bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locally advanced colorectal cancer: Is a second look surgery and prophylactic HIPEC warranted?
Authors: Bhamre Rahul , Anam Jay Rashmi , Bhandare Manish , Saklani Avanish 
Published: September 2018

e15056 Background: Peritoneal recurrence/carcinomatosis (PC) after curative surgery for colorectal cancer is the second most common site of recurrence and carries a poor prognosis. PC present relatively in the later stage, are difficult to detect by conventional imaging on follow up, and have limited options to treat after diagnosis. Second look surgery is the only definite option to diagnose early PC and presents an opportunity for disease control by cytoreductive surgery (CRS) and HIPEC. Multiple studies have attempted to identify clinico-pathological risk factors that predict high chances of PC. Our aim is to analyze the recurrence patterns and survival in locally advanced colorectal cancer, in an attempt to identify high risk factors for PC, which can be used as an indication for second look surgery and prophylactic HIPEC in such cases. Methods: Retrospective analysis of a prospectively maintained data of all colorectal cancer patients presenting to a tertiary cancer care referral center in India, from May 2010 to October 2015 was done. All patients who underwent surgery with curative intent and were clinico-pathological stage T4 and/or N2 M0 were included in the analysis. Results: 182 patients underwent curative resection with a clinico-pathological staging of T4 and/or N2 M0. There were 71 recurrences, out of which 30 (42.2%) were peritoneal, 7 (9.9%) were hepatic only while 34 (47.9 %) were non-hepatic systemic or multiple site. For a median follow up of 26 months, the estimated 3 year OS was 78 % while the 3 year DFS was 50.4 %. The median time to diagnosis of peritoneal recurrence was 13 months (4.7 – 55.7). The 3-year OS for patients with peritoneal recurrence was 48.6 % as against 57 % for liver only recurrence and 59.9 % for non liver systemic and multiple site recurrence, with a trend towards poorer survival for peritoneal recurrences, although non-significant (p – 0.377). Conclusions: Locally advanced colorectal cancer has a high risk of peritoneal recurrence which negatively impacts the survival. Well-designed RCTs need to be conducted to identify the high risk factors for PC and whether second look surgery and prophylactic HIPEC in such patients will improve survival with acceptable morbidity and mortality.
Efficacy and tolerability of second-line intra-arterial 5FU or mitomycine C after intra-arterial oxaliplatin failure in patients with colorectal cancer and unresectable liver metastases.
Authors: Pernot Simon , Velut Guillaume , Kourie Hampig Raphael , Amouyal Gregory , Sapoval Marc , Pointet Anne-Laure , Landi Bruno , Zaaimi Yosra , Lepère Céline , Pellerin Olivier , Taieb Julien 
Published: September 2018

e15061 Background: Hepatic arterial infusion (HAI) chemotherapy of oxaliplatin is an option in the management of metastatic colorectal cancers (mCRC) with dominant liver metastases (LM). However, despite prolonged control some patients (pts) experience disease progression or dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. This pilot study is evaluating treatment outcomes in pts receiving HAI of 5-FU or mitomycine C (MMC), after HAI oxaliplatin (HAI-ox) in heavily pretreated pts. Methods: 24 pts with unresectable mCRC were enrolled, metastases were exclusively or dominant in the liver (≥80% of overall total metastatic tumour burden in the liver), all pts received prior HAI-ox. They were treated with either biweekly HAI 5-FU with dose ranging from 600 to 1200mg/m2 over 2 hours (17 patients), or monthly MMC 7mg/m2 over 1 hour (7 patients). Results: Mean age was 62 years. 42% of pts (10/24) had extra-hepatic metastases and 75% (18/24) had 8 LM or more. Including prior HAI-ox, pts had previously received a median of 3 prior lines of treatment (range:2 to 5). Previous HAI-ox was stopped for toxicity in 17 pts (allergy, neuropathy or abdominal pain) or progression in 7 pts. At baseline, 62% of pts had progressive disease. All pts but one received concomitant systemic therapies together with HAI 5FU or MMC. The overall RECIST V1.1 objective response rate and disease control rate were respectively 42% (10/24) and 71% (17/24). Median progression free survival (PFS) and overall survival (OS) were respectively 5.6 and 25.8 months; hepatic PFS was 8.5 months. 3 pts benefited from further curative intent treatments after 2nd line HAI (2 radiofrequency, 1 surgery). No toxic death occurred and toxicity profile was acceptable, with only 2 grade 3 events reported (diarrhea and thrombocytopenia). Conclusions: 2nd line HAI with 5-FU or MMC seems feasible and efficient in heavily pretreated mCRC with liver dominant disease when progressing or not tolerating oxaliplatin HAI. A phase II study is going to be performed to confirm these first results.
A retrospective study of raltitrexed combined with S-1 as salvage treatment for patients with metastatic colorectal cancer after failure of standard chemotherapy.
Authors: Guo Weijian , Wu Zhenhua , Huang Mingzhu , Zhang Xiaowei 
Published: September 2018

