bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of adjuvant chemotherapy following chemoradiation and surgery for locoregionally advanced rectal cancer: A Veterans Health Administration analysis.
Authors: Spiegel Daphna , Boyer Matthew , Hong Julian C. , Williams Christina D. , Kelley Michael J. , Rangwala Fatima A. , Salama Joseph Kamel , Palta Manisha 
Published: January 2019

741 Background: Adjuvant chemotherapy (AC) following chemoradiation (CRT) and total mesorectal excision (TME) for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States despite limited data. The purpose of this study was to examine the role, optimal regimen, and duration of AC in the mandatory, prospectively collected cancer registry of the largest integrated health system in the US. Methods: Using the VA Central Cancer Registry, stage II-III rectal cancer patients diagnosed between 1/2001-4/2011 were included if they received neoadjuvant CRT followed by TME with or without AC. Adequate chemotherapy was defined as at least 4 months of therapy. Kaplan-Meier and Log-Rank tests were used to assess survival. Propensity score (PS) adjustment was performed to compare survival outcomes while adjusting for baseline characteristics, including AJCC stage, age, gender, race, smoking status, and comorbidity. Results: 649 patients were identified; 323 received AC while 326 did not (OBS). Median follow-up was 66 months. Mean age was 63 years. 85.1% were white; 98.8% were male. 49.2% had stage II disease. Median overall survival (OS) for all patients was 92 months; 6-year OS was 56.8%. Median OS was 72 months for the OBS group and not reached (NR) for the AC group (p < 0.001). OS at 6 years was 49.5% for OBS and 64.1% for AC (p < 0.0001). On PS matched analysis, OS was improved favoring AC (p < 0.0001). Median disease-specific survival (DSS) was NR for the whole group and NR for the OBS and AC groups. 6-year DSS was 73.6% for the whole group and 67.9% for OBS vs. 79.2% for AC (p < 0.001). PS matched analysis for DSS favored AC (p = 0.0004). There was no significant difference in OS (p = 0.554) or DSS (p = 0.680) when comparing single versus multi-agent chemotherapy and no significant difference in OS (p = 0.766) or DSS (p = 0.271) when comparing adequate ( > / = 4 months) versus inadequate chemotherapy ( < 4 months). Conclusions: In this VA population of LARC patients treated with neoadjuvant CRT followed by TME, the addition of AC was found to improve both OS and DSS compared to OBS. There was no improvement in OS or DSS with the addition of a multi-agent over single-agent chemotherapy.
Effect and safety of proton beam therapy for locally recurrent rectal cancer.
Authors: Ogi Yusuke , Yamaguchi Tomohiro , Kinugasa Yusuke , Shiomi Akio , Kagawa Hiroyasu , Yamakawa Yushi , Furutani Akinobu , Yamaoka Yusuke , Manabe Shoichi , Hino Hitoshi , Nagasawa Yoshinobu , Suzuki Takuya , Torii Kakeru , Kato Shunichiro , Koido Kohei , Murayama Shigeyuki 
Published: January 2019

