bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the positional differences between bone matching and fiducial marker matching in target localization of the expiratory breath-hold radiation therapy for pancreatic cancer.
Authors: Ashida Ryo , Goto Yoko , Akimoto Mami , Mukumoto Nobutaka , Kishi Takahiro , Sakanaka Katsuyuki , Nakamura Mitsuhiro , Yoshimura Michio , Mizowaki Takashi
Published: January 2019

517

Background: In radiation therapy, the accuracy of target localization is very important to increase the agreement between the planned treatment and the actual dose delivered to the patient. Therefore, image-guided techniques, such as bone matching, soft-tissue matching, fiducial marker (FM) matching and so on, are used to improve the precision and effectiveness of radiation therapy. In this study, we evaluate the positional differences of the target localization between bone matching and FM matching in the expiratory breath-hold radiation therapy (BH-RT) for pancreatic cancer. Methods: We analyzed 15 patients who underwent BH-RT for pancreatic cancer using FM matching between July 2016 and August 2017 in our institution. The FMs were implanted in the pancreatic cancer using endoscopic ultrasound. Prior to each treatment session, bone matching using orthogonal kilovolt x-ray images and FM matching using cone beam computed tomography at end-exhalation (BH-CBCT) was performed. A total of 226 matching data from 15 patients was analyzed. The positional differences of these matching were evaluated in the left - right (LR), anterior - posterior (AP) and superior - inferior (SI) directions. Results: The systematic and random errors between bone matching and FM matching were 3.6 and 3.0 mm, 3.3 and 2.0 mm, and 3.7 and 3.5 mm in the LR, AP and SI directions, respectively. Absolute positional differences of > 5 mm were observed in 78 fractions (34.5%), 40 fractions (17.7%), and 69 fractions (30.5%), and those of even > 10 mm were observed in 14 fractions (6.2%), 2fractions (0.6%), and 11 fractions (4.9%) in each direction, respectively. There were no significant correlations between positional differences in SI and both LR and AP. Conclusions: In pancreatic irradiation using BH-RT, it was considered that bone matching alone was insufficient for accurate target localization and other target matching techniques, such as FM matching, were required to achieve effective treatment.
Oncological outcomes in a Mexican cohort of patients with gallbladder cancer.
Authors: Meneses Medina MÃ³nica Isabel , Valenzuela Ana Karen , Nieto Zuleyma , Camargo Vanessa Rosas , Casanova Sánchez Iván Eliud , Gamboa Dominguez Armando , Contreras Saldívar Alan Gabriel , Huitzil Melendez Fidel David
Published: January 2019

518

Background: gallbladder cancer is the most common malignancy of the biliary tract. Treatment modalities and outcomes for this disease in Mexican population have been infrequently reported. Methods: we retrospectively reviewed medical records from 61 patients with histologically confirmed gallbladder cancer treated at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán from January 2005 to December 2015.Clinical and pathological information was recorded. Survival was estimated by Kaplan Meir method and compared by Log rank test. Results: we found 68.9% women and 31.1% men, with a median age of 68 years (32-93). Clinical stage was advanced in 65.6% (n=40), regional in 23% (n=14), localized in 4.9% (n=3) and in situ in 6.6% (n=4). For patients with localized disease (n=21), which included in situ, localized and regional disease, a potentially curative surgery was attempted in 100% of patients, achieving a R0 resection in 47.6% (n=10) of cases. The morbidity rate was 33.3% (n=7). There were 5 surgical deaths. For advanced disease (n=40), the initial treatment was: 42.5% (n=17) palliative surgery, 25% (n=10) palliative care and for 30% (n=12) systemic chemotherapy, more frequently gemcitabine plus cisplatin (n=7). At progression seven patients received second-line chemotherapy. Median overall survival (OS) in the global cohort was 5.6 months (IC 95, 2.4-8.77). According to clinical stage survival at 5 years was 100% for in situ and 67% for localized disease. Median survival was 6.3 months (IC 95, 2.3-10-3) for regional disease and 4.2 months (IC 95, 1.1-6.4) for advanced disease. For patients with localized disease not achieving R0 resection (p=0.03) and perineural invasion (p=0.025) were associated with decreased survival. For patients with advanced disease poor performance status (p=0.004) and absence of chemotherapy (p=0.002) were adverse prognostic factors. Conclusions: global poor outcomes may be explained by metastatic disease at presentation. Even for patients with apparent localized disease, a potentially curative resection could be offered to only half of the patients.
Treatment strategy and prognostic factors for Krukenberg tumors of gastric origin: Report of a 10-year single-center experience from China.
Authors: Pengfei Yu , Huang Ling , Du Yian
Published: January 2019

