bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of ASA404, a vascular disrupting agent, on tumor growth of gastric cancer in an experimental model.
Authors: Lang S. A. , Moser C. , Jung E. M. , Pfister K. , Geissler E. K. , Schlitt H. J. 
Published: February 2017

48 Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 (Novartis Oncology) reduces tumor growth in a model of gastric cancer. Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS). Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (p < 0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (p < 0.05). Conclusions: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer. No significant financial relationships to disclose.
Deferral of rectal surgery following a continued response to preoperative chemoradiotherapy (Watch and Wait) study: A phase II multicenter study in the United Kingdom.
Authors: Yu S. K. , Brown G. , Heald R. J. , Chua S. , Cook G. , Barbachano Y. , Chau I. , Wotherspoon A. , Tait D. M. 
Published: February 2017

489 Background: Neoadjuvant chemoradiotherapy (CRT) and surgical resection are standard components of therapy for patients locally advanced rectal cancer (T3,T4 or N+) in UK. In 15%-30% of patients treated pre-operatively with CRT will develop pathological complete response (CR). The time from completion of CRT to maximal tumour response is as yet unknown. This study is the first prospective study to attempt to identify the percentage of patients who can safely omit surgery and the safety of deferred surgery in patients who achieve clinical complete response post CRT. Of the 59 patients required for the study, this provides an update on 19 patients entered. Methods: Patients with locally advanced rectal cancer requiring neoadjuvant treatment are identified in the multidisciplinary meet (MDT). Patients undergo CRT using a minimum of 50.4Gy in 28 # daily conformal CT planned CRT with concomitant Capecitabine at 825mg/m2 BD. MRI pelvis and body CT are repeated 4 weeks post CRT and rediscussed at MDT. If there is a good partial response or CR, patients are considered for Deferral of Surgery Study. Based on the pre treatment clinical staging, patients are considered for adjuvant chemotherapy as per NICE guidance. At any point of the study, if there is histology proven tumour regrowth or progression, patient undergo surgery. Results: 10 (53%) patients remain in CR. 6 (32%) patients underwent surgical resection with clear margin after detection of tumour regrowth at from 2-23 months post CRT. 5 out of 6 of the patients with tumour regrowth underwent PET CT as per protocol, and all tumour regrowth in those 5 patients were detected by PET CT, i.e. FDG avid disease. The pathological stages on these 6 patients were ypT2N0 CRM negative in 5 and ypT3N0 CRM negative in 1. 3 (15%) patients with tumour regrowth refused surgery. Conclusions: In the 19 recruited patients, all the patients with tumour regrowth underwent surgical resection with clear margins. PET CT appears a useful tool for detecting tumour regrowth. The median time for tumour regrowth is 17.5 months post CRT. The trial will be successful if at least 11/59 patients are able to safely omit surgery. Accrual of patients continues. No significant financial relationships to disclose.
Review of completed and ongoing trials of capecitabine-based adjuvant therapy in patients with early-stage colon cancer.
Authors: Cassidy J. , Scotto N. , Diaz-Rubio E. 
Published: February 2017