743 Background: The first choice of treatment for locally recurrent rectal cancer is surgical resection. However, the operation is often difficult with high perioperative risk. For surgically unfit cases, proton beam therapy (PBT) is proposed as the treatment option. However, its efficacy for locally recurrent rectal cancer remains unclear. Therefore, this study aimed to evaluate the efficacy and safety of PBT for locally recurrent rectal cancer. Methods: A total of 23 patients with locally recurrent rectal cancer who received PBT were retrospectively evaluated, from November 2005 to July 2014. Patients with single lesion, who refuse the radical surgical therapy, or who were considered unfit for the operation were included in this study. All patients were treated with 2.8Gy relative biological effectiveness (RBE)/fraction. Twenty-five irradiations were performed, with a total irradiation of 70Gy RBE. Unfit for operation criteria include invasion to the vertebra higher than the third sacrum or lateral lymph node recurrence after a lateral lymph node dissection. To assess the safety of PBT, adverse events were evaluated by using the Common Terminology Criteria for Adverse Effects (CTCAE version4.0). To assess the efficacy, the overall and relapse-free survival rates and local control rate were evaluated. Results: Sixteen patients were unfit for operation, and seven refused surgery. Three patients experienced Grade 3 late adverse events in the CTCAE (two ileum fistula and one urinary tract obstruction). The median follow-up time was 28.9 months. The 5-year overall and relapse-free survival rates were 47.6% and 20.2%, respectively. Fifteen patients (65.2%) showed distant metastasis or regrowth at the locally recurrent site. The 5-year local control rate was 39.0%. Ten patients (43.4%) showed regrowth at the proton beam irradiation site. Conclusions: PBT was relatively effective for locally recurrent rectal cancer with manageable adverse effects. Therefore, PBT may be considered as the therapeutic option for selected locally recurrent rectal cancer patients.
The impact of indoleamine 2,3-dioxygenase (IDO) expression on stage III gastric cancer.
Authors: Kashihara Hideya , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Tokunaga Takuya , Nishi Masaaki , Takasu Chie , Ishikawa Daichi 
Published: January 2019

75 Background: Indoleamine 2,3-dioxygenase (IDO) downregulates T cell activation and is related to immune tolerance. The aim of this study was to clarify the significance of IDO expression and to analyze the relationships among the expression of IDO, TGF-b, and Foxp3 in gastric cancer (GC). Methods: Sixty patients who underwent curative gastrectomy for stage III gastric cancer were included in this study. The expressions of IDO, TGF-b, and Foxp3 were examined by immunohistochemistry. The patients were divided into two groups: the IDO-positive group (n = 23) and negative group (n = 37). Clinicopathological factors were compared between the two groups. Univariate analysis was used to assess overall (OS) and disease-free survival (DFS) in several prognostic factors. Multivariate analysis was used to identify the independent prognostic factors. Results: IDO expression was not positively correlated with any clinicopathological factors. IDO expression was positively correlated with TGF-b expression (p < 0.05) and TGF-b expression was positively correlated with FoxP3 expression (p < 0.05). Overall survival (OS) rates were significantly poorer in the IDO-positive group compared with the IDO-negative group (3-year OS, 78.5% vs. 90%, respectively; p < 0.05). Multivariate analysis identified IDO expression as independent prognostic factors in OS. Disease-free survival (DFS) was significantly poorer in the IDO-positive group compared with the IDO-negative group (3-year DFS, 59.3% vs. 69.3%, respectively; p < 0.05). Conclusions: IDO is associated with poor prognosis and immuno-tolerance through Treg in Stage III GC.
SIDE in metastatic colon cancer: SEER Database analysis.
Authors: Muzaffar Mahvish , Kaur Sandeep , Naqash Abdul Rafeh , Jonnalagadda Sweta , Vohra Nasreen A. 
Published: January 2019

753 Background: Recent data suggests side of colon cancer is a prognostic factor and a potential predictive factor for biologic therapy. We sought to analyze SEER database to study impact of colon cancer side. Methods: The SEER database (version 8.3.4) was reviewed for patients with Stage IV colon cancer from 2004-2014. We only included patients with labeled primary site, and excluded appendiceal, rectal or unlabeled cases. Variables included were: age, race, gender, stage, grade and side of the tumor. Primary outcome was overall survival and disease specific survival. Cox proportional hazard regression model was employed to test the association between survival and side of cancer. Results: 48,306 patients met the inclusion criteria, median age was 67 years (range 20-108), 51% were male, and 77% patients were white. 19831 (41%) patients had left colon cancer (LCC). Right colon cancer (RCC) was associated with inferior OS and DSS compared to LCC. The median overall survival was 15 months (mo) for left side and 9 months for right colon cancer (p<0.0001). Estimated 3-year OS for RCC was 14% and 24% for LCC (p <0.0001). RCC was associated with poor outcome across different variables, among patients < 60 years of age median OS was 23 mo for LCC, and 16 mo for RCC (p .0001). In the age group ≥ 60 years, 10 mo for left side and 7 mo for RCC (p < 0.0001). Among male patients RCC had 10 mo median OS vs 16 mo for LCC (p <0.0001), women 15mo for LCC vs 9mo for RCC (<0.0001). Cox regression model suggested age (<0.001), race (<0.0001), year of diagnosis (<0.0001) and grade (<0.0001) correlate with outcome. Conclusions: Right side colon cancer is associated with poor outcome compared to left colon cancer. These findings are consistent with other recent reports.
Does stereotactic body radiation therapy have a role in oligoprogressive metastatic colorectal cancer?
Authors: Jin Will , Burke Aidan M. , Rashid Abdul , Marshall John , Unger Keith Robert 
Published: January 2019