52

Background: Gastric cancer patient with ovarian metastasis, i.e. Krukenberg tumor, is common in clinical practice, but it is still uncertain whether surgical resection of ovarian metastasis could improve the outcome. This study aimed to explore the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone in the treatment of Krukenberg tumors arising from gastric cancer and to identify prognostic factors. Methods: All patients who were diagnosed with gastric cancer and ovarian metastases between January 2005 and December 2014 were included in the current study. Patients were subdivided according to treatment modality: the metastasectomy group (metastasectomy plus chemotherapy) and the non-metastasectomy group (chemotherapy alone). The clinicopathological features and the treatment records were reviewed in detail and their association with survival were analyzed. Results: A total of 152 patients were identified, including 93 patients with synchronous ovarian metastasis and 59 patients with metachronous ovarian metastasis. Overall survival (OS) was significantly better in metastasectomy group relative to the non-metastasectomy group for patients with synchronous ovarian metastasis (19.0 months vs. 11.8 months; P < 0.001) and those with metachronous ovarian metastasis (24.6 months vs. 14.3 months; P = 0.02), respectively. Metastasectomy (hazard ration [HR] 0.486; 95% confidence interval [CI] 0.323–0.729; P < 0.001), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230–3.049; P = 0.004), and expression status of ER-β (HR 0.404; 95% CI 0.251–0.648; P < 0.001) and PR (HR 0.496; 95% CI 0.301–0.817; P < 0.001) were independent predictors of OS. Conclusions: Metastasectomy plus chemotherapy was associated with survival benefits in patients with Krukenberg tumors from gastric cancer. Metastasectomy, peritoneal carcinomatosis, and expression status of ER-β and PR were independent prognostic factors for survival.
Colorectal cancer screening: Why do some people never participate? Results from the EDIFICE surveys.
Authors: Viguier Jerome , Eisinger François , Touboul Chantal , Lhomel Christine , Morere Jean F.
Published: January 2019

565

Background: The aim of EDIFICE surveys is to improve insight into the behavior of the French population with regard to cancer prevention and participation in screening programs. Via the colorectal cancer (CRC) screening program, all average-risk individuals in the 50-74-yr age group are invited every 2 years to do a guaiac-based or immunochemical fecal occult blood test. This analysis focuses on lay-population reasons for not undergoing the test. Methods: The 5th nationwide observational survey was conducted by phone interviews using the quota method. A representative sample of 1299 individuals with no history of cancer (age, 50-74 yrs) was interviewed between 22 November and 7 December 2016. Those who had never undertaken a screening test were asked for their reasons. Results: In total, 64% reported having undergone a screening test (colonoscopy, fecal occult blood test) at least once in their lifetime (coverage). There was a non-significant (NS) increase in coverage rates over the period 2014-2016. In 2016, the most frequently (36%) cited reason for not being screened was “individual negligence/not a priority”. This figure was significantly higher than in 2014 (24%, P < 0.05). Between one in four and one in five respondents answered “no risk factor” in both 2014 and 2016. Approximately one in ten respondents gave “pointlessness” as their reason for not being screened (12% in 2016 vs 8% in 2014, NS) while “fear of the examination or fear of the results”, “reasons related to the physician (he never suggested it” [3.8% in 2016] or “he recommended against screening” [2.5% in 2016]), or “refusal to participate”, all dropped significantly between 2014 and 2016. Conclusions: The issue of “individual negligence” requires further analysis so as to clearly define the categories of individuals who remain unreceptive to screening and identify how best to involve them. The significant mention of “no risk factors” reveals ignorance of the fact that the colorectal cancer screening program actually targets all individuals in a given age group, regardless of individual risk factors. The decrease in reasons involving “fear" or related to the physician may be a result of awareness campaigns and GP mobilization.
Compliance with NCCN screening and chemoprevention recommendations among carriers of deleterious mutations in the adenomatous polyposis coli gene.
Authors: Kazmi Syed Mohammad Ali , Mauer Caitlin , Pirzadeh-Miller Sara , Watson Elise , Beg Muhammad Shaalan , Ross Theodora S.
Published: January 2019

571

Background: Deleterious mutations in adenomatous polyposis coli gene (APC) lead to familial adenomatous polyposis [FAP] and attenuated FAP (aFAP) syndromes associated with hereditary colorectal cancer (CRC) and extra-colonic neoplasms. Reports suggest only two-third of such patients (pts) comply with recommended screening guidelines. The objective of this study was to assess compliance of FAP/aFAP pts with NCCN recommended guidelines of screening endoscopies and chemoprevention in our population. Methods: Retrospective review of clinical charts of pts with APC mutations, identified through multi-gene panel or single-gene testing, and seen in our NCI designated Comprehensive Cancer Center between 01/2013 and 09/2017. Results: Out of 53 pts with deleterious APC gene mutations, 31 pts (58.5%) had mutations associated with an FAP (27 pts; mean-age 31 years) or aFAP (4 pts, mean-age 33 years) phenotype and were included in analyses. Ten of these 31 pts (32.3%) were diagnosed with FAP after diagnosis of CRC; the rest had family history of FAP/aFAP. Documentation of total-colectomy was found in 17 pts (54.8%), 4 pts (12.9%) did not undergo colectomy and this information was unknown in 10 pts (32.3%). Colonoscopy/EGD after diagnosis of FAP/aFAP was documented in 22 pts (71.1%) while subsequent annual EGD/colonoscopy was documented only in 14 pts (45.1%); records were missing in 13 pts (41.9%). Extra-colonic secondary neoplasms such as duodenal polyps were documented in 8 pts, gastric polyps in 7 pts, desmoid tumor in 2 pts and malignant cancer of ampulla of Vater in 1 pt. Other malignant neoplasms, unrelated with FAP/aFAP, were reported in 3 pts (9.6%, 1 breast, 1 kidney and 1 endometrial cancer). Chemoprevention with sulindac was used in 3 pts (9.7%), 3 pts (9.7%) declined such treatment, 17 pts (54.8%) records were without evidence of this being discussed. Conclusions: The rate of compliance in FAP/aFAP pts with NCCN recommended screening and chemoprevention guidelines in our cohort was low but similar to prior literature. A multidisciplinary approach and interventions to improve compliance among pts are necessary to improve annual screening and chemoprevention rates.
A real world analysis of recurrence risk factors for early colorectal cancer T1 treated with standard endoscopic resection.
Authors: Vila Clara Martinez , Pericay Carles , Oliveres Helena , Fernandez Paula Ribera , Alcala Maria Marin , Ruiz Juan Carlos Pardo , Joaquin Julia Giner , Romero Jose Manuel Cabrera , Serra Javier , Ballesteros Eva , Munte Antoni Malet , Casado Alejandro Casalots , Macias Ismael , Saigí Eugeni
Published: January 2019

