bluuebunny/crossref_metadata_2025 huggingface dataset:
Visceral fat as a predictive marker of response to bevacizumab-based treatment in metastatic colorectal cancer.
Authors: Miyamoto Yuji , Sakamoto Yasuo , Watanabe Masayuki , Baba Hideo
Published: March 2020

e14665

Background: A large amount of visceral adipose tissue might be correlated with high VEGF levels and with resistance to bevacizumab-based regimens in metastasic colorectal cancer (mCRC). The aim is to evaluate that abdominal obesity can be a predictive marker of response to bevacizumab-based therapy in mCRC. Methods: From January 2005 to December 2010, we performed a retrospective analysis of 74 consecutive patients with mCRC received bevacizumab-based first line treatment. Pretreatment CT was used to measure visceral fat volume (VFV), subcutaneous fat volume (SFV) an waist circumference (WC) in 74 patients with mCRC who received bevacizumab-based first-line treatment (bevacizumab group, n=37) or chemotherapy alone (chemotherapy group, n=37). Associations linkingVFV, SFV and WC to tumor response, progression free survival (PFS) and overall survival (OS) were evaluated. For all analyses, VFV, SFV and WC were dichotomized using the median as the cut-off point. Results: In the bevacizumab group, median follow-up lasted for 25 months (7-47). VFV, SFV and WC values were not associated with response or OS. PFS was shorter in patients with high VFV (12.8 vs 7.7 months; p=0.04). By multivariate analysis, high VFA was independently associated with PFS (HR=4.32, p=0.045). In the chemotherapy group, median follow-up lasted for 26 months (2-68). VFV, SFV and WC were not associated with response, PFS or OS. Conclusions: Visceral fat volume plays a role of predictive marker of PFS to bevacizumab-based therapy for Japanese patients with mCRC.
Predictive significance of VEGF and HIF-1α expression in metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab.
Authors: Berk Veli , Deniz Kemal , Karaca Halit , Inanc Mevlude , Bozkurt Oktay , Duran Ayse Ocak , Ozkan Metin
Published: March 2020

e14672

Background: There is no suggested molecular indicator in identifying which patients will benefit from anti-angiogenic treatment in metastatic colorectal cancer. Over expression of vascular endothelial growth factor (VEGF) and Hypoxia Inducible Factor 1-alpha (HIF-1α) are associated with bad prognosis. In this study, VEGF and HIF-1α expression and their clinical significance are studied in tumor tissues of patients with colorectal cancer receiving treatment with bevacizumab. Methods: VEGF and HIF-1α were observed immunohistochemically in primary tumors of 53 patients. The expressions were separated by evaluating low and high of VEGF and HIF-1α expression. We evaluated whether expression of VEGF and HIF-1α can help to predict treatment response, progression free survival (PFS), and overall survival (OS). Results: Fifty-three patients were enrolled in the study. Median age was 55. VEGF was strongly expressed in 30 patients (57%) whilst low expression was observed in 23 of them (43%). When VEGF expression was evaluated in association with therapy response rates; the clinical benefit rate was 38% in the low expression group whereas it was 62% in high expression group. This difference was statistically significant (p=0.01). In the group with strong VEGF expression PFS was 10 months whereas it was 8 months in the low expression group (p=0.009). When evaluated for OS, 26 months versus 15 months was in favor of highly expressed VEGF group (p=0.03). Highly expressed HIF-1α was found in 29 patients (55%), on the other hand low expressed HIF-1α was detected in 24 (%45) patients. For clinical benefit rates, PFS and OS there was no difference between high and low expressed HIF-1α groups. Conclusions: It has been demonstrated that VEGF and HIF-1α expressions are associated with poor prognosis in several tumors, mainly colorectal carcinomas. With the better understanding of carciogenesis and angiogenesis at molecular level, especially VEGF and HIF-1α became target molecules of the therapy. According to results of our study, VEGF expression is a predictive factor in designating the metastatic colorectal cancer treatment.
Clinical features and outcome of sporadic colorectal carcinoma in young adults: A single center, cross sectional analysis.
Authors: Zahir Muhammad Nauman , Mahpara Eisha , Rafiq Sobia , Ghias Kulsoom , Shabbir-Moosajee Munira
Published: March 2020

e14680

Background: Early onset colorectal carcinoma (CRC), defined as CRC at