755 Background: Patients with metastatic colorectal cancer undergoing systemic therapy may enter an oligoprogressive state. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation. We hypothesize that LAT for oligoprogressive lesions with stereotactic body radiation therapy (SBRT) is a feasible alternative to surgical interventions and may delay progression of disease. Methods: An IRB-approved retrospective review of patients with oligoprogressive, metastatic colorectal cancer who were treated with SBRT at Georgetown University Hospital from 2012-2016 was performed. Results: 40 patients with 41 metastatic lesions of the lung (n = 11), liver (n = 10), lymph nodes (n = 8), soft tissue (n = 6), and bone (n = 6) were reviewed. Median follow-up, overall survival, and freedom from distant progression were 10.6, 17.3, and 6.4 months, respectively. Crude one year local control and overall survival were 82.9% and 75%, respectively. First site of progression was distally in 63.4% of patients. Patients treated with SBRT in the liver were significantly more likely to locally progress than other treated sites (13.18 vs. 39.81 months, p = 0.007). On univariate analysis, non-lymph node treated tumors (p = 0.046), larger CEA change at 6 month follow-up (p = 0.048), and right sided primary tumors (p = 0.004) were associated with local failure within 1 year. On multivariate analysis, only right sided primary tumors were significantly more likely to locally progress (p = 0.009). Conclusions: Patients with oligoprogressive colorectal cancer can be effectively treated with SBRT to achieve acceptable rates of local control and potentially delay progression of disease.
Robotic surgery for rectal cancer: Short-term and oncological outcomes for 607 consecutive patients.
Authors: Shiomi Akio , Yamaguchi Tomohiro , Kagawa Hiroyasu , Yamakawa Yushi , Furutani Akinobu , Yamaoka Yusuke , Manabe Shoichi , Ogi Yusuke , Hino Hitoshi , Nagasawa Yoshinobu 
Published: January 2019

756 Background: Conventional laparoscopic surgery (CLS) for rectal cancer has several inherent technical difficulties, including a limited range of motion of the instruments.Robot-assisted laparoscopic surgery (RALS) has some technical advantages over CLS because it improves dexterity with an increased range of movements at the tips of the instruments. The purpose of this study was to evaluate the short-term and oncological outcomes of RALS for rectal cancer, including robotic, autonomic nerve-preserving, lateral lymph node dissection (RALLD), a new, technically challenging procedure. Methods: Between December 2011 and August 2017, 607 consecutive patients underwent RALS for rectal cancer. Surgical outcomes, pathological results, and oncological results were investigated retrospectively. Results: There were 403 males and 204 females; 577 patients had adenocarcinoma, 19 had carcinoid tumor, 8 had GIST, and 2 had other malignant tumor. The types of procedures performed were: 453 anterior resections, 93 intersphincteric resections, and 61 abdominoperineal resections. RALLD was performed in 202 patients (33.3%). Preoperative chemoradiotherapy was performed in 34 patients. The overall median operative time was 257(109-683) min. In cases without RALLD, the median operative time was 217 (109-545) min, while median operative time was 420 (162-683) min with RALLD. None of the cases was converted to an open or laparoscopic procedure.There was no surgical mortality. The overall complication rate for Clavien-Dindo classification grade III-IV was 3.0%. The oncological results for 279 patients with primary rectal adenocarcinoma, operated before December 2014 was also investigated (Stage I/II/III 115/48/116). The 5-year overall survival was 96.6%, the 3-year relapse free survival was 88.3%, and 3-year local relapse free survival was 98.5%. The 3-year RFS of pStage I/II/III was 96.2/89.6/79.6% respectively. Conclusions: RALS for rectal cancer is a feasible procedure with low morbidity and a low conversion rate, and acceptable oncological results.
Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.
Authors: Kawazoe Akihito , Kuboki Yasutoshi , Komatsu Yoshito , Nishina Tomohiro , Shinozaki Eiji , Hara Hiroki , Yuki Satoshi , Shitara Kohei , Bando Hideaki , Takahashi Koji , Mikamoto Yuichi , Hasegawa Hiromi , Hirano Nami , Nomura Shogo , Togashi Yosuke , Nishikawa Hiroyoshi , Sato Akihiro , Ohtsu Atsushi , Yoshino Takayuki 
Published: January 2019

