bluuebunny/crossref_metadata_2025 huggingface dataset:
Resection of primary tumor in patients who present with stage IV colon cancer may result in improved survival.
Authors: Lewis Aaron , Nelson Rebecca A. , Lai Lily L.
Published: February 2017

726

Background: Resection of the primary cancer in patients with metastatic disease has been shown to result in improved survival in cancers such as renal cell carcinoma. Currently, the impact primary tumor resection has on survival in stage IV colon cancer patients is unknown. Methods: The SEER dataset was queried for patients who presented with histologically confirmed, stage IV colon cancer from 1998-2011. We excluded patients with rectal cancer, multiple primary tumors, age <18 or >90 years, diagnosis upon autopsy/death record, mortality within 30 days of diagnosis, or resection of other tumor sites (regional or distant). Cox proportional hazard models were used to assess demographic and clinical factors predictive of disease specific and overall survival. To limit group differences, a 1:1 matched analysis was also performed on patients who underwent primary resection compared to patients who did not. Results: A total of 28,068 stage IV colon cancer patients were evaluated, of which 70.3% underwent resection. Among the variables studied, multivariate models showed that patients who underwent primary tumor resection were at lower risk of disease-specific and overall mortality, with hazard ratios (HR) of 0.44 (0.43-0.46) and 0.45 (0.43-0.47), respectively. In the matched analysis (n=5,410 in each group), patients who underwent resection of the primary tumor remained at decreased risk of disease-specific and overall mortality, HR 0.48 (0.45-0.52) and 0.49 (0.46-0.53), respectively. The median survival and 3-year survival after matching was 17 and 9 months and 23% and 6% in the resection and nonresection groups, respectively, p<0.0001. Conclusions: The majority (70.3%) of patients in the United States with stage IV colon cancer undergo resection of primary tumors. Analyses of SEER data suggests that resection of the primary tumor may result in improved DSS and OS in patients with stage IV colon cancer. A prospective, randomized trial is warranted to confirm a survival benefit.
Timeline analysis of adjuvant therapy timing in colorectal cancer to improve adherence to the 120-day quality measure.
Authors: Rashid Omar Maen , Coyne Karen A. , Ross Thomas W. , Shibata David
Published: February 2017

729

Background: Multiple organizations, including ASCO, have developed accountability quality of cancer care measures that have been incorporated into accreditation, managed care contracts and quality monitoring. Institutional adherence to adjuvant chemotherapy (chemo) for stage III colon cancer (CC) provided within 120 days of diagnosis (Dx) is one such measure. We previously reported our institutional experience with reasons for non-adherence to this measure. We undertook an in-depth comparison of the clinical management timeline in adherent (A) and non-adherent (NA) cases to identify potential areas for process improvement to address this issue. Methods: All CC cases reported at a single institution from 2008–2012 were reviewed using ACS Commission on Cancer coding standards. Student t-test was used for statistical comparisons. Results: Of the 122 measure-eligible cases 16 (13.1%) were deemed NA. Of NA cases, 2(12.5%) were lost to follow up and 14(87.5%) received delayed chemo. In NA cases, the mean time from initial Dx to chemo was 159.5(+/-51) days vs. 68.7(+/-24.5) days in A cases (p=2x10-6). The Table reports the mean interval times between diagnosis, initial visit, surgery, medical oncology consultation, and receipt of chemo. The most significant differences between A and NA cases were in the pre-operative time period and related to obtaining the initial consultation and subsequent surgical treatment. Conclusions: Treatment timeline analysis revealed the most prominent delays were time to initial presentation and to surgical intervention. These areas could potentially be addressed by measure awareness, streamlining of scheduling and improved inter-provider communication. With the inevitable implementation of such measures, institutions may benefit from similar systematic evaluations for process improvement. [Table: see text]
Amphiregulin (AREG) expression and response to first-line panitumumab (pmab) plus FOLFIRI in metastatic colorectal cancer (mCRC).
Authors: Kohne Claus-Henning , Hofheinz Ralf , Mineur Laurent , Letocha Henry , Greil Richard , Thaler Josef , Twomey Brian , Oliner Kelly Smith , Boedigheimer Michael , Terwey Jan-Henrik , Karthaus Meinolf
Published: February 2017

731

Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]
A phase II trial of panitumumab with irinotecan and S-1 (IRIS) as second-line treatment in patients with wild-type KRAS metastatic colorectal cancer.
Authors: Shimoyama Rai , Kimura Tetsuo , Takaoka Toshi , Sakamoto Kazuki , Kawamoto Shunji , Yoshizaki Koji , Negoro Yuji , Goda Fuminori , Tsuji Akihito , Nakayama Tsuyoshi , Miyamoto Hiroshi , Takayama Tetsuji , Niitsu Yoshiro
Published: February 2017