e15066 Background: The FOLFOX regimen consisting of fluorouracil (5-FU) and oxaliplatin, and the FOLFIRI regimen consisting of 5-FU and irinotecan serve as either first- or second-line treatment for metastatic colorectal cancer (mCRC), and there is no third-line chemotherapy regimen after failure of 5-FU, oxaliplatin, and irinotecan. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with 5-FU and may be used for mCRC after failure of 5-FU. In the present study, we retrospectively analyzed the efficacy and safety of raltitrexed combined with S-1 in the treatment of mCRC after failure of conventional chemotherapy. Methods: Eighteen patients with mCRC treated with raltitrexed combined with S-1 after failure of fluorouracil, oxaliplatin and irinotecan between February 2014 and August 2016 were included in this study. Raltitrexed (3 mg/m2) intravenous infusion was given on the first day, and the administration of S-1 (daily dose according to body surface area (BSA): 100 mg/day when BSA ≥1.25 m2 to < 1.5 m2; 120 mg/day when BSA≥1.5 m2) continued for 2 weeks, and stopped for one week. The regimen was repeated every 3 weeks. Tumor response was evaluated according to RECIST 1.1 criteria. Toxicity was graded according to NCI-CTC 4.0 version. Results: Among 18 patients, 2 had PR, 8 had SD, and 8 had PD. The ORR (objective response rate) was 11.1%, and the DCR (disease control rate) was 55.6%. The median PFS (progression free survival) and OS (overall survival) were 2.5 months and 7.0 months respectively. Adverse reactions included fatigue, abnormal liver enzymes, neutropenia, stomatitis, pyrexia, arrhythmia, hypertension, diarrhea, nausea and most of these were grade 1-2. Only one patient had grade 3 neutropenia and grade 3 diarrhea. Conclusions: The combination of raltitrexed and S-1, both of which targeting TS, preliminarily showed promising effects for metastatic colorectal cancer after failure of standard chemotherapyand may be used as third-line treatment regimen.
A budget impact model of third-line or later trifluridine/tipiracil treatment of metastatic colorectal cancer.
Authors: Ferrufino Cheryl , Wiseman Fred , Wert Tim D , Barghout Victoria 
Published: September 2018