760 Background: The anti–programmed death 1 (PD-1) antibody, pembrolizumab provided an objective response rate (ORR) of 40% in patients (pts) with Mismatch Repair–Deficient (dMMR) or Microsatellite Instability–High (MSI-H) metastatic colorectal cancer (mCRC) vs 0% in pts with MMR-proficient/Microsatellite Stable (MSS) mCRC. The WNT/β-catenin signaling has been reported to prevent anti-tumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies. This study investigates efficacy and safety of the combination of BBI608, which blocks phosphorylated STAT3 and downregulates WNT/β-catenin signaling, with pembrolizumab in pts with mCRC (both MSS and MSI-H). Here, we present the results of the phase I part. Methods: Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). We also conduct biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: Five pts were enrolled in level 1, and 3 pts in level 2. All pts were MSS mCRC. Seven pts were included in the safety analyses. Two pts in level 1 were excluded from dose-limiting toxicity (DLT) evaluation because of disease progression during DLT evaluation period. No DLTs were observed at either level. Grade 3 or worse treatment-related adverse events (TRAEs) were not observed. Grade 1 or 2 TRAEs included diarrhea related to BBI608 (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%) without unexpected safety signals. One patient in level 2 showed a tumor shrinkage lasting more than 12 weeks for lung and lymph node metastases with remarkable decline of CEA level. Analysis of repeated tumor samples from this case demonstrated that CD8+ T-cells infiltration inside the tumor on treatment was observed by immunohistochemistry and flow-cytometry. Conclusions: BBI608 480mg BID with pembrolizumab was tolerable and determined as RP2D. This combination showed a hint of activity and might evoke immunity in MSS mCRC, which will be confirmed by ongoing phase II part. Clinical trial information: NCT02851004..
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial.
Authors: Kopetz Scott , Spira Alexander I. , Wertheim Michael , Kim Edward , Tan Benjamin R. , Lenz Heinz-Josef , Nikolinakos Petros , Rich Patricia , Smith David A. , Helwig Christoph , Dussault Isabelle , Ojalvo Laureen , Gulley James L. 
Published: January 2019

764 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398.
Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer (mCRC) treated with fruquintinib in a phase II clinical trial.
Authors: Li Jin , Xu Ruihua , Bai Yuxian , Xu Jianming , Liu Tianshu , Shen Lin , Wang Liwei , Pan Hongming , Han Rubing , Chen Yun , Peng Cike , Fan Songhua , Hua Ye 
Published: January 2019