575

Background: Currently, endoscopic resection of early colorectal cancer (ECC) defined as carcinoma with invasion limited to the mucosa (Tis), and submucosa (T1) is possible due to advances in instrumentation. However, when tumor invades submucosal layer, lymph node dissemination is present in 16.2% of cases, requiring additional surgery and limfadenectomy. Risk factors for lymph node dissemination and independent for relapse have been previously described in literature. Methods: We performed a retrospective analysis of all patients with colorectal T1 tumors, treated at our center with endoscopic resection and some with additional surgery between 2006 and 2017. Stadistical analysis was perfomed with IBM SPSS Statistics 24.0. Results: 159 patients (p) were treated with endoscopic resection, 56.6% (90p) underwent additional surgery. Mean age was 68.74 years and 69.9% (111p) were male. Endoscopic resection: negative margins 87.6%, vascular 3.1%, lymphatic 2.5% and perineural invasion 3.8%, high degree of histological differentiation 1.3%. Surgical resection: negative margins 100%, lymph node spread 8.8%. In a mean follow-up of 23.36 months since endoscopic treatment, 13 patients had relapsed. Risk of relapse did not differ between patients who received additional surgery and those who only underwent endoscopic resection (p = 0.791). On the other hand, lymph node dissemination (p = 0.007) and a positive margin (p = 0.01) were independent risk factors for risk of relapse. Vascular, lymphatic and perineural invasion, nor degree of histological differentation were stadistically significant. However, there was a positive association between lymph node dissemination and lymphatic (p = 0.07), vascular (p = 0.007) and perineural (p = 0.001) invasion and also degree of histological differentiation (p = 0.000). Conclusions: In our study, relapse rate was under 10% in eleven years. The only independent risk factors for relapse were a positive margin and lymph node dissemination. Perineural, vascular and lymphatic invasion obtained from polypectomy sample, could infer the probability of positive lymph nodes and indirectly be an indicator for risk of relapse.
Clinicopathological characteristics and HER2 status in metastatic colorectal cancer patients: Results of a diagnostic model development study.
Authors: Sartore-Bianchi Andrea , Amatu Alessio , Porcu Luca , Ghezzi Silvia , Lonardi Sara , Bergamo Francesca , Bonazzina Erica Francesca , Mauri Gianluca , Cremolini Chiara , Ciardiello Fortunato , Valtorta Emanuele , Truini Mauro , Martino Cosimo , Marsoni Silvia , Di Nicolantonio Federica , Siravegna Giulia , Bardelli Alberto , Trusolino Livio , Torri Valter , Siena Salvatore
Published: January 2019

581

Background: We have reported with the HERACLES Trial that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer (mCRC). With present study, we aim to develop and internally validate a new diagnostic model for HER2 status in patients with mCRC based on clinicopathological characteristics to improve selection for HER2-targeted therapies and to refine negative selection for EGFR-targeted agents. Methods: Patients with KRAS exon 2 WT mCRC underwent molecular screening of HER2 according to HERACLES criteria (immunohistochemistry 3+ or 2+ in equal or more than 50% of cells, confirmed by FISH) for enrollment in HERACLES clinical trials with HER2-targeted therapies. All HER2-positive cases and a fraction of negative consecutive cases were annotated with clinical and pathological variables. A multivariable logistic regression model with a linear combination of all clinical and pathological characteristics as predictors was fitted to the complete set of data. A regression modeling strategy was applied to the full model to identify predictors explaining the bulk of HER2 amplification. Results: From August 2012 to June 2017, a total of 80 HER2-positive mCRC cases were detected out of 1355 screened patients. The large majority of HER2-positive primary tumors appeared to be left colon- or rectal-sided (88.0%). None of the relevant clinicopathological features explained the bulk of HER2 amplification, even though trends were observed for sidedness (left colon and rectal > proximal, OR 1.75, 95% CI 0.76-4.16), tumour grading (high > low, OR 2.21, 95% CI 0.19-26.38), and metastatic burden (high > low, OR 1.29, 95% IC 0.94-1.77). In a secondary analysis, patients with HER2-amplified mCRC who received treatment with anti-EGFR agents (n = 64) showed poorer outcome (objective response rate: 30% vs 55%, p = 0.044 and progression-free survival: 5.8 months vs 7 months, p = 0.056). Conclusions: Testing for HER2 should be offered to all patients with mCRC since it is unlikely to predict the occurrence of this biomarker based on main clinicopathological features. Patients with HER2-amplified mCRC are less likely to respond to anti-EGFR therapy.
Estimating 1- and 5-year relative survival trends in colorectal cancer (CRC) in the United States: 2004 to 2014.
Authors: Crooke Hannah , Kobayashi Monica , Mitchell Brian , Nwokeji Esmond , Laurie Melissa , Kamble Shital , McKenna Mike , Masood Ashiq , Korytowsky Beata
Published: January 2019