495 Background: Capecitabine is an established alternative to 5-FU in gastrointestinal cancers. In metastatic colorectal cancer, capecitabine is non-inferior to 5-FU and capecitabine + oxaliplatin (XELOX) is non-inferior to FOLFOX4. Capecitabine is also an effective adjuvant treatment for early-stage colon cancer. Here we review the evidence available from completed studies of adjuvant capecitabine and describe ongoing trials in this setting. Methods: The X-ACT trial included 1,987 patients (pts) with resected stage III disease receiving either capecitabine (n=1,004) or bolus 5-FU/LV (n=983). NO16968 included 1,886 pts with resected stage III disease receiving either XELOX (n=944) or 5-FU/LV (n=942). The primary efficacy endpoint of both trials was DFS. Other large phase III trials of capecitabine in high-risk stage II/stage III pts include AVANT (XELOX + bevacizumab vs. FOLFOX4 ± bevacizumab), QUASAR2 (capecitabine vs. capecitabine + bevacizumab), SCOT (capecitabine or 5-FU/LV + oxaliplatin 12w vs. 24w), and a Japanese study of single-agent capecitabine. Results: In X- ACT, capecitabine was at least equivalent to 5-FU/LV in terms of DFS (HR=0.88; 95% CI, 0.77–1.01) and OS (HR=0.86; 95% CI, 0.74–1.01). In a preplanned multivariate analysis, capecitabine led to significantly superior DFS (p=0.02) and OS (p=0.02) vs. bolus 5-FU/LV [Twelves et al. WCGIC 2010]. In NO16968, DFS was significantly superior for XELOX vs. 5-FU/LV (HR=0.80; 95% CI, 0.69–0.93; p=0.0045) [Haller et al. ECCO-ESMO 2009]. There was a trend towards improvement in OS with XELOX (HR=0.87; 95% CI, 0.72–1.05; p=0.1486); follow-up is ongoing. Capecitabine-based therapy had an acceptable safety profile in both trials [Twelves et al. NEJM 2005; Schmoll et al. JCO 2007]. Data have yet to be reported from the AVANT, QUASAR2, SCOT and Japanese trials, although results from these trials in over 15,000 pts are awaited with interest. Conclusions: Adjuvant capecitabine is non-inferior to 5-FU/LV when given as monotherapy and superior to 5-FU/LV when given in combination with oxaliplatin. Capecitabine should be considered as a standard component of adjuvant treatment regimens for pts with stage III disease. [Table: see text]
Survival outcomes based on race in gastric carcinoma: A SEER database analysis.
Authors: Didwaniya N. , Edmonds R. J. , Silberstein P. T. , Subbiah S. 
Published: February 2017

5 Background: Gastric cancer is one of the leading causes of cancer related deaths worldwide with the incidence declining in the United States. However the prognosis remains poor with variable survivals being reported among different races. We analyzed the effect of race on patterns of disease presentation and survival rates using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: A total of 9,851 patients were diagnosed with gastric cancer from year 2004 to 2007 were identified from SEER database. Age, race, TNM staging, grade, treatment modalities utilized and cancer specific survival was collected. Results: Out of 9,851 patients, 64.63% were white, 12.17% were black, and 13.04% were Asian-Pacific islanders. Median age was 73 years for whites, 70 years in blacks, and 71 years in Asians. Sex distribution amongst races was more or less similar with 58.83% of whites, 59.47% of blacks, and 54.24% of Asians being men. 23.62% of whites had T1 lesions, 28.10% had T2, 19.58% were T3 and 28.70% had T4 lesions. 26.76% of blacks presented with T1 lesions, 26.63% with T2, 16.08% with T3 and 30.53% with T4. 18.69% of Asians had T1 lesions, 26.84% with T2, 23.44% had T3 and 31.03% had T4 lesions. 37.80% of whites, 36.70% of blacks, and 44.44% of Asians had lymph node involvement. Tumor grade was similar among all races. Surgery was performed in 31.49% of whites, 33.13% of blacks, and 40.48% of Asians. 14.68% of whites, 14.10% of blacks, and 19.43 % of all Asians underwent radiation therapy. Median overall survival in localized disease was 44 months, 43 months and 98 months (p < 0.0001) while in regional disease it was 16 months, 15 months and 23 months in whites, blacks and Asians respectively (p < 0.0001). Median survival in distant disease was 4 months in both whites and blacks; it was 5 months in Asians (p < 0.0001). Conclusions: Cancer-specific survival in gastric carcinoma is significantly better in localized, regional and metastatic disease in Asians when compared to whites and blacks independent of T stage, grade, nodal involvement and treatment modalities utilized. The reason for this observation is unclear, exposure and genetic factors are potential causes and this needs to be investigated. No significant financial relationships to disclose.
Gene-expression profiles related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells.
Authors: Chang H. , Rha S. Y. , Jeung H. , Ahn J. , Jung J. , Kim T. , Kwon H. , Kim B. , Chung H. C. 
Published: February 2017

