bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of recurrence pattern and survival in locally advanced rectal cancer treated with neoadjuvant chemoradiation and surgery: 25 years of experience.
Authors: Cienfuegos Javier A. , Baixauli Jorge , Rotellar Fernando , Sola Iosu , Arredondo Jorge , Martfnez-Ortega Patricia , Beorlegui Carmen , Hernandez-Lizoain Jose Luis 
Published: February 2017

744 Background: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (CRT) followed by total mesorectal excision (TME). Despite the significant reduction (~ 40%) in local recurrence, the overall survival (OS) and disease free survival (DFS) remain stable during last decade. We aimed to study the pattern of recurrence and it’s relationship with clinico-pathological data in 356 patients with LARC treated with CRT and TME in last 25 years. Methods: From a total of 621 patients, 356 with LARC were analyzed. In 55 (15.4%) the tumor was localized in upper third, in 120 (33.7%) in middle third and in 181 (50.8%) in distal third. The median dose of radiotherapy for the 3 groups was between 47.5 - 48.52 Gy. Chemotherapy was based on 5-FU or capecitabine combined with oxaliplatin. Type of surgery, pathological response grade, circumferential resection margin, lymphovascular invasion, colloid response, local recurrence incidence, distal relapse, OS and DFS were analyzed. Results: The median interval between the end of CRT and surgery was 40 days. 52 low anterior resection were carried-out in upper third (94.5%), 112 (93.3%) in middle third and 92 (50.8%) in distal third. Four patients from the middle third (3.3%) underwent abdominoperineal resection and 72 (39.8%) in the distal location. No differences were observed in number of lymphoid nodes, vascular perineural invasion, and pathological response grade. A pathological complete response was assessed in 5 patients (9.1%) in upper third, in 12 (10%) in middle third, as well in 32 (17.7%) in distal third. Median follow-up of 187 months. The 5-10 year DFS for the 3 groups was 75%, 76%, and 69%, and 75%, 71%, and 66% respectively. The local recurrence rate was 3.6%, 4.2%, and 6.1%. The distal recurrence was more frequent in the lung, 10.9%, 16.7%, 23.8%, with tendency to be significant (p<0.007) in distal third. Conclusions: In spite of the good local control with the association of preoperative CRT and TME in treatment of LARC, the development of distant metastases, especially in distal third, gives rise to new therapeutics schemes. Further research is warranted as to the benefits of adjuvant chemotherapy.
Comparison of survival outcomes of rectal squamous cell carcinoma with rectal adenocarcinoma.
Authors: Lin Chi , Bhirud Abhijeet , Li Jinluan , Charlton Mary E. 
Published: February 2017

745 Background: Rectal squamous cell carcinoma (RSCC) is a rare disease. It is unclear whether the prognosis or treatment outcomes differ from that of rectal adenocarcinoma (RAC). The objective of this study is to compare the overall survival (OS), cancer specific survival (CSS) and prognostic factors of RSCC to those of rectal adenocarcinoma (RAC) using the Surveillance, Epidemiology, and End Results (SEER) registry. Methods: A total of 42,317 patients diagnosed with RSCC (999) and RAC (41,318) without distant metastasis between 1998 and 2011 were identified from the SEER database. Factors analyzed included histology (RSCC/RAC), age (≤56/>56), gender, race (white/nonwhite), tumor size (<5 cm/≥5 cm), grade (well-moderate/poor-undifferentiated), stage (local/regional), year of diagnosis (1998-2003/2004-2011), with or without surgery, and with or without radiotherapy (RT). OS and CSS were evaluated using the Kaplan-Meier method. Cox proportional hazards regression analysis was performed to examine the prognostic factors for survival. Results: The median follow up is 77 months (M). The entire group had 5 year OS and CSS of 62% and 77% with a median OS of 95 M but did not reach a median CSS. Compared to patients with RAC, patients with RSCC tend to be younger, female, diagnosed more recently, with less advanced stage but higher grade and larger tumor size. For patients with RSCC, 40% underwent surgery and 75% received RT. In contrast, for patients with RAC, 89% underwent surgery and 59% received RT. Patients with RSCC had a higher median OS than those with RAC (105 vs 94 M, Log-rank p <0.05). Cox proportional hazards analysis showed that patients with RAC had worse OS (hazard ratio [HR] 1.4) and CSS (HR 1.6) than patients with RSCC (p<0.05), after adjusting for all prognostic factors. Factors associated with improved OS and CSS in both RSCC and RAC included age ≤56, nonwhite, early stage, well-moderate differentiated, undergoing surgery and receiving RT. Gender is a prognostic factor for OS but not for CSS. Conclusions: Patients with rectal squamous cell carcinoma had a significantly superior OS and CSS than patient with rectal adenocarcinoma. Future studies should seek to explore the optimal management for these two distinct diseases.
Prolonged survival after two-stage resection of advanced colorectal liver metastases: Impact of an intensified chemotherapy.
Authors: Pissas Marie-Hélène , Carrere Sebastien , Roca Lise , Colombo Pierre-Emmanuel , Bertrand Martin , Sgarbura Olivia , Portales Fabienne , Samalin Emmanuelle , Ychou Marc , Saint-Aubert Bernard , Rouanet Philippe , Quenet François 
Published: February 2017