587

Background: Patient survival is impacted by several factors, one of which is stage at diagnosis. From 1976 to 2014, CRC death rate in the United States (US) declined by 51%. This retrospective study was conducted using US Surveillance, Epidemiology and End Results (SEER) data to evaluate 1- and 5-year relative survival for patients with CRC by American Joint Committee on Cancer (AJCC) stage, age and sex at diagnosis. Methods: The study included adults (age ≥20 years) in the SEER-18 registry diagnosed with CRC in 2004-2014. One- and 5-year relative survival rates were stratified by AJCC stage, age group (20-64 vs. ≥65 years) and sex. Results: One- and 5-year survival was calculated by age and stage at diagnosis (Table), and by sex (data not shown). Overall, 5-year survival rates declined compared to 1-year rates, with the biggest decline observed in stage IV patients. Survival was higher in the younger cohort than in patients ≥65 years of age regardless of stage. Both men and women diagnosed with stage IIB CRC had lower 1- and 5-year survival compared to stage IIIA and IIIB groups, consistent with previous findings. Patients with stage IV had the lowest survival irrespective of age or sex. Conclusions: Overall trends in 1- and 5-year relative survival for CRC varied by AJCC stage, age and sex. Since survival is lowest among CRC patients diagnosed at stage IV, particularly in elderly patients, it reinforces the need for early diagnosis and availability of innovative late stage therapies in this population. [Table: see text]
Safety of administration of bevacizumab within a week from placement of a totally implantable central venous port system.
Authors: Muranaka Tetsuhito , Komatsu Yoshito , Yagisawa Masataka , Kawamoto Yasuyuki , Nakatsumi Hiroshi , Yuki Satoshi , Sakamoto Naoya
Published: January 2019

589

Background: Totally implantable central venous port systems (TICVP) are easy to implant on an in- or outpatient basis and provide reliable, long-lasting central venous access for treatment of intravenous anti-cancer chemotherapy in patients with cancer but it is needed to cut 3cm of patients’ skin at the operation. Bevacizumab is one of the anti vascular endothelial growth factor (ant-VEGF) antibody which is known to improve overall survival in patients with colorectal cancer but have a side effect of delayed wound healing. There are few reports about the safety of administration of bevacizumab in a short period of time from the small surgery such as placement of TICVP. Methods: Patients who were placed TICVP in Department of Gastroenterology of Hokkaido University Hospital from July 2009 to December 2016. We planned to compare the rate of post-operative wound dehiscence (POWD) and surgical site infection (SSI) between patients who administered bevacizumab within a week from placement of TICVP (Group A) and the other patients (Group B). Patients who didn’t receive any chemotherapy after placement of TICVP were excluded. Results: We found 432 patients who implanted TICVP, and excluded 32 patients who didn’t receive any chemotherapy. 50 patients were assigned to Group A and 350 patients were assigned to Group B. Median age in both group were 67.5 in Group A and 65 in Group B. The averages of operation time were 38.7 (+/-19.3) minutes in Group A and 36.4 (+/-19.5) minutes in Group B. Prophylactic antibiotics were given to 27 patients (54%) in Group A and 146 patients (48.7%) in Group B. The rate of POWD was 0.0% (0/50) in Group A vs 1.1% (4/350) in Group B ( p = 0.45 ) , and the rate of SSI was 0.0%(0/50) in Group A vs 1.1% (4/350) in Group B ( p = 0.45 ) . The average of operation time of patients with and without POWD was 56.4 minutes and 36.7 minutes (p = 0.013). Conclusions: In our study, it was found that there is no significant increase of incidence by administration of bevacizumab within a short period from placement of TICVP. The long operation time tends to increase the rate of POWD.
First results of universal screening for Lynch syndrome in a Mexican cohort of colorectal cancer patients.
Authors: Nieto Zuleyma , Valenzuela Ana Karen , Huitzil Melendez Fidel David , Meneses Medina MÃ³nica Isabel , Gamboa Dominguez Armando , Camargo Vanessa Rosas , Arteaga Vazquez Jazmin , Pineda Mauricio Mora
Published: January 2019

590

Background: universal screening has been proposed as an alternative to clinical criteria for detection of Lynch syndrome (LS). Results of such policy have not been evaluated in mexican population with low incidence of colo-rectal cancer (CCR). Objective: to determine the proportion of patients tested by immunohistochemistry (IHC) for mismatch repair-deficient (dMMR) and characterize subsequent molecular and clinical work up for abnormal results. Methods: we identified all consecutive cases of CCR during 2016 at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico. We recorded clinical variables, IHC for mismatch repair (MMR) proteins and/or clinical genetics evaluation and molecular confirmation of LS if available. Results: universal screening policy was adopted by our institution in 2016. 209 CRC patients had an outpatient consultation. The median age at diagnosis was 59.8 years. 103 IHC for MMR proteins were done (49%) regardless of age at diagnosis and a family history of CRC. 36/103 (35%) IHC showed abnormal result meaning lack of expression of at least one of four MMR proteins: 26 MLH1, 7 MSH2, 10 MSH6 and 23 PMS2. 11/36 patients (30%) had a family history of CRC. 26/36 (72%) were evaluated by clinical genetics service. Of 26 MLH1 deficient patients, only one case was tested for BRAF mutation. 14/36 patients (39%) were tested by sequencing analysis: 7 MLH1, 5 MSH2, 1 MSH6, 1 PMS2. 2/14 patients were tested by MLPA assay given negative sequencing analysis. Germ-line mutations were identified in 7/36 patients (19%). All mutations were identified in patients with a clinical suspicion given strong family history of CRC. No identified mutations could be attributed to universal screening policy. Conclusions: during the first year of implementing universal screening for LS in CRC patients only half of the patients were screened by IHC. Despite MLH1/PMS2 deficiency was the most frequent abnormality, BRAF mutation analysis was not performed as recommended, given the lack of access to the test. A clinical suspicion of LS was a determinant driver for confirmatory molecular testing therefore limiting the usefulness of universal screening.
Systematic review and meta-analysis of the effect of pre-operative PET/PET-CT in the management of patients with potentially resectable colorectal cancer liver metastasis.
Authors: Serrano Aybar Pablo Emilio , Daza Julian Felipe , Solis Natalie , Parpia Sameer , Gallinger Steven , Moulton Carolanne
Published: January 2019