50 Background: We evaluated the cytotoxic effects of combining of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, with taxanes in human gastric cancer cell lines, and evaluated the pre-treatment difference of gene profile to identify genes that could potentially mediate the cytotoxic response. Methods: Twenty-five gastric cancer cell lines with 22K gene expression data were treated with SAHA and paclitaxel or docetaxel, and the synergistic interaction between the drugs was evaluated in vitro using the combination index (CI) method. We performed significance analysis of microarray (SAM) to identify chemosensitivity-related genes in gastric cancer cell lines that were concomitantly treated with SAHA and taxane. We generated a correlation-matrix between gene expression and CI values to identify genes whose expression correlated with a combined effect of taxanes and SAHA. Results: Taxane and SAHA combination had a synergistic cytotoxic effect against taxane-resistant gastric cancer cells. We selected 49 chemosensitivity-related genes, which were commonly identified in paclitaxel and docetaxel combined with SAHA, via SAM analysis. Among them, nine common genes (SLIT2, REEP2, EFEMP2, CDC42SE1, FSD1, POU1F1, ZNF79, ETNK1, and DOCK5) were extracted from the subsequent correlation-matrix analysis. Conclusions: Taxane and SAHA combination could be efficacious for the treatment of gastric cancer. The genes which were related with the synergistic response to taxane and SAHA could serve as surrogate biomarkers to predict the therapeutic response in gastric cancer patients. We are researching to determine the expression of the nine genes in malignant human gastric cancer tissue and to correlate them with clinical information. No significant financial relationships to disclose.
Prospective assessment of symptoms and quality of life in localized rectal cancer patients receiving chemoradiotherapy.
Authors: Herman J. M. , Griffith K. A. , Narang A. K. , Zalupski M. M. , Azad N. S. , Chan J. , Olsen L. , Efron J. , Lawrence T. S. , Ben-Josef E. 
Published: February 2017

504 Background: Neoadjuvant conformal chemoradiotherapy (CRT) is an important component of treatment for locally advanced rectal cancer, yet its morbidity has not been well characterized using quality of life (QOL) instruments. The present study attempts to establish a baseline distribution of QOL scores before, during, and after CRT and to correlate these changes with symptoms. Methods: Patients undergoing 3-4 field neoadjuvant CRT for localized rectal cancer were prospectively enrolled at two institutions. Fifty patients completed the QOL instruments at three time points: pretreatment, week 4 of treatment, and 1 month post-treatment. QOL information was captured using three validated questionnaires, the EORTC QLQ-30, QLQ-38, and QLQ-29. Additionally, institutional symptom inventories and CTCAE toxicity data were collected. Results: Average age was 59.2 years and 72% were men. During CRT, patients had a statistically significant decline in global QOL (70 to 60, p = 0.0024), which normalized (71) following completion of treatment. During therapy, patients also experienced a significant increase in GI symptoms (21 to 27, p = 0.028), urinary symptoms (16 to 30, p < 0.0001), male sexual dysfunction (23 to 34, p = 0.013), and chemotherapy related side effects (8 to 20, p = 0.0001). While these measures returned to baseline 1 month post-CRT, overall sexual function (25 vs. 37, p = 0.0062) and sexual enjoyment (53 vs. 67, p = 0.0070) remained persistently low compared to pretreatment levels. Diarrhea (27%) and proctitis (22%) were the most common grade 3 toxicities. Those patients who experienced grade 3 toxicity during treatment showed markedly decreased global QOL (mean difference = 34). Conclusions: While rectal cancer patients experienced impaired QOL during neoadjuvant CRT, the vast majority of measures normalized one month after treatment. In contrast, significantly decreased sexual function and enjoyment persisted. This data can be used as a baseline to compare future neoadjuvant conformal CRT regimens and/or assess the toxicity and QOL of new RT modalities such as intensity modulated radiation therapy. No significant financial relationships to disclose.
Predicting pathologic response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using FDG PET/CT.
Authors: Shanmugan S. , Arrangoiz R. , Nitzkorski J. R. , Yu J. Q. , Li T. , Konski A. A. , Farma J. M. , Sigurdson E. R. 
Published: February 2017