748 Background: Patients with advanced colorectal liver metastases (CRLM) experience poor prognosis. The impact of two-stage resection (TSR) after downstaging by chemotherapy is still controversial. Methods: Data on 899 patients with CRLM in a single institution during a 9-year period (2004–2013) were prospectively collected. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR associated with intensified chemotherapy before and between the two surgical stages. Results: 73 patients were eligible for the first stage of TSR. In this population, 54 patients underwent an intensified chemotherapy based on FOLFIRINOX (26 patients) or a standard chemotherapy associated with cetuximab or bevacizumab (28 patients). The first surgical stage was a clearance of the left liver in 56% of cases. An average of two radio-frequency ablations and two wedge resections were necessary. The post-operative morbidity of the first stage was 18%. 78% of patients received chemotherapy between the two stages. The average interval between two stages was 228 days (36-1561). 68% of TSR patients completed the second stage. The second resection was mainly a standard right lobectomy (32%). Morbidity after the second resection was 12%. One patient died post-operatively because of post operative liver failure. Median overall survival of patients who completed TSR was 48 months. In contrast, there was no survival advantage for patients who underwent only the first stage because of progression (median overall survival: 19 months) (p = 0.0003). The median overall survival of the whole population was 43 months and the median recurrence-free survival was 15 months. Conclusions: Intensified chemotherapy in association with TSR allows excellent outcome in patients with advanced CRLM. Chemotherapy delivered between the two surgical stages is responsible for an important waiting time but could contribute to a better control of the evolution of the disease.
Overexpression of DEK in human gastric carcinoma and its clinicopathological significance.
Authors: Lin Kwang-Huei , Tsai Chung-Ying 
Published: February 2017

75 Background: Gastric cancer (GAC) is the second most common cancer worldwide and the fifth leading cause of cancer-related death in Taiwan. To improve the survival of gastric cancer patients, biomarkers for early detection and effective anticancer therapy are required. Methods: Dysregulated proteins in GAC tumor cells were captured and identified by laser capture microdissection (LCM) and an isobaric tags for relative and absolute quantitation (iTRAQ)-labeling following basic-RP HPLC coupled to LTQ-orbitrap MS analysis. DEK, one of the most highly-expressed proteins in both intestinal and diffuse gastric cancers in iTRAQ analysis, was selected for further study. DEK proto-oncogene is originally identified as a fusion with the CAN nucleoporin protein in a subset of acute myeloid leukemia (AML) patients carrying the t(6;9) translocation, and DEK has been implicated in acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. The overexpression of DEK was confirmed using real-time quantitative-reverse transcription-polymerase chain reaction (Q-RT–PCR), Western blot, and immunohistochemical (IHC) analysis. Results: The data revealed that the expression of DEK mRNA was up-regulated in tumor tissues (compared with adjacent non-tumor tissues) of about 55.1% gastric patients. The expression of DEK protein was also up-regulated in tumor tissues identified by Western blot and IHC. To further understand the role of DEKgene in the human gastric cancer cells, the DEK knockdown stable clones were prepared in AZ521. The cells migration ability was reduced in DEK depletion stable clones, and the antitumor drug sensitivity and anoikis were increased in DEK depletion cells. Conclusions: These results indicate that DEK overexpression may contribute the poor prognosis of patients.
Association of perineural invasion with outcomes after neodjuvant chemoradiation for locally advanced rectal adenocarcinoma.
Authors: Chablani Priyanka Vinod , Nguyen Phuong , Robinson Charles Andrew , Pan Xueliang Jeff , Walston Steve Andrew , Wuthrick Evan John , Williams Terence Marques 
Published: February 2017