732

Background: Panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in second-line chemotherapy increased objective response rate and prolonged progression-free survival (PFS) versus FOLFIRI alone in patients with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) (Peeters et al, J Clin Oncol 2010). This trial (UMIN000004659) evaluated tolerability and efficacy of combination therapy with irinotecan and S-1, an oral fluoropyrimidine (IRIS) plus panitumumab as second-line chemotherapy in patients with WT KRASmCRC. Methods: Main inclusion criteria were: patients with WT KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥20 years. Patients received panitumumab (6 mg/m2) and irinotecan (100 mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was completion rate of protocol therapy (CRT). The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-seven patients were enrolled in 9 centers. The overall CRT was 62.2% (23/37). Most frequent grade 3/4 toxicities were: skin rash (24%), diarrhea (16%), and appetite loss (11%). The overall RR was 32.4% (12/37). Of these, four patients underwent conversion surgery. Median PFS and OS were 9.5 months (95% CI: 3.5-15.4 months) and 20.1 months (95% CI: 16.7-23.2 months), respectively. Conclusions: IRIS plus panitumumab has acceptable toxicity profile and promising efficacy in patients with previously treated WT KRAS mCRC. This regimen can be an additional treatment option for second-line chemotherapy in WT KRAS mCRC. Clinical trial information: UMIN000004659.
Stereotactic body radiotherapy (SBRT) in difficult-to-treat areas (para-aortic lymphadenoapthy and pelvic recurrence) in oligometastatic colorectal carcinoma.
Authors: Bhattacharya Indrani Subarna , Woolf David , Hughes Robert , Harrison Mark
Published: February 2017

733

Background: Oligometastatic (OM) colorectal carcinoma (defined as three or fewer sites of isolated metastatic disease) may occur in potentially difficult to treat areas (including para-aortic lymphadenopathy and pelvic recurrence). Proximity of critical structures and previous irradiation may prove treatment of OM disease challenging. The aim of this study was to identify local control, overall survival (OS), and progression free survival (PFS) of patients receiving SBRT for difficult to treat oligometastatic disease (para-aortic lymphadenopathy and pelvic recurrence). Methods: Data were prospectively collected for patients receiving SBRT between 1/9/10-31/3/14, including demographic details, SBRT date, date of local/distant progression, toxicity, and date of death. Data was collected until 1/6/14. All patients were discussed within a specialist SBRT MDT and planned for treatment utilizing the Cyberknife (Accurray) treatment system. Treatment doses included 24 Gy/3F (22.7%), 27 Gy/3F (27.3%), 30 Gy/3F (13.6%), 30 Gy/5F (4.5%), 33 Gy/3F (22.7%), 36 Gy/3F (9.1%). Total dose was determined by surrounding normal tissue toxicities. Results: 9 received SBRT for para-aortic lymphadenopathy and 13 for pelvic recurrence. Median age was 58 (38-81) years. 14 were male. Median follow-up was 8.0 (0.5-28.0) months. 59.1% patients were treated within a prior radiotherapy treatment volume. 31.8% patients were disease free after SBRT. 63.6% had distant relapse and 4.5% had local and distant relapse. Local control was 95%. Median time to relapse was 4.5 (1.2-37.2) months. OS was 72% at 1 year and 46% at 2 years. PFS was 36% at 1 year and 27% at 2 years. Significant toxicities included 1 patient with duodenal ulcer formation following para-aortic node SBRT. Conclusions: Our prospective series confirms excellent local control (95%) with SBRT for OM colorectal carcinoma in areas considered to be difficult to treat, and with limited toxicity.
Surrogacy of progression-free survival (PFS) for overall survival (OS) in rectal cancer trials with preoperative therapy: Literature-based meta-analysis.
Authors: Mizusawa Junki , Nakamura Kenichi , Kataoka Kozo , Eba Junko , Katayama Hiroshi , Shibata Taro , Fukuda Haruhiko
Published: February 2017

