SCC. The 1-year and 2-year relative survival rates were significantly lower in patients with SCC than AC. The 1-year relative survival rate was 15.8% (95%CI = 10.4-22.3) for SCC, compared with 24.7% (95%CI = 24.3-25.1) for AC, p < 0.001. Conclusions: Although primary squamous pancreatic carcinoma is a rare neoplasm, incidence rates for this subtype are markedly rising. Relative to adenocarcinoma, pancreatic squamous cell carcinoma is characterized by poorly differentiated histology and worse survival.
Identification of a high-response patient population to S-1 via predictive enrichment strategy analysis of the S-CUBE phase III trial.
Authors: Kudo Masatoshi , Okusaka Takuji , Kaneko Shuichi , Furuse Junji , Takeuchi Madoka , Fang Xuemin , Date Yoshito , Takeuchi Masahiro
Published: February 2017

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Background: S-CUBE was a randomized, double-blind, phase III trial evaluating the efficacy and safety of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (HCC). The study’s primary outcome was presented at the 2015 ASCO Annual Meeting. Although S-1 did not significantly improve overall survival (OS) in all cohort (hazard ratio [HR] = 0.86; confidence interval [CI] = 0.67–1.10; P = 0.2201), we conducted predictive enrichment strategy analysis (PESA) to identify a patient population with a better response to S-1. Methods: Predictive enrichment strategy is a newly introduced concept proposed by the United States Food and Drug Administration, “to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population. (Temple R. [2012] )” Therefore, in our study, PESA provides robust results and identifies advanced HCC patients who are more likely to respond to S-1. Clinically meaningful baseline characteristics were selected to create a scoring system; patients were ranked based on their scores, and the population with a better response was identified. Patient mapping was used to further characterize the population. Results: The full S-CUBE analysis set consisted of 333 patients, including 222 in the S-1 arm and 111 in the placebo. PESA and patient mapping identified 219 patients (65.8% of the total population) as the high-response patient population. High-response patients are classified as those with the following criteria; 1) TNM stage III, IVa, or IVb, 2) Child-Pugh class A, and 3) Levels of both the tumor markers are not high (AFP ≥ 400 ng/mL and PIVKA-II ≥ 10000 mAU/mL). In this population, the median OS of S-1 group was significantly longer than that of placebo group (426.0 days vs. 375.5 days; HR, 0.69; 95% CI, 0.51 to 0.93; P = 0.0156). Conclusions: PESA and patient mapping identified a high-response patient population to S-1. This statistically robust analysis demonstrated S-1 showed survival benefit for identified clinically-important population of sorafenib-refractory advanced HCC patients. Clinical trial information: JapicCTI-090920.
Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): A study using MSK-IMPACT.
Authors: Raj Nitya Prabhakar , Soumerai Tara , Valentino Emily , Hechtman Jaclyn Frances , Berger Michael F. , Reidy Diane Lauren
Published: February 2017

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Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in chromatin modeling genes (MEN1, DAXX, and ATRX), and in the mTOR pathway. NGS brings this technology to the clinic but its relevance in practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD pNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements. Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Results: MSK-IMPACT results are available in 39 patients (pts). Actionable alterations were identified in 13/39 pts (33.3%). These actionable alterations included BRAF V600E (2 pts; 5.1%), and mutations in TSC1 (1 pt; 2.6%), TSC2 (5 pts; 12.8%), PTEN (4 pts; 10.3%), CDKN1B (2 pts; 5.1%), CDKN2A (2 pts; 5.1%), CDKN2B (2 pts; 5.1%), CDKN2C (1 pt; 2.6%), and ARID1A (5 pts; 12.8%). Other recurrently altered genes included MEN1 (23 pts, 59.0%), DAXX (13 pts, 33.3%), and ATRX (10 pts, 25.6%). Notably, 7 pts (17.9%) had alterations in the histone methyltransferase SETD2. All 7 pts presented with metastatic liver disease. No tumors were low grade; 6/7 (85.7%) were intermediate grade and 1/7 (14.3%) were high grade. All 7 pts received capecitabine/temozolomide (cape/tem); 6 pts (85.7%) had disease shrinkage and 1 pt (14.3%) had stable disease. Conclusions: The mutational landscape in our study was in line with prior work in pNET whole exome sequencing. In one-third of our cohort, potentially actionable alterations were identified through NGS but have not yet been shown to be therapeutically relevant. An exploratory analysis to identify responses to different therapies is ongoing. In addition, we report a novel finding of SETD2 alterations in pNETs. All pts with SETD2 alterations had intermediate to high grade tumors that responded to cape/tem. The clinical significance of SETD2 in pNETs is unknown, and evaluation using tissue microarrays is ongoing.
Tumor profiling of 431 pancreatic tumors from elderly patients.
Authors: Xiu Joanne , Rakszawski Kevin , Reddy Sandeep K. , Jia Yuxia
Published: February 2017