591

Background: It has been proposed that PET with 18F-fluorodeoxyglucose alone or combined with CT improves detection of extra hepatic disease in the setting of colorectal cancer liver metastasis (CRLM). However, there remains conflicting evidence on the added benefit of PET/PET-CT prior to liver resection, and its effect on long-term survival. Thus, we set out to perform a systematic review of literature and meta-analysis. Methods: From 2000 to April 2017, MEDLINE, EMBASE, and CENTRAL were searched for studies (prospective and retrospective) investigating the preoperative use of PET/PET-CT in the management of patients with CRLM. We excluded studies in which neoadjuvant chemotherapy was given 2 weeks prior to PET/PET-CT. Screening, data abstraction, and quality assessment was performed in duplicate. Primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), pre-operative change in surgical management, and open-close surgery. Random effect models were used to pool treatment effects. The protocol was published in PROSPERO. Results: Of 4034 articles reviewed, 37 met the inclusion criteria and were analyzed, and 8 compared PET/PET-CT to conventional imaging. All studies included PET (n=18), PET-CT (n=17), or both (n=2). OS for all patients was similar whether or not pre-operative staging included PET/PET-CT (HR 0.94, 95% CI 0.69-1.26). A similar effect was seen in the subgroup of patients who underwent surgery (HR 0.92, 95% CI 0.72-1.17). DFS in patients who underwent surgery was not different either (HR 0.93, 95% CI 0.81-1.08). PET/PET-CT reduced the odds of undergoing an open-close surgery (OR 0.52, 95% CI 0.35-0.76) and changed the surgical management of 23.4% patients (95% CI 19.33-27.47), however heterogeneity (I2=100%). Conclusions: Pre-operative PET/PET-CT may have a meaningful impact on surgical decision making in CRLM, however heterogeneity between studies is high, likely due to different study designs. It may also reduce the rate of open-close surgeries. The addition of PET/PET-CT to routine pre-operative imaging does not improve OS or DFS.
Early colorectal cancer detection on routine CT to improve patient's 5-year survival.
Authors: Rodriguez Ricky , Perkins Bryce Daniel , Park Peter Yong Soo , Koo Phillip , Kundranda Madappa N. , Chang John
Published: January 2019

593

Background: Prognosis of colorectal cancer (CRC) is greatly influenced by stage at diagnosis. Early colorectal cancer can be subtle on CT scans showing only mild wall thickening, small polyps, or subtle lymph nodes. Identifying these lesions on CT performed for nonspecific symptoms can help identify interval CRC and improve patient outcome. The purpose of the present study is to classify missed CRC on abdominal CT by their imaging features and whether early identification can downstage CRC patients. Methods: A retrospective analysis was conducted of patients (pts) diagnosed with CRC. Data collection included age, gender, ECOG, KRAS mutation status, overall survival (OS). CT obtained prior to and at diagnosis were evaluated. Images were reviewed for multiple CT features including appearance of mass, mesenteric infiltration, abnormal draining lymph nodes, contrast enhancement relative to adjacent mucosa, and intralesional calcifications. Staging was evaluated using available CT scan and based on the TNM staging system for CRC. Results: The 41 pts with 51 prediagnostic CTs from 1/1/2012 - 12/31/2015 had mean age of 68 years (range:44-90 ) Mean ECOG status for the population was 1.46. 41% of the prediagnostic CTs had missed findings. 52 and 43 % of the missed findings were in the rectosigmoid and ascending colon respectively. Of the 15 missed masses, 9 appeared as asymmetric wall thickening, 3 as concentric wall thickening, and 3 as polyps. Of the 14 missed lymph node groups, 2 were excluded due to stability or nonrelated condition. The remaining lymph nodes were found in the associated draining station and averaged 3±1.2 mm in size. On average, the stage at prediagnostic CT was 3A and the diagnostic CT was 3C (p = 0.0015). Average time lapse between prediagnostic and diagnostic CT was 21 months (3-64 months). Conclusions: High percentage of CRC findings are missed on abdominal CT due to their subtle feature, with most misses in the rectosigmoid and ascending colon. A dedicated search can improve detection by specifically looking for polyps, wall thickening, and small lymph nodes in the draining station. Early detection of CRC can improve survival by lowering the stage from 3C to 3A, thus providing 36% improvement in 5-year survival.
The expression of pAKT/survivin and their role in colorectal cancer.
Authors: Gu Junjie , Sun Zhao , Bai Chunmei , Luo Fei
Published: January 2019