734

Background: Disease-free survival (DFS) after adjuvant chemotherapy in colon cancer has been validated as a surrogate endpoint for OS. An analysis of individual patient data from two randomized controlled trials evaluating preoperative chemoradiotherapy for rectal cancer has already shown that PFS might be a surrogate endpoint for OS (Eur J Cancer, 2012). However, since the report was derived from only two trials, the further evaluation of surrogacy with a larger number of trials is desirable. This study was conducted to explore the trial level correlations between PFS and OS in resectable rectal cancer with preoperative therapy. Methods: A systematic literature search of randomized trials of preoperative chemoradiotherapy, radiotherapy or chemotherapy for rectal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R2) within PFS and OS. 95% confidence interval of R2 was estimated by bootstrap method. The primary analysis included trials in which the HR of PFS and OS were reported. A sensitivity analysis included the trials in which either HR or 5 years point estimates of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the point estimates of PFS and OS assuming exponential distribution. Results: Of 1,048 articles, 14 trials (7,233 patients) were selected for the primary analysis and 18 (8,020) for the sensitivity analysis. Median numbers of enrolled patients were 332 (range 113-1,805) in primary analysis, and 296 (113-1,805) in sensitivity analysis. The primary analysis did not show the correlation between treatment effects on PFS and OS(R2 0.408; 95% CI [0.133-0.845]). The sensitivity analysis showed modest correlation between PFS and OS (R2 0.603; 95% CI [0.296-0.871]). Conclusions: The primary analysis showed that PFS was not suitable as a surrogate endpoint, which is contradictory to the previous report. Based on our results, OS is still preferable as the primary endpoint in the trials of preoperative therapy for resectable rectal cancer.
Colorectal cancer surgery in extreme elderly population.
Authors: Gallego Plazas Javier , Asensio Martinez Elena , Ore Martin , Cotes Almudena , Ricote Guillermo , Lozano Inmaculada , Ors Mamen , Magdaleno Alejandra , Baron Jose M. , Escudero Maria J , Navarro Jose M , Morcillo Miguel A
Published: February 2017

738

Background: Colorectal cancer surgery in extreme elderly population ( ≥80 years) is a growing problem and a subject in question. Experiences and results in this scenario are limited. Methods: Medical records of patients ≥80 years old hospitalized in General Surgery Department in Vega Baja Hospital between January 1, 2008, and December 31, 2012, were retrospectively reviewed. Patients diagnosed with colorectal cancer (CRC) were selected. Data regarding comorbidity, treatment performed, complications, and survival were collected. Results: 95 patients (74 colon, 21 rectum) were identified: median age 83.9 years (80-93), 64.2% males. 93.7% of patients were operated on: median hospital and post-operative stay of 14.1 and 11 days, respectively; curative intention surgery 82.1%. 5.4% of patients were treated with interventionist procedures, and 2.1% of patients in a conservative way. 17.9% and 4.2% of patients came up with early and late complications, respectively. Early and late mortality occurred in 9.5% and 3.2% of patients, respectively. There was no statiscally significant association between number of comorbidities and morbi-mortality. Early complications were more frequently associated to bronchopathy (33%) or cardiopathy (25.9%), while late complications were to diabetes (15%), congnitive disorders (12.5%), and cardiopathy (7.4%). Late mortality ocurred more frequently associated to diabetes (5%) and cardiopathy (3.7%). Colon cancer was more frequently associated to early complications and early and late mortality, maybe explained with more unscheduled surgeries. By March 2014, with a median folluw up of 43.8 months, 37.9% of patients are alive free of relapse, 2.1% are alive with disease, 26.3% had died of cancer, 10.5% had died of surgery related complications, and 23.2% of patients had died of other causes. Conclusions: Certain comorbidities and not the addition of them were associated with morbidity and mortality due to CRC surgery. Personalizing CRC treatment in a extreme elderly population may result in extended survival in this increasing subgroup of patients.
Antitumorigenic effect of plumbagin by induction of SHP1 in human gastric carcinoma cell lines.
Authors: Koh Jin Sung , Park Jong-Jae , Joo Moon Kyung , Yoo Hyo Soon , Kim Jiwon , Jeoung Yong , Kim Ho , Choe Jung Wan , Lee Beom Jae , Kim Jae Seon , Bak Young-Tae
Published: February 2017

74

Background: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a plant-drived natural agent extracted from the root of Plumbago zeylanic. A recent study reported that plumbagin down-regulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various anti-tumor effects. We aimed in this in vitrostudy to demonstrate the inhibition of JAK2-STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in gastric cancer cell line. Methods: We performed Wetern blot to measure SHP1, phospho-JAK2/STAT3 level, and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate target gene expression of STAT3. Several functional studies such as water soluble tetrazolium-1 (WST-1) assay, wound closure assay and matrigel invasion assay were also performed. Results: Plumbagin induced SHP1 expression and simultaneously down-regulated phospho-JAK2/STAT3 level via dose-and time-dependant manner in MKN28 cell, a gastric carcinoma cell line which has negative SHP1 expression. This effect was consistent when JAK2-STAT3 signaling was activated by interleukin-6, and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor. Furthermore, plumbagin significantly reduced gene expression of cyclin D1, VEGF1, survivin, MMP9, known target products of STAT3 activation in gastric cancinogenesis. The functional effect of plumbagin could be validated as inhibition of cell proliferation, migration and invasion, which are the results of activation of JAK2-STAT3 pathway in gastric cancer cells. Conclusions: Plumbagin is a potential negative regulator of cellular growth, migration and invasion by inhibiting both constitutive and inducible STAT3 activity through induction of SHP1 in gastric cancer cells.
Attitudes of patients towards cancer clinical trials.
Authors: Ayodele Olubukola , Akhtar Mateen , Eastwood Mathew Chad , Linkeviciute-Koneko Aiste , Keegan Niamh M. , Calacsan Flordeliza , O'Connor Miriam , Calvert Paula , Horgan Anne M.
Published: February 2017