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Background: Pancreatic cancer (PC) is frequently a disease of the elderly and controversy exists as to whether these patients benefit from aggressive treatments. We aimed to investigate biomarker features from tumors taken from elderly PC patients to identify therapeutic implications. We also compared the results to those from younger patients to assess differences. Methods: PC tumors were tested at Caris Life Sciences between 2009 and 2015 by immunohistochemistry, fluorescent/chromogenic in-situ hybridization and sequencing. De-identified biomarker data were analyzed. Results: A total of 431 tumors from PC patients aged > = 75 were analyzed: 50% were samples from pancreas, 50% were from metastatic sites. 26 of 47 genes sequenced carried mutations with frequencies ranging from 0.6% to 84%. The highest mutation rates were seen in KRAS (84%), TP53 (55%), BRCA2 (21%), SMAD4 (12%), ATM (4.4%), BRCA1 (4.2%) and PIK3CA (3.8%). Overexpression of TOPO1 and low expression of ERCC1, RRM1 and TS were seen in 45%, 73%, 86% and 79%, respectively, indicating potential benefit from irinotecan, platinums, gemcitabine and fluoropyrimidine, respectively. Tumor expression of PD-L1 was seen in 14% and tumor-infiltrating lymphocyte expression of PD-1 was seen in 45%. Overexpression of EGFR and cMET were seen in 91% and in 62%, respectively. When compared to 470 tumors from PC patients aged < = 50, KRAS mutations were significantly more common in the elderly than in younger patients (84% vs. 74%, p = 0.0018), while MLH1 mutations were seen exclusively in younger patients (0% vs. 4%, p = 0.0241). Moreover, expression of TOP2A (53%vs. 45%), ERCC1 (36% vs. 27%), RRM1 (20% vs. 14%), SPARC (20% vs. 14%) and PR (5% vs. 1%) were significantly more prevalent in the younger group (all p < 0.05). Conclusions: Tumor profiling of 431 tumors from elderly PC patients suggests therapeutic opportunities including cytotoxic, biological as well as targeted agents for this patient group. A comparison with younger patients indicated that irinotecan, fluoropyrimidine and taxanes may provide equal benefit to elderly and younger patients, while platinums and gemcitabine may be more likely to benefit elderly patients.
Role of MEK inhibition in improving anti-tumor responses in xenograft models of BRAF-mutated metastatic colorectal cancer.
Authors: Morris Van Karlyle , Wu Ji , Adam Liana , Tian Feng , Gagea Mihai , Hong David S. , Menter David , Kopetz Scott
Published: February 2017

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Background: BRAFV600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival outcomes. Addition of anti-EGFR therapy improves responses when combined with BRAF inhibition, yet acquired resistance to targeted therapies invariably develops. Novel therapeutic approaches to deepen anti-tumor activity are warranted for patients with this subset of mCRC. Methods: Patient-derived xenograft (PDX) models of BRAFV600E mCRC were established and treated with vemurafenib (V) +/- cetuximab (C) until acquired resistance. DNA from resistant tumors was sequenced and compared to that of untreated controls. BRAFV600E mCRC tumors from PDX mice with acquired mutations in MAPK signaling were reimplanted into another generation of nude mice and treated with V +C or trametinib (T) + cetuximab. Results: Twelve resistant models were developed in BRAFV600E mCRC PDX models treated with V +/- C, with nine models demonstrating acquired mutations resulting in MAPK pathway re-activation, including codons 12 or 13 KRAS mutations. While sensitivity to V + C was observed in BRAFV600E /KRASwild-type mCRC tumors, this combination demonstrated no anti-tumor response in BRAFV600E models with acquired KRASG12R or KRASG12D mutations. In these PDX models harboring dual BRAF/KRAS mutations, the combination of T + C generated sustained tumor regression not observed with V+C (P <.001 for both BRAFV600E / KRASG12R and BRAFV600E /KRASG12D models). Addition of T following resistance to V+C restored sensitivity in both models. Conclusions: Dual blockade of BRAF + EGFR has shown promise in early-phase clinical trials for patients with BRAFV600E mCRC, and MAPK pathway reactivation appears to be a critical mechanism of resistance. These results suggest that use of a MEK inhibition may reverse such acquired resistance. While MEK + EGFR targeting has been associated with excessive skin toxicity in humans, these data provide rationale for the pursuit of triple BRAF + MEK + EGFR inhibition in patients with BRAFV600E mCRC.
Development of a multidisciplinary program for evaluation and treatment of pancreatic cancer in a community healthcare system.
Authors: Hermann Robert C. , Early Scott , Goel Sachin , Hart Justin , Huertas Magali , Khulman Chad , Webb Leigh , Wilson Barbara J , Shroff Sahir
Published: February 2017