595

Background: Colorectal cancer(CRC) is the fourth most prevalent cancer and the leading cause of cancer mortality worldwide. Drug resistance remains the main obstacle to the success of cytotoxic therapies. It is reported that soluble factors released by carcinoma-associated fibroblasts(CAFs) can induce the translocation of AKT, Survivin, P38 to the nucleus of tumor cells, which might be the mechanism of microenvironment-mediated drug resistance to nonspecific conventional chemotherapeutic agents, such as platinum compounds or 5-FU. Methods: Clinicopathological data of colorectal cancer patients who underwent chemotherapy (XELOX or FOLFOX) were collected, followed up and evaluated. p-AKT and survivin expression were assessed by immunohistochemical (IHC) staining. The relationships between p-AKT and survivin expression and patients’ resistance to chemotherapy were analyzed by Chi square respectively. The expression between p-AKT and survivin expression and progression-free survival(PFS) of patients were analyzed by Kaplan-Meier. Results: 51 CRC patients were enrolled in our research. Among them, 21 patients were resistant to chemotherapy(PD), and 30 patients were sensitive to chemotherapy(PR). P-AKT and survivin were assessed by IHC in 47 patients. Among them, 17 patients were p-AKT positive, and 29 patients were survivin positive. Patients of progressive disease(resistant to chemotherapy) were significantly associated with p-AKT positive and survivin positive(p = 0.009, 0.000). Poorer progression-free survival(PFS) was observed in patients with survivin positive compared to those with survivin negative(6.323±0.9m, 13.857±2.664m, Breslow chi square = 4.885, p value = 0.027). There is no significant difference between p-AKT expression and PFS(Breslow chi square = 2.403, p value = 0.121). Conclusions: CRC patients with p-AKT positive or survivin positive were more likely to be resistant to chemotherapeutic agents. CRC patients with survivin positive had a shorter DFS.
Time to surgery in colon cancer: Predictors and association with survival—An analysis of the National Cancer Database (NCDB).
Authors: Satish Mohan , Aurit Sarah J , Zhang Yang , Walters Ryan W
Published: January 2019

599

Background: Time-to-surgery (TTS) refers to the wait time from the diagnosis of cancer to surgical resection of the primary tumor. In breast and bladder cancers, longer TTS has been shown to be associated with lower long-term survival. Prior evidence in colon cancer, has shown that older age, urban residence, and comorbidity are independent predictors of TTS. However, evaluation of TTS with survival in colon cancer has been limited to mostly single-center studies. Using the NCDB, this study aimed to both evaluate patient and clinical factors associated with TTS, and determine if TTS was associated with overall survival in colon cancer. Methods: Patients with colon cancer who underwent partial or subtotal colectomy/hemicolectomy were included, excluding those receiving neoadjuvant therapy. With prior colon cancer studies showing a median TTS of 15-20 days, we dichotomized the number of days from diagnosis to definitive surgery (TTS) as ≤ 21 days or > 21 days. A modified Poisson regression model was utilized to evaluate relative risk of TTS > 21 days. Overall survival in association with TTS was estimated using both the Kaplan-Meier method and multivariable Cox regression model, adjusting for patient-, disease- and facility-level characteristics. All analyses were conducted with SAS version 9.4, p-values < 0.05 were considered significant. Results: We identified 26,999 colon cancer patients from 2006-2012 from the NCDB. Approximately 25.7% of patients had a TTS > 21 days. Patients with comorbidities, who were older, were African American, with lower disease stage, and treated in academic facilities located in the Northeast, had a significantly increased relative risk of a TTS > 21 days. Considering survival, a TTS > 21 days was associated with a 24.5% decreased adjusted risk of death (95% CI: 21.6% to 27.2%). Conclusions: A longer TTS with colon cancer is understandably associated with older age, greater comorbidity, and lower stage, but questionably so in African American patients. However, given that TTS > 21 days was associated with a lower adjusted risk of death, it may indicate that a reasonable delay could be pursued for more accurate preoperative evaluation and staging in colon cancer.
BRCA1 and BRCA2 gene mutations and colorectal cancer risk: Systematic review and meta-analysis.
Authors: Oh Mok , McBride Ali , Yun Seongseok , Bhattacharjee Sandipan , Slack Marion , Jeter Joanne M. , Abraham Ivo
Published: January 2019

605

Background: The risks of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations are well established. Investigations of the association of BRCA mutations and the risk of colorectal cancer(CRC) have yielded conflicting results. We performed a systematic review of published and unpublished studies evaluating BRCA and CRC risk, and meta-analyses to quantify overall CRC risk and in subgroups of BRCA mutation carriers. Methods: Eligible studies were retrieved from PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios were used to derive pooled estimates of CRC risk overall (combined BRCA1/BRCA2) and in subgroups defined by mutation type, comparison group, and study design. Both fixed and random effects models were estimated with the latter having priority. We followed the guidelines summarized in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as well as the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statements. Results: A total of 18 studies were included in the systematic review: 7 cohort studies comparing to the general population, 5 case-control studies, 4 cohort studies involving pedigree analysis, and 2 kin-cohort studies. Fourteen studies included in the systematic review were used in the meta-analysis. The overall BRCA1/BRCA2 meta-analysis revealed an increased CRC risk in a fixed-effects (OR = 1.22, 95%CI = 1.01-1.48, p = 0.041, I2= 19.5%) but not in a random-effects model (OR = 1.20, 95%CI = 0.96-1.50, p = 0.111). In subgroup random-effects meta-analyses, BRCA1 was associated with increased CRC risk (OR = 1.48, 95%CI = 1.13-1.94, p = 0.005, I2= 3.7%) but BRCA2 was not. Analyses stratified by study design and comparator found no association between BRCA mutation and CRC risk (all 95%CIs crossing 1, all p > 0.05). Conclusions: Although studies differed in their findings about the association between BRCA mutations and CRC risk, meta-analyses revealed a potential 1.22-fold greater risk of CRC in BRCA mutation carriers. This elevated CRC risk was attributable largely to a 1.48-fold greater risk in BRCA1 mutation but not in BRCA2 carriers, regardless of age.
A proteomics analysis of cell signaling pathways in colon cancer.
Authors: Kit Oleg Ivanovich , Vodolazhsky Dmitriy I. , Kutilin Denis S. , Enin Yaroslav S. , Gevorkyan Yuri , Kharin Leonid V. , Panina Svetlana B.
Published: January 2019