750 Background: Perineural invasion (PNI) as a prognostic indicator has not been well studied in patients with rectal adenocarcinoma treated with neoadjuvant chemoradiation (nCRT). In this study, we investigated the incidence and prognostic significance of PNI in patients with stages II-III locally advanced rectal cancer treated with nCRT. Methods: We performed a retrospective study of 110 consecutive patients treated with nCRT for locally advanced rectal adenocarcinoma at a single institution from 2004 to 2011. 88 of these patients had residual tumor in the resected specimen after nCRT. We evaluated the association of PNI with clinical outcomes, including disease-free survival (DFS), distant-metastasis-free survival (DMFS), and overall survival (OS), using log-rank and Cox proportional hazard modeling. Results: Of the 88 patients with residual tumor at surgery, 14 patients (16%) had PNI and 74 patients (84%) did not. Baseline distribution of selected variables in the PNI+ and PNI- groups are shown in Table 1. Median follow-up was 27 months (range 0.9 to 84 months). The median DFS was 13.5 months for PNI+ patients and 39.8 months for PNI- patients (p<0.0001). The median DMFS was 13.5 months for PNI+ patients and median not reached (> 40 months) for PNI- patients (p<0.0001). We did not detect a significant association between the presence of PNI and worse OS, perhaps due to a high rate of censored patients in the OS analysis. In a multivariate model including pT stage, pN stage, tumor location, tumor size, type of surgery, and radial margin status, PNI remained a significant predictor of DFS (HR 16.8, 95% CI, 3.7–75.5, p<0.0002) and DMFS (HR 18.9, 95% CI, 4.4–81.9, p<0.0001). Conclusions: For patients with locally advanced rectal cancer treated with nCRT prior to surgical resection, PNI found at the time of surgery is significantly associated with worse DFS and DMFS. [Table: see text]
KRAS mutations to predict survival of yttrium-90 radioembolization therapy in patients with unresectable colorectal liver metastases.
Authors: Lahti Steven John , Xing Minzhi , Kim Hyun Sik 
Published: February 2017

754 Background: The significance of KRAS mutations in predicting response to Yttrium-90 radioembolization (Y90) of colorectal cancer (CRC) liver metastases is unknown. The purpose of this study was to compare overall survival (OS) in patients receiving Y90 with wild-type (wt) and mutant KRAS. Methods: Consecutive patients with unresectable CRC liver metastases and KRAS mutation status who were treated with Y90 from 2002-2014 were studied. Patient demographics, lab and molecular markers, disease stages, therapy regimens, treatment parameters, OS from primary CRC diagnosis, from liver metastasis and from first Y90 were compared between patients with KRAS wt and mutant. Kaplan-Meier estimation and Cox proportional hazard models were used for survival analysis and to assess independent prognostic factors for OS. Results: A total of 107 patients with unresectable CRC liver metastases underwent KRAS mutation analysis prior to Y90; 43 (40.2%) were mutant and 64 (59.8%) were wt. At the time of analysis, 13 patients were censored due to loss to follow-up. Groups were similar in age, sex, race, Child class, mean pre-Y90 carcino-embryonic antigen (CEA) levels, and % receiving Y90 as third-line therapy (p>0.05 for all). OS from primary diagnosis, liver metastasis, and from first Y90 was significantly greater in KRAS wt than in mutant (p=0.022, 0.002, and 0.022). Median OS from first Y90 for KRAS wt and mutant were 9.4 and 5.1 months, respectively. On multivariate analysis adjusting for age, sex, race, Child class, and pre-treatment CEA level, wt KRAS remained an independent predictor of greater survival (HR=0.64, p=0.049). Conclusions: Patients with unresectable mCRC to the liver with KRAS wt demonstrated significantly greater post-Y90 survival compared with KRAS mutant. [Table: see text]
Influence of systemic and local immune response on overall survival after hepatic resection of colorectal liver metastasis.
Authors: Hamada Takeomi , Ishizaki Hidenobu , Haruyama Yukihiro , Hamada Rouko , Ikeda Takuto , Otani Kazuhiro , Fujii Yoshiro , Kataoka Hiroaki , Kondo Kazuhiro 
Published: February 2017