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Background: The incidence and mortality of pancreas cancer is rising in the United States. Only patients who are able to have complete (R0) resection have the potential of cure. Optimal surgical outcomes are influenced by local center volume and multidisciplinary support. We describe the development of a multidisciplinary approach to the evaluation and treatment of pancreas cancer in a community health care system. Methods: This project was initiated by the WellStar Cancer Program, encompassing 5 hospitals. An Institutional Guideline was developed, based upon NCCN, with refinements related to local capabilities and preferences. The Guideline emphasized the review of cases at a weekly tumor board for multidisciplinary coordination of care. Standards for staging evaluations, medical imaging, chemotherapy choices, radiation therapy, and surgical approach were included. A GI Nurse Navigator attended the conferences and assisted in the coordination of care. Specific outcomes were tracked by the Nurse Navigator and the Cancer Registry. Here we describe the program impact related to staging, treatment, nurse navigation, volume and outcomes during the 2011-2014 development phase of the program. Results: A total of 308 cases of pancreas cancer were captured by the registry in 2011-2014. 131 were diagnosed with stage IV disease and offered palliative therapy. 30 Stage I and 139 Stage II-III underwent staging evaluation and consideration of multidisciplinary care, summarized in the table below, and compared to a baseline registry cohort of the 4 preceding years. Conclusions: The development of a Multidisciplinary Team approach to pancreas cancer within a 5 hospital community system has led to improvement in treatment outcomes, including R0 resection rate. Full 2-year results to be updated at the meeting. [Table: see text]
Prognostic influence of clinical biomarkers in patients (pts) with advanced hepatocellular carcinoma (HCC) receiving sorafenib: A single institution experience.
Authors: Abdel-Rahman Omar , Lamarca Angela , Salu Ismail , McNamara Mairead G , Valle Juan W. , Hubner Richard
Published: February 2017

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Background: Identification of HCC pts with higher probability of benefit from sorafenib warrants investigation. Hypertension (HTN) and hand foot syndrome (HFS) are sorafenib-specific toxicities; the development of these toxicities is prognostic in pts with renal cell cancer receiving sorafenib, their significance in HCC remains uncertain. Methods: HCC pts treated with sorafenib at the Christie NHS Foundation Trust (Nov-09-Feb-15) were identified. The primary end-point was overall survival (OS). Kaplan-Meier and Cox regression models were employed for identification of prognostic factors. Results: Eighty-five eligible pts were identified [median follow-up 6.2 months (range: 0.4-31.4)].Median age 68 yrs (range 29-89); 87% male; 80% background liver cirrhosis ;88% ECOG performance score 0/1; Child-Pugh (CP) A5 (64%), A6 (29%) and B (7%); 41% baseline AFP > 400 IU/L; 45% previous liver-directed therapy. Sorafenib (400mg BD),was started in 68% (median dose intensity 49.9% (range 0.7-100)), remaining patients started at reduced dose. Fifty-one percent had pre-existing HTN (91% treated).The most common grade ≥ 3 treatment-related toxicities were HTN (42% no prior history of HTN), fatigue (8%), and HFS (8%);59% of pts developed any grade HFS and/or worsening HTN (HFS/HTN). Toxicity-related dose reduction/cessation was required in 46 (54%) pts (15% due to HFS, 7% due to HTN). Estimated median progression-free (PFS) and OS were 5.5 (95% CI 4.1-7.0) and 6.5 (95% CI 4.9-8.0) months, respectively. Age at diagnosis, previous liver-directed therapy, CP score, baseline AFP and development of HFS/HTN were included in multivariable analysis: CP-A (vs. B; p-value < 0.001) and development of HFS/HTN (vs. no; HR 0.4 [95% CI 0.2-0.7] p-value 0.001) were independent prognostic factors. The prognostic influence of HFS/HTN was preserved when limiting analysis to pts developing worst grade HFS/HTN in the first 3 months of treatment (53 pts; HR 0.5 [95% CI 0.3-0.9] p-value 0.030) making time-on-treatment bias unlikely. Conclusions: The development of sorafenib-specific toxicities, HFS and HTN, are prognostic factors associated with prolonged OS.