608

Background: Colorectal cancer is the second most common cancer in women and third most common cancer in men. Major signaling pathways are known to be deregulated in cancer, however, there are only a few studies addressing activation status of more than one or two pathways in colorectal cancer in comparison with the normal tissue. The present study aims to compare the expression pattern of proteins associated with cell signaling in paired tumor and non-tumor samples of patients with colon cancer, as well as to define the cluster of proteins to differentiate patients with non-metastatic (Dukes’ grade B) and metastatic (Dukes’ grade C&D) colon cancer. Methods: Frozen tumor and non-tumor samples were collected after tumor resection from 19 patients with colon cancer. The "Panorama" (Sigma-Aldrich) Antibody Microarray-Cell Signaling kits were used for the analyses. The expression ratios of paired tumor/non-tumor samples were calculated for the each protein. We employed R packages ‘samr’, ‘gplots’, ‘supclust’ ( pelora, wilma algorithms), ‘glmnet’ for the differential expression analysis, supervised clustering and penalized logistic regression, respectively. Results: Significance analysis of microarrays revealed 9 up-regulated proteins, including protein kinase C gamma, c-Myc, MDM2, bCOP, p14ARF, p57kip2, GRB2, APP, pan cytokeratin, and 1 down-regulated protein (GAP1) in tumoral mucosa. Pan cytokeratin and amyloid precursor protein were up-regulated in tumor vs. non-tumor tissue, and were selected in the predictive cluster to discriminate colon cancer type. Higher levels of S-100b and phospho-Tau-pSer199/202 were confirmed as the predictors of non-metastatic colon cancer by all of employed regression/clustering methods. Conclusions: Deregulated proteins in colon cancer are involved in oncogenic signal transduction, cell cycle control, and regulation of cytoskeleton formation/transport. Further studies are needed to validate potential protein markers of colon cancer development and metastatic progression.
Tumor-associated macrophages as predictive biomarkers for postoperative adjuvant chemotherapy in patients with stage II colon cancer.
Authors: Xu Jianmin , Feng Qingyang , Chang Wenju , Wei Ye , Ren Li , He Guodong , Zhong Yunshi , Zhu Dexiang , Chen Jingwen , Yi Tuo , Lin Qi , Zheng Peng , Ji Meiling
Published: January 2019

620

Background: For stage II colon cancer, the effect of postoperative adjuvant chemotherapy is still controversial. It is well known that tumor-associated macrophages (TAMs) play an important role in tumor progression. The aim of this study is to determine the effect of TAMs as predictor for adjuvant chemotherapy for stage II colon cancer. Methods: From July 2009 to June 2012, 521 patients with pathological stage II colon cancer were included. TAMs were detected using tissue microarray and immunohistochemistry (all TAMs detected by CD68; M2 subtype detected by CD206). The density of CD68+ TAMs, CD206+ TAMs and the ratio of CD206+ TAMs / CD68+ TAMs (CD206 / CD68 ratio) were calculated. The cut-off values were defined using X-Tile software. Results: High CD206+ TAMs density and high CD206 / CD68 ratio were significantly associated with reduced disease-free survival (DFS, P < 0.001 and P < 0.001, respectively) and overall survival (OS, P < 0.001 and P < 0.001, respectively). And CD206 / CD68 ratio had a better prognostic power. Furthermore, for patients with low CD206 / CD68 ratio, adjuvant chemotherapy made no benefit. But for high CD206 / CD68 ratio, adjuvant chemotherapy significantly improved DFS and OS (as shown in Table 1). In subgroup analysis, for T3 with high-risk factors or T4 tumors, CD206 / CD68 ratio was also a significant predictor for adjuvant chemotherapy (interaction P = 0.024 in DFS). Conclusions: For stage II colon cancer, CD206 / CD68 ratio was a good prognostic and predictive biomarker for adjuvant chemotherapy. Together with clinicopathological high-risk factors, it might facilitate patient counselling and individualise management. [Table: see text]
Prognostic impact of PD-L1 and PD-1 expression by primary tumor location in colorectal cancer.
Authors: Berntsson Jonna , Larsson Anna , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: January 2019