756 Background: Colorectal cancer progression is dependent on complex interactions between the tumor and the host. Tumor infiltrating lymphocytes (TIL) have been reported as a prognostic factor in colorectal cancer. The aim of this study was to assess the prognostic value of pre-operative systemic immune biomarkers and TIL in patients with resectable colorectal liver metastases (CLM). Methods: Clinicopathological data were reviewed for patients (n=31) who underwent hepatic resections for CLM between 2000 and 2008. Prognostic variables from the primary lesion, metastatic lesion, and host inflammatory biomarkers measured as routine pre-operative blood tests (modified Glasgow Prognostic Score and neutrophil to lymphocyte ratio [NLR]) were evaluated by univariate and multivariate analyses. To evaluate the local immune responses of resected metastatic lesion, immunohistochemical analysis was performed. The immune subsets were CD8+ T cells, CD45RO+ T cells, Fork head box p3+ (FOXP3+) T cells, and CD66b+ neutrophils. We also evaluated PD-L1 expression in the metastatic lesion. Results: The number of metastases ≥ 4, extrahepatic metastasis, adjuvant chemotherapy, and NLR > 4.1 were correlated with cancer-specific survival in univariate analysis. On multivariate analysis, the number of metastases (HR: 0.09, CI: 0.01-0.56, p=0.0102), adjuvant chemotherapy (HR: 0.08, CI: 0.01-0.39, p=0.0025), and raised NLR (HR: 0.11, CI: 0.01-0.99, p=0.0494) remained independent prognostic indicators. Accumulation of CD45RO+ memory T cells in the metastatic tumors was significantly associated with favorable survival in patients with resectable CLM (p=0.020). Interestingly, increased neutrophils in peripheral blood showed significant correlation with reduced accumulation of CD45RO+ memory T cells in metastatic lesion (p=0.023). Conclusions: Based on the present results and the existing validation literature, systemic immune response including NLR and local immune response including CD45RO+ memory T cells may be promising prognostic factor of patients with resectable CLM. Further functional analysis of neutrophils in CLM patient will be needed.
A phase II study of oxaliplatin reintroduction in patients pretreated with oxaliplatin and irinotecan for advanced colorectal cancer (RE-OPEN study).
Authors: Suenaga Mitsukuni , Mizunuma Nobuyuki , Matsusaka Satoshi , Shinozaki Eiji , Ozaka Masato , Ogura Mariko , Chin Keisho , Yamaguchi Toshiharu 
Published: February 2017

758 Background: Re-introduction of oxaliplatin (L-OHP) for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy regimens including L-OHP, irinotecan (CPT-11), and fluorouracil was thought to be effective approach. We performed a single arm, open-label phase II study (UMIN ID: 000004884), and the reported results of interim analysis were promising. Methods: Patients with prior chemotherapy including L-OHP and CPT-11 achieved tumor response or stable disease during prior L-OHP based therapy, and 6 months or over from confirmed progression disease during previous L-OHP based therapy was eligible for this study. Patients received FOLFOX regimens every two weeks. Primary endpoint was disease control rate (DCR) after 12 weeks of treatment start. Tumor response was evaluated by RECIST v1.1, and DCR was defined as complete response (CR), partial response (PR) or stable disease. This trial followed a Simon’s two-stage minimax design. Assuming the expected and threshold DCR after 12 weeks of treatment start would be 40% and 20%, 33 patients (18 in Step I and 15 in Step II) were required with a one sided α-level of 5% and a power of 80%. Results: Between February 2011 and August 2013, 33 patients were enrolled in this study. Characteristics of patients were as follows (n=33): median age of 62 years (35-77); male/female: 19/14; ECOG PS0: 84.8%; and colon/rectum: 14/19. All patients received mFOLFOX6 regimen. The DCR after 12 weeks of treatment start was 39.4% (95% CI: 21.8-57.0%), and the primary endpoint was met. The response Rate (CR or PR) was 6.1%. The median number of courses of chemotherapy was five, and the median total dose of L-OHP was 366.9 mg/m2. The median progression free survival was 98 days and the median overall survival was 300 days. The incidence of allergic reaction was 24.4% and peripheral neuropathy was 90.9%, graded as mild to moderate events. There were no other severe adverse events and treatment related deaths. Conclusions: Reintroduction of L-OHP was effective and could be a new salvage option for patients with mCRC refractory to previous L-OHP based therapy. Clinical trial information: 000004884.
Organotypic slice cultures of human gastric cancer (GC) and esophagogastric junction adenocarcinoma (AEG): A new technology to study treatment response, resistance, and tumor heterogeneity.
Authors: Koerfer Justus , Kallendrusch Sonja , Merz Felicitas , Kubick Christoph , Kassahun Woubet , Schumacher Guido , Moebius Christian , Gassler Nikolaus , Eckmann Christian , Koerfer Alfred , Weimann Arved , Wiechmann Volker , Geister Daniela , Aigner Achim , Bechmann Ingo , Lordick Florian 
Published: February 2017