765 Background: In a randomized phase II trial of mCRC patients who have failed at least 2 lines of standard therapy, fruquintinib has demonstrated superior progression free survival (PFS) and overall survival (OS) benefits over placebo. We further assessed the between-treatment difference of quality of life (QoL) using a Q-TWiST analysis, to elucidate the trade-off between adverse events and treatment benefits. Methods: Mean PFS and OS were estimated using the Kaplan-Meier method. OS in Q-TWiST analysis was partitioned into 3 health states: TOX (time with toxicity before progression), TWiST (time without symptoms or toxicity) and REL (time from progression until death). The algorism of Q-TWiST is the sum of the mean durations for the 3 health states, with each state weighted by its respective utility coefficient. The 95% confidence intervals of mean are calculated with z method and the standard error is generated by bootstrap method. The relative Q-TWiST gains of > = 10% and > = 15% are considered as a clinically important and clearly clinically important, respectively (Revicki, 2006). Results: A total of 71 patients were included in this post-hoc analysis. The 47 patients of fruquintinib arm had significant longer PFS, compared with the 24 patients in the placebo arm (mean: 5.0 vs. 2.2 months, difference [95% CI]: 2.8 [1.4, 4.3]). The benefit of OS was numerically superior (mean: 8.6 vs. 6.9 months, difference [95% CI]: 1.7 [-0.5, 4.0]). Patients treated with fruquintinib showed numerically longer overall Q-TWiST (mean: 5.8 vs. 4.4 months, difference [95% CI]: 1.4 [-0.1, 2.9] than those received placebo with the relative gain of 20.3% over OS, assuming the utility during TOX/REL period is 0.5 and that during the TWiST is 1.0. Sensitivity analysis demonstrated that the Q-TWiST gain may range from -0.7% to 41.2% at various utility assignments. Conclusions: In this phase II trial, mCRC patients treated with fruquintinib had clearly clinically important QoL benefit. Further studies with larger sample size are needed to confirm this finding. Clinical trial information: NCT02196688.
18F-FDG PET-defined therapy response to predict acute hematologic toxicity for anal cancer patients treated with chemoradiation.
Authors: David John , Yue Yong , Blas Kevin , Fraass Benedick , Hendifar Andrew Eugene , Kabolizadeh Peyman , Tuli Richard 
Published: January 2019

775 Background: Hematologic toxicities (HT) induced during chemoradiotherapy (CRT) for anal cancer can lead to increased infection rates, bleeding, asthenia, and unplanned breaks compromising treatment efficacy. We hypothesize that HT in anal cancer patients treated with CRT correlate with change in active bone marrow (ABM) characterized by pre- and post-CRT 18F-FDG PET/CT (PET). Methods: Twenty-eight locally advanced anal cancer patients treated with definitive CRT from 2011-2016 were identified. PET scans were obtained 0-2 weeks pre- and 6-8 weeks post-CRT. HT was evaluated by weekly white blood cell count, absolute neutrophil count (ANC), hemoglobin (Hg) and platelet nadirs. Total bone marrow (TBM) was defined on CT images, and segmented into three subregions: lumbosacral (LS), left and right iliac pelvis. PET images were normalized to bone outside of the TBM uptakes. ABM was characterized in all PET images as the volume having standard uptake value SUV > 40% of SUVmax in the TBM. Image variables (global, subregional SUVmean, SUVmax, ABMs) of pre- and post-CRT and their differential changes were evaluated as predictors of HT. Locoregional radiomics features were calculated using a 3D kernel-based approach. HT prediction was modeled by logistic regression with the Lasso algorithm with 10-fold cross-validation. HT endpoints were defined as change between baseline blood nadir and the lowest nadir values during and up to 2 weeks after CRT. Results: The lasso regression identified 5 predictors of HT (pre-SUVmax, post-LS-ABM, LS-ABM change, homogeneity texture change, and variance). Ratios of LS-ABMs to TBM were reduced from 18.9% (pre-CRT) to 16.3% (post-CRT). This reduction of LS-ABM significantly correlated with acute HT measured by ANC (p < 0.001) and Hg (p < 0.001) nadirs. Conclusions: PET-derived active BM changes between pre- and post-CRT significantly associated with HT in anal cancer patients undergoing definitive CRT. LS-ABM is a robust surrogate for evaluation of HT and can be used to develop BM-sparing radiotherapy for reduction of potential HT.