e15070 Background: Trifluridine/tipiracil (FTD/TPI) was recently approved for the treatment of third-line or later (3L+) metastatic colorectal cancer (mCRC). The objective of this study was to develop a payer-perspective budget impact model to estimate the 1-year budgetary consequences of adding FTD/TPI to a health plan’s formulary when a portion of the eligible mCRC patients who are currently treated with regorafenib are treated with FTD/TPI. Methods: The baseline annual budget for treating 3L+ mCRC patients, including pharmacy, administration, monitoring, and adverse-event (AE) costs, and excluding FTD/TPI, was estimated. Pharmacy costs were calculated using wholesale acquisition costs, and all other costs, AE rates, dosing administration, and monitoring guidelines were obtained from publically available sources. The model assumes that all treatment costs were incurred over 1 year, all AEs were mutually exclusive, and 30% of serious AEs (grades 3 and 4) were treated on an inpatient basis. Medication costs associated with outpatient AE management were not included. Using a regorafenib replacement strategy which pulls FTD/TPI market share from regorafenib, the projected annual budget was calculated assuming 30.5% adoption by FTD/TPI. Results: Of the hypothetical population of 1 million, approximately 107 were mCRC patients eligible for receiving 3L+ treatment. A net saving of $230,949 (−6.3%) in total costs was achieved when FTD/TPI therapy was included on total costs of $3,412,713, with the greatest savings in medication (−7.7%) and AE management costs (−0.3%). The reduction in cost per treated patient per year was $2150.12, and the net budget impact was −$0.02 (−6.3%) per member per month. Conclusions: Inclusion of FTD/TPI therapy in the model resulted in net savings in medication, AE management, and total costs, and costs per treated patient per year. These data suggest potential savings if FTD/TPI is added to a health plan formulary for the 3L+ treatment of mCRC patients. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion.
Versican proteolysis as a key regulator of CD8+ T-cell infiltration in colorectal cancer.
Authors: Deming Dustin A. , Hope Chelsea , Emmerich Philip , Pagenkopf Adam , Matkowskyj Kristina , Van DeHey Dana , Payne Susan , Clipson Linda , Callander Natalie Scott , Hematti Peiman , Miyamoto Shigeki , Johnson Michael G , Asimakopoulos Fotis 
Published: September 2018

e15082 Background: Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes (TILS) in the tumor bed may substantially augment clinical immunotherapy responses. Proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, with putative immunostimulatory activities. Methods: Matched normal and CRC tissue samples were collected from 122 patients with cancers across all stages and locations throughout the colon and rectum. These samples were stained for VCAN, αDPEAAE (neoepitope generated in cleaving VCAN to versikine), and CD8 and scored by a pathologist. Tumors were classified as VCAN proteolysis-predominant (VPP) if their staining for total VCAN staining intensity was < 1+ and staining for VCAN proteolysis (αDPEAAE antibody) was > 2. Conversely, tumors were classified as VCAN proteolysis-weak (VPW) if intact VCAN staining intensity was > 1+ or αDPEAAE intensity was < 2+. IHC for mismatch repair (MMR) proteins was also performed. Results: Overall increased VCAN staining was observed in cancer versus (vs) normal tissue. VPP tumors had a 10 fold greater infiltration of CD8+ T-cells vs VPW cancers (p < 0.001). The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in both cancers with proficient (p) MMR and deficient (d) MMR. In both pMMR and dMMR, the VPP tumors had the greatest degree of CD8+ T-cell infiltration (Wilcoxon rank sum tests: pMMR p = 0.006; dMMR p = 0.03). Among the VPP tumors there was a greater degree of CD8+ T cell infiltration in the dMMR cancers vs pMMR cancers (35 versus 14.8 TILs per high power filed, p = 0.04). Nuclear CTNNB1, a marker for activation of WNT signaling, negatively correlated with CD8+ T cell infiltration( p = 0.014). In addition, VCAN accumulation correlated with the presence of nuclear CTNNB1 (p < 0.001) Conclusions: This is the first description indicating that VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker.
The maturation stage of tumoral tertiary lymphoid structures to predict recurrence risk in localized colorectal cancer.
Authors: Posch Florian , Silina Karina , Petrausch Ulf , Leibl Sebastian , Muendlein Axel , Moch Holger , Siebenhuener Alexander Rheinhard , Pestalozzi Bernhard C. , Riedl Jakob M. , Stotz Michael , Szkandera Joanna , Stoger Herbert , Pichler Martin , Stupp Roger , Schraml Peter , Gerger Armin , Winder Thomas 
Published: September 2018