741

Background: Older patients (pts) with cancer are under-represented in clinical trials (CTs). To better understand the causes for low accrual rates, the pts perspective must be explored. Objectives: To determine the attitudes of Irish pts towards enrolment into cancer CTs and in particular, the differences between the attitudes of older and younger pts. Methods: Pts with a gastrointestinal cancer, receiving treatment or in follow-up in University Hospital Waterford were eligible. Pts completed a self-dministered questionnaire comprising three sections: attitudes towards CT participation, reasons to participate, and reasons to decline participation. Pts were given three CT scenarios and were asked if they would participate: these included a cancer prevention/screening CT; a CT comparing standard to new treatment and a trial of a new drug where no standard exists. Summary statistics were used to describe the respondents. Differences between the groups were investigated using the Fishers exact test. Results: From March 2014, 69 pts were accrued, 31 <65 yrs (32-64) and 38 ≥65 yrs (65–85). Five (16%) younger and 3 (8%) older pts had been or were actively enrolled on a CT (p=0.45). An additional 4 (17%) younger and 5 (13%) older pts were invited to participate in a CT, all of whom declined. No patient in either group had actively enquired about CT availability. For the CT scenarios, 22 (71%) younger vs. 22 (58%) older pts would participate in a prevention/screening CT (p=0.32); 14 (45%) vs. 19 (50%) for standard vs. new drug CT (p=0.81), and 23 (74%) vs. 31 (82%) for a CT where no standard exists (p=0.56). The most common reasons to participate in a CT included the potential to feel better, reported in 100% of younger and older pts, the potential to live longer (100% vs. 92%) and the potential to help others (97% vs 89%). Age was deemed an important consideration in 20 (65%) younger and 25 (66%) older pts. Conclusions: The attitudes of older and younger pts to cancer CTs are similar. Physician barriers and availability of appropriate studies impact accrual of both older and younger cancer pts into trials. No patient in this study actively sought out a CT, suggesting a need for better patient awareness and education. This study is ongoing and updated results will be presented.
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

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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

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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

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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.
Time to adjuvant chemotherapy (TTAC) after open or laparoscopic resection surgeries in colorectal cancers (CRC).
Authors: Miller Selene A. , Sevick Laura , Acuna Sergio , Mercado Marck , Baxter Nancy N. , Burnstein Marcus J. , De Montbrun Sandra , Rotstein Ori D. , Tang Grace , Varatheswaran Winthya , Brezden-Masley Christine
Published: February 2017

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Background: This single institution retrospective study evaluates the reason for delay in Time To Adjuvant Chemotherapy (TTAC) from curative resection surgery to start of adjuvant therapy in CRC. The reason for this study was to determine if type of surgery (laparoscopic versus open) increased TTAC of which evidence indicates poorer disease free survival and overall survival (Biagi J, Raphael M, Mackillop W, Kong W, King W, Booth C. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA, 305(22):2335-42. doi: 10.1001/jama.2011.749.) Methods: CRC patients treated at St. Michael’s Hospital in Toronto, Canada were included if diagnosed with stage II or III disease, underwent curative resection surgery between January 1, 2006, and December 31, 2012, and either received systemic adjuvant chemotherapy or surveillance protocol. Results: Among 259 patients, 92 patients (35.7%) underwent curative laparoscopic resection and 166 open resection (64.3%). Intraoperative and/or postoperative complications were experienced in 73 patients. Complications were less prevalent among patients who underwent laparoscopic surgery versus open resection (11.9% vs. 36.8%; p<0.0001). Of these 73 complications, wound infection (39.7%), intraoperative procedural complication (14.3%), and postoperative gastrointestinal complications (6.4%) were most prevalent. After adjusting for complication and clustering within the operating surgeon, there were no statistical differences in TTAC between open (51.310 ± 1.7 days) and laparoscopic (49.2 ± 1.6 days) resection surgeries (p=0.1996). However, presence of a complication was associated with delay in TTAC (HR 0.501; 95% CI, 0.43-0.58; p<0.001). Conclusions: TTAC in CRC patients does not differ statically for each type of resection surgery. However, presence of a complication is associated with delays in TTAC and is over three-fold more prevalent in open than laparoscopic resections. Therefore, there is an increased risk of delay in TTAC for open resection surgeries than laparoscopic resections due to a higher prevalence of surgical complications.