505 Background: Pathologic complete response (pCR) after neoadjuvant chemoradiation has been observed in 15% to 30% of patients with locally advanced rectal cancer. The utility of FDG PET/CT scans in the management of patients with stage II or III rectal cancer is not well defined. The objective of this study is to determine if FDG PET/CT can be used to predict pCR and disease-free survival in patients receiving neoadjuvant chemoradiation with locally advanced rectal cancer. Methods: A retrospective chart review was conducted in patients with endorectal ultrasound-staged T3 to T4 rectal tumors who underwent preoperative and postoperative FGD PET/CT imaging. All patients were treated with neoadjuvant chemoradiotherapy (CRT). Maximum standardized uptake value (SUV) of each tumor was recorded. Logistic regression was used to analyze the association of pre-CRT SUV, post-CRT SUV, % SUV change, and time between therapy and surgery in comparison to pathological complete response. Kaplan-Meier estimation was used to look for significant predictors of survival. Results: Seventy patients (mean age 62; 42M:28F) with preoperative stage T3Nx (n = 60) and T4Nx (n = 10) underwent pre-CRT and post-CRT FDG PET/CT scans between November 2002 and March 2009. All patients underwent definitive surgery after therapy with standard pathologic evaluation.The pCR rate was 26%. Median pre-CRT SUV was 10.5 while the median post-CRT SUV was 4.05. Patients with pCR had a lower mean post-CRT SUV compared to those without pCR (2.7 vs. 4.5, p = 0.02). Median SUV decrease was 61% (range 6% to 95%) and was significant in predicting pCR (p = 0.004). Patients with a pCR had a greater time interval between neoadjuvant therapy and surgery (median 57 days vs. 50 days) than those without (p = 0.05). Furthermore, patients with post-CRT SUV < 4 had a lower local recurrence rate compared to those with post-CRT SUV > 4 (p = 0.03). Patients with SUV decrease > 61% had improved overall survival at mean follow-up of 39 months than those without (p = 0.01). Conclusions: PET/CT can predict response to neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Pre-CRT SUV was the only predictor of disease-free survival. No significant financial relationships to disclose.
A phase I study of neoadjuvant chemoradiotherapy with S-1/oxaliplatin in patients with gastric cancer.
Authors: Lee D. , Lee J. , Lim D. , Kim S. , Park S. , Park J. , Park Y. , Lim H. , Kang W. 
Published: February 2017

51 Background: To determine the maximum tolerated dose (MTD) of concurrent radiotherapy with S-1 and oxaliplatin, and antitumor activity of the combination treatment in patients with gastric cancer. Methods: This was a phase I, escalating multiple-dose tolerability trial. S-1 and oxaliplatin were administered concurrently with radiotherapy for 4 weeks before surgery. The dose escalation scheme is provided in the table below. S-1 was continuously administered during radiotherapy and oxaliplatin was administered weekly for 4 weeks during radiotherapy. Results: From March 2009 to June 2010, twelve patients were entered at two dose levels. The most common dose-related grade 1 and 2 adverse events were nausea, vomiting, anorexia and abdominal pain. Two of six patients treated at level 1 developed DLT (disabling abdominal pain, stomach perforation). The dose of S-1/oxaliplatin was reduced to 30 mg/m2 bid and 40 mg/m2 (Level -1). There one DLT (vomiting and anorexia, grade 3) observed in the expanded cohort of 6 patients at Level -1. Among 12 patients, 1 patient demonstrated pathological CR after neoadjuvant chemoradiation therapy. Conclusions: Neoadjuvant CCRT with S-1/oxaliplatin was well tolerated, at a dose 30 mg/m2 bid for S-1 and 40 mg/m2 for oxaliplatin that at which antitumor activity was seen. Phase II study is planned to investigate further the efficacy, tolerability and optimal dose. [Table: see text] No significant financial relationships to disclose.
Associations between county-level surgeon density and colorectal cancer (CRC) mortality.
Authors: Albarrak J. S. , Ho M. Y. , Cheung W. Y. 
Published: February 2017