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II & III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25th-75th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1st, 2nd, and 3rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.
Impact of colonoscopy on patients older than 75.
Authors: Karam Dhauna , Al-Hamadani Mohammed , Pallavi Shah , Shanshal Mohamed , Molnar Janos 
Published: September 2018

e15096 Background: Colorectal cancer is the second leading cause of cancer related deaths in the United States. As per current screening guidelines, screening should begin by age 50 and be continued till age 75. Routine screening over 75 years is not recommended. Methods: Our primary objective was to compare survival time in patients undergoing colonoscopy aged 75 years or older to those aged 50-74. The study was conducted at Captain James A. Lovell Federal Health Care Center (FHCC), North Chicago, United States between 2002 and 2012. A retrospective chart review was performed for patients who underwent colonoscopy. Mortality in terms of survival time was compared between patients equal or older than 75 versus those aged 50-74 years with similar procedural indications and life expectancy of 5 years or more. Survival analysis was performed via Kaplan Meier curve with log-rank test. Results: A total of 213 patients were included in the study . Fifty one percent of the patients (108) were 50-74 years old (young age group), while 49% (105) were 75 or older (old age group). Patients had colonoscopy done for following indications: 92 (43%) screening colonoscopy, 62 (29.1%) diagnostic colonoscopy and 59 (27.7%) surveillance colonoscopy. There was no statistical difference between the age groups based on indication of colonoscopy (P = 0.899). Overall mean survival time for all patients was 123.6 months (10.3 years). Survival time was significantly higher for young age group with a mean overall survival of 131.1 months (10.9 years). Older age group had a mean overall survival time of 106.9 months (8.9 years). P-value = 0.009. The highest overall mean survival time was observed in patients who were under 75 and had colonoscopy for screening purposes 138.9 months (11.6 years) (P = 0.019). The lowest overall mean survival time was seen in those who were > 75 years and had colonoscopy due to diagnostic purposes 93.6 months(7.8 years). (P = 0.055) Conclusions: Although statistically significant higher survival time was noted in patients younger than 75, older patients also had a survival time of more than 7 years. This will impact the decision to offer screening colonoscopy to older people who will definitely benefit from the test.
Which side is better? The impact of primary tumor side in early stage colorectal cancer (CRC).
Authors: Lee Margaret , Mackinlay Andrew , Semira Christine , Jimeno Antonio Jose , Lee Belinda , Gunn Natalie , Tie Jeanne , Wong Rachel , Kosmider Suzanne , Tran Ben , Field Kathryn Maree , Gibbs Peter 
Published: September 2018

e15106 Background: Multiple studies have indicated the prognostic and potential predictive significance of primary tumor side in metastatic CRC. To date, the few studies examining its impact in early stage disease have either combined data across multiple stages or restricted analysis to overall survival (OS) data. A by stage analysis of the impact of tumor side on recurrence risk is critical if it is to impact adjuvant therapy decisions. Methods: We examined data from a multi-site Australian registry of consecutive patients diagnosed from 2003-2016. Tumors at and distal to the splenic flexure, including the rectum, were considered a left primary (LP). Rectal patients treated with initial chemoradiation were excluded. Clinico-pathologic and outcome data were examined. Data analysis was provided by the healthcare group at IBM Research Australia. Results: A total of 6123 patients were identified, of which 1046 (17.1%) had initial stage I, 1892 (30.9%) had stage II, 1708 (27.9%) had stage III, and 1477 (24.1%) had stage IV disease. Most patients were male (55.2%), and had a LP (n = 3818, 62.4%). Median age at diagnosis was 68.8 years, was higher in patients with a right primary (RP) (71.6 versus 67.0 years for LP, p < 0.001), with more females in the RP group (51.1% vs 41.0% for LP, p < 0.001). The proportion of RP varied by stage, highest in stage II (44.9%), lowest in stage IV (31.5%). For all stage IV disease, including metachronous cases, OS was worse with a RP (HR 1.32, 95% CI 1.14-1.53). For early stage cases, distant recurrence free survival (DRFS) was similar for RP vs LP for stage I (HR 0.63, 95% CI 0.32-1.23), better for stage II RP (HR 0.72, 95% CI 0.55-0.95) and worse for stage III RP disease (HR 1.22, 1.01-1.48). OS did not differ for RP vs LP for stage I or II disease, but was worse for stage III disease with a RP (HR 1.39, 95% CI 1.13-1.70). Furthermore, post recurrence survival was poorer in stage III RP disease (HR 1.61, 95% CI 1.33-1.96). Conclusions: Primary tumor side has potential as an important prognostic marker in early stage CRC. Our novel finding of a variable impact by stage indicate that an assessment of cohorts where recurrence data is available is critical to fully understanding the implications of tumor side for adjuvant therapy decision making.
Impact of expression of SIRT1 and SIRT2 on outcome in the very elderly patients with colorectal cancer.
Authors: Woo In Sook , Jung Yun Hwa , Lee In Kyu 
Published: September 2018