628

Background: A plethora of studies report abundant expression of programmed death-ligand 1 (PD-L1) on tumors to be associated with poor outcome in several cancer forms, whereas immune cell-specific expression of PD-L1 has been associated with improved prognosis in colorectal cancer. However, none of these studies have investigated the association with prognosis according to primary tumor location. This study aimed to investigate the clinicopathological correlates and prognostic impact of PD-L1 and its receptor PD-1 in colorectal cancer, with particular reference to the anatomical subsite of the primary tumor. Methods: Immunohistochemical expression of PD-L1 and PD-1 was analysed in tissue microarrays with tumors from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. Results: High PD-L1 expression on tumor-infiltrating immune cells correlated significantly with an improved 5-year OS in univariable and multivariable analysis, adjusted for age, sex, TNM stage, differentiation grade, and vascular invasion, in the full cohort (HR = 0.49; 95 % CI 0.35-0.68), and in primary tumors of the right (HR = 0.43; 95 % CI 0.25-0.74) and the left colon (HR = 0.28; 95 % CI 0.13-0.61), but not in rectal cancer. High tumor-specific PD-L1-expression was not significantly associated with prognosis in neither the full cohort nor according to primary tumor location. High expression of PD-1 on tumor-infiltrating immune cells was significantly associated with an improved 5-year overall survival in the entire cohort (HR = 0.42; 95 % CI 0.21-0.87), but not in subsite analysis according to primary tumor location. Conclusions: This study is, to the best of our knowledge, the first to investigate the prognostic impact of PD-L1 and PD-1 expression according to primary tumor site in colorectal cancer. Dense infiltration of PD-L1+ immune cells was found to be an independent favorable prognostic factor in primary tumors of the right and left colon, but not in the rectum.
Association of increased neutrophil-lymphocyte ratio after curative surgery with prognosis in patients with locally advanced esophagogastric adenocarcinoma.
Authors: Suzuki Akihiro , Kubota Keisuke , Fujikawa Aoi , Taketa Takashi , Sunagawa Hiroki , Ohigashi Seiji , Kishida Akihiro
Published: January 2019

63

Background: The neutrophil-lymphocyte ratio (NLR) is associated with the inflammatory status of patients with some cancers. We hypothesize that increased NLR was associated with prognosis in patients with stage II/III esophagogastric adenocarcinoma. Methods: We retrospectively analyzed 220 patients with stage II/III gastric cancer who underwent curative resection with suitable lymphadenectomy at our hospital, between 2000 and 2014. All patients underwent baseline staging, including blood tests, computed tomography, and endoscopic biopsy. The relationship between NLR and clinical outcomes was analyzed by univariate and multivariate analyses. Results: Average age was 67.9 [95% confidence interval (CI); 43.8, 92.1] years, and majority of the patients were male. After surgery, 111 (50.5%) patients underwent adjuvant chemotherapy, most of all patients received S-1 according to Japanese treatment guideline. Median follow-up time was 74.8 (95% CI; 69.9, 79.7) months. The preoperative NLR was 3.2 (95% CI; -4.2, 10.6), whereas the postoperative NLR was 3.0 (95% CI; -6.9, 12.8). In univariate analyses, age, stage, preoperative NLR, baseline CA19-9 levels, postoperative white blood cell (WBC) count, postoperative hemoglobin levels, postoperative NLR, increased NLR after surgery and adjuvant chemotherapy were associated with overall survival (OS). In multivariate analyses, age ( p < 0.001), stage ( p = 0.001), and increased NLR after surgery ( p = 0.048) were associated with OS. The prognosis of patients with increased NLR after surgery was observed to be worse than that of those with decreased NLR after surgery ( p = 0.001). Conclusions: Our findings indicated that increased NLR after curative resection was associated with poor OS in patients with locally advanced esophagogastric adenocarcinoma, suggesting that perioperative increased NLR was a potentially useful marker for individual therapy.
Phenotypic subtypes and risk of local recurrence after radical resection for rectal cancer.
Authors: Knight Katrina , Roseweir Antonia K. , Park James Hugh , Edwards Joanne , McMillan Donald C , Horgan Paul G. , Roxburgh Campbell SD
Published: January 2019

637

Background: Phenotypic subtypes for CRC are reported to stratify outcomes. The four subtypes are based on features within the consensus molecular subtypes (CMS): immune, canonical, latent and stromal. In 81 pts, we recently reported concordance between CMS and phenotypic subtypes. Of note, the stromal subtype matched the CMS4 subtype in 84%. Local recurrence (LR) after rectal cancer surgery remains a problem. Identifying those at risk determines who should receive neoadjuvant therapy (NT) and guides surgery. We evaluated whether phenotypic subtypes are associated with LR after radical treatment of rectal cancer. Methods: From a CRC database, pts with rectal cancer and phenotypic subtyping available were identified. Subtyping was performed based on immune cell infiltrate, stromal volume and tumor proliferation. LR was considered pelvic or peritoneal. Results: Between 1997-2007, 260 pts had surgery for rectal cancer. Most were > 65yrs (63%), male (58%) and TNM stage II (39%) or III (37%). 32 (13%) received NT. For phenotypic subtypes, 88 (35%) were Immune, 47 (19%) Canonical, 48 (19%) Latent and 67 (27%) Stromal. Median FU was 138 months (min 88). 70 pts (27%) developed recurrence: LR in 23 (8.8%) and systemic in 44 (16.9%). LR was associated with higher T stage (pT1-3 7% vs pT4 17%, p = 0.024), presence of vascular invasion (15% vs 6%, p = 0.018), serosal involvement (21% vs 6%, p = 0.001), margin involvement (22% vs 7%, p = 0.010), > 50% tumor stroma (18% vs 3%, p = 0.002) and phenotypic subtype (immune 5%, canonical 6%, latent 4% and stromal = 21%, p = 0.002). Similar LR rates were obtained after excluding pts who had NT: Immune (4%), canonical (4%), latent (5%) and stromal (23%). Of the 23 LRs, most were Stromal subtype (n = 14) vs Immune (n = 4), Canonical (n = 3) and Latent (n = 2). Apart from increased node positivity (50% vs 30-44% p < 0.05), there were no differences in rates of pT4 disease, tumor grade, vascular invasion, serosal involvement and margin positivity between stromal subtype and other groups. Conclusions: LR after rectal cancer surgery was associated with the stromal subtype. Validation is needed but pre-treatment tumor subtyping may identify subsets at risk of LR and have implications for patient selection for neoadjuvant therapy.