511 Background: Strong associations between surgeon procedure volumes and patient outcomes have been observed for many types of cancers. Whether surgeon density in a population has a similar impact on cancer outcomes is unclear. Our aims were to 1) explore the effect of US county-level surgeon density on CRC mortality and on annual changes in death, 2) compare the relative importance of colorectal surgeon (CS) versus general surgeon (GS) density on these CRC outcomes, and 3) identify other county characteristics associated with reduced mortality. Methods: Using county-level data from the Area Resource File, US Census and National Cancer Institute, we developed multivariate regression models to determine the effect of a) CS and b) GS on overall CRC mortality and changes in death between 2002 and 2006, while controlling for CRC incidence, county demographics and other socioeconomic factors. Results: A total of 1,187 US counties were included: mean CRC incidence and death rates were 64.9 and 19.9, respectively; 57% were metropolitan and 43% were rural counties; mean CS and GS densities were 1.23 and 1.94 per 100,000 people, respectively. When compared to counties with no CS and no GS, those with at least of one of these surgeons had a statistically significant decrease in CRC-specific mortality (beta coefficients were -0.035 and -0.051 for CS and GS, respectively; p=0.014). Increasing the county-level density of surgeons improved outcomes, but increasing it beyond 8 CS or 12 GS per 100,000 people did not continue to result in significant reductions in CRC mortality. Similar associations between surgeon density and annual changes in CRC-related death were observed. Counties with a high proportion of Medicare enrollees also showed increased CRC mortality. Conclusions: The presence of CS and GS at the county level is each associated with lower mortality from CRC. However, there appears to be a ceiling effect at which point further increases in their density do not produce continued improvements in CRC outcomes. A balanced strategy of allocating healthcare resources and distributing the surgical workforce evenly across all counties will likely offer the most substantial population-based improvements in CRC mortality. No significant financial relationships to disclose.
Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.
Authors: Starodub A. , Cohn A. L. , Arrowood C. , Haley S. , Morse M. , Uronis H. E. , Blobe G. C. , Hsu S. D. , Zafar Y. , Hurwitz H. 
Published: February 2017

513 Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhibitor of SRC kinase activity. Preclinical data suggests the addition of D to standard chemotherapy agents for colon cancer may increase anti-tumor activity. We evaluated D in combination with capecitabine (C), oxaliplatin (O) and bevacizumab (B) in a phase I dose escalation study followed by an expanded cohort in 1st line colorectal. Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ and bone marrow function and no increased risk for class-related toxicities. B and O were given intravenously, and C and D were orally administered; cycle length was 21 days. C was dosed at 850 mg/m2 on days 1-14; O was dosed at 130 mg/m2 and B was dosed at 7.5 mg/kg on day one of each cycle. D was dosed at 50 mg twice daily in cohort one and 70 mg once daily in cohort -1. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: Dose escalation is complete with 10 subjects evaluable for toxicity and 11 subjects evaluable for efficacy. Two DLTs were observed out of 5 evaluable subjects in cohort one. Six evaluable subjects were enrolled in the -1 cohort with 1 DLT. Possible grade ≥ 3 treatment-related adverse events (AEs) included neutropenia, febrile neutropenia, anorexia, diarrhea, fatigue, anemia, hypophosphatemia, hyponatremia and grade 5 GI-perforation. One non-treatment related death was due to disease progression. D-related nausea and fatigue were responsive to low dose oral steroids; fluid retention was responsive to diuretics. Of 10 subjects evaluable for efficacy, 1 subject had a partial response (PR), 2 had a minor response (MR), and 4 had stable disease (SD). Four subjects had disease control (PR, MR, or SD) ≥ 6 months. Conclusions: D in combination with C, O and B is well-tolerated with a toxicity profile similar to standard C, O and B.The recommended phase II dose is C at 850 mg/m2 on days 1-14, O at 130 mg/m2 and B at 7.5 mg/kg on day one of each cycle, and D at 70 mg once daily. Enrollment in the expanded cohort of 1st line colorectal is ongoing. [Table: see text]