e15107 Background: Surtuins(SIRTs), NAD+-dependent deacetylases, participate in cell metabolism and ageing associated diseases including cancer. The elderly has higher cancer incidence and mortality compared to the young. Many of patients with colorectal cancer are over the age of 80. The role of SIRT 1 and 2 in tumorigenesis remains debated and it has not been reported for the very elderly patients with cancer. We investigated the relationship of clinicopathologic parameters and expression of SIRT1 and 2 in colorectal cancer patients 80 years of age or older and the impact of ageing comparing with the younger patients. Methods: The expression of SIRT1 and 2 were evaluated in colorectal cancer tissues of 101 patients aged ≥80 years and 29 patients aged ≤40 years by immunohistochemistry. And correlations between expression of these proteins and clinicopathological features were analyzed. Results: High expression of SIRT1 was observed in 65/101 (64.4%) elderly patients and 11/29 (37.9%) young patients(p = 0.011). Similarly, high expression of SIRT2 was more commonly observed in 58/99 (58.6%) elderly patients than 8/29 (27.6%) young patients(p = 0.003). In all patients high SIRT2 expression was associated with comorbid DM, and stage of CRC were not associated with SIRT1 or SIRT2 expression status. Comparison of Kaplan-Meier survival curve using log rank test revealed that high expressions of SIRT1 and SIRT2 were significantly associated with worse prognosis (median OS 24.9ms vs 38.6ms, p = 0.027) and better prognosis (median OS 37.9ms vs 17.3ms, p = 0.006) respectively in elderly patients. No prognostic significances were observed in younger patients. In multivariate analysis, only high SIRT1 expression retained statistical significance as a poor prognostic factor in elderly patients with CRC. Conclusions: :High SIRT1 expression might become a significant poor prognostic factor for elderly CRC patients although further study is needed for younger patients to clarify the difference of expression according to the age between elderly and young patients with CRC. High SIRT2 expression showed association with comorbid DM, further studies are warranted to establish prognostic significance in CRC patients.
Association of HIPEC with survival in patients with ovarian metastases of gastrointestinal origin.
Authors: Srinivasamaharaj Srividya , Chaudhary Dhruv Ranchhodbhai , Wu Xiaoyong , Rai Shesh , Sanders Mary Ann , Redman Rebecca A. 
Published: September 2018

e15124 Background: Metastatic ovarian involvement in primary gastrointestinal (GI) carcinomas (CA) is associated with a poor prognosis. We performed a survival analysis in patients with ovarian metastases, based on site of primary GI CA (appendiceal, colorectal (CRC), gastric, and pancreatic). We also examined the association between hyperthermic intraperitoneal chemotherapy (HIPEC) and death in these patients. Methods: A search was conducted in a single institution pathology database for patients with primary GI CA and ovarian metastases diagnosed from 2010 to 2017. The search yielded 39 patients, and data pertaining to tumor characteristics and treatment were obtained by chart review. Chi-square (log rank) test was used to test for associations between both site of primary GI CA and HIPEC, and death, and Kaplan-Meier analysis was done. P-value < 0.05 was deemed statistically significant. Results: CRC accounted for the majority of patients (51.29%) with appendiceal CA accounting for 23.08% and gastric and pancreatic cancer making up the remainder. Primary site of malignancy was associated with survival (p = 0.036), favoring those with appendiceal and colorectal primaries. A total of 30 patients (76.92%) received HIPEC. Having undergone HIPEC was significantly associated with survival (p = 0.017). Conclusions: Ovarian metastases secondary to gastric and pancreatic cancer were associated with inferior survival as compared to those with appendiceal or colorectal primaries. A significant association was demonstrated between HIPEC and survival. Further investigation to define the role of HIPEC in the treatment of carcinomas of gastrointestinal primaries is warranted.