76 Background: GC and AEG have an unpredictable response to cytotoxic treatment and a poor prognosis. There is an urgent need for new research methods allowing for the determination of chemotherapy sensitivities, the analysis of resistance mechanisms and tumor heterogeneity. Here, we describe a novel technique extending our recent findings in other tumors (Gerlach et al. 2014; Merz et al. 2013), by which cancer specimens can be cultured in vitro and maintained in their natural micro-environment. Methods: Using a tissue chopper, fresh surgical and endoscopic tissue samples from GC and AEG were cut in 400 µm thick slices and cultivated in 6-well plates for up to 6 days. The slices were then fixed, embedded in paraffin and cut for routine histopathology and immunohistochemistry. Cytokeratin stains (CK8 and AE1/3) were used for determining tumor cellularity, ki-67 for proliferation, and cleaved caspase 3 staining for apoptosis. The slices were examined under naïve condition and following in-vitro exposure to 5-FU, cisplatin or docetaxel over a period of 2-4 days. Results: GC and AEG slice cultures from resection specimens (n=14) and endoscopic biopsies (n=17) revealed a good preservation of tissue morphology and tumor cell integrity during the culture period in most cases. The stroma and the tumor cellularity remained stable over at least 4 days, proving the viability of cancer in slice cultures. The amount of sampled tissue from endoscopic biopsies was identified as a critical determinant for the feasibility of slice cultures. During treatment of cultures with chemotherapy, a significant loss of tumor cellularity and an increase of apoptotic cells were observed, although a systematic and reproducible read-out still needs to be established. Conclusions: Slice cultures of GC and AEG were successfully established. They can be expected to provide a unique and powerful in vitro platform for the determination of sensitivities of a given tumor towards chemotherapy, to examine mechanisms of drug-resistance and to analyze tumor heterogeneity in patient samples.
Subgroup analysis of patients enrolled in the United States in the CORRECT phase 3 trial of the multikinase inhibitor regorafenib (REG) in metastatic colorectal cancer (mCRC).
Authors: Lenz Heinz-Josef , Van Cutsem Eric , Verma Udit N. , Saltzman Marc , Fuloria Jyotsna , Khojasteh Ali , Wiesenfeld Martin , Cihon Frank , Wagner Andrea , Grothey Axel 
Published: February 2017

767 Background: The CORRECT trial (NCT01103323) showed that REG improves overall survival (OS) vs placebo (PBO) in patients with mCRC who failed approved therapies (OS HR 0.77; 1-sided p=0.0052; Grothey 2013). A total of 760 patients were randomized to REG (n=505) or PBO (n=255) in more than 100 centers across North America, Europe, Asia, and Australia. We conducted a post-hoc exploratory subgroup analysis of the 83 (11%) patients from 18 US centers. Methods: Eligible patients had an ECOG PS ≤1 and had received approved therapies, including a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, and if KRAS wild-type cetuximab and/or panitumumab. Data from the overall cohort, including US patients, are provided for perspective. Descriptive statistics are shown. Results: Of the 83 US patients, 36 (43%) were randomized to PBO and 47 (57%) to REG. Baseline characteristics of the US group were consistent with the overall cohort: median age in the US was 58 yr (range, 34 – 85) vs 61 (22 – 85) overall, 49% of US patients were ECOG PS1 (vs 46%), and 46% received ≤ 3 treatments for mCRC (vs 52%). KRAS status mutant/wild-type was 57%/34% in the US vs 57%/39% overall. All patients in the trial had prior bevacizumab and 57% of US patients also had prior cetuximab and/or panitumumab (vs 51% overall). However, higher proportion of patients in the US were Black (11% vs 2%), KRAS status unknown (10% vs 4%), and had colon as the primary disease site (82% vs 65%). Mean percentages of planned REG dose were similar (76% US vs 79% overall) and mean REG treatment duration was 3.1 mos in US vs 2.8 mos overall. Rates of dose modifications REG/PBO were 87%/47% in the US vs 76%/38% overall and grade ≥3 adverse events REG/PBO were 74%/64% vs 78%/49%, respectively. Based on 44 total death events, the HR for OS in the US subgroup was 0.46 (95%CI 0.25 – 0.84) favoring REG; median OS was 4.7 mos for PBO, but could not be estimated for REG due to censored data. However, this analysis was based on a relatively small sample size and event count. Conclusions: Patients treated in the CORRECT study in the US appear similar to the overall cohort and results are generally consistent with the overall findings of the trial. Clinical trial information: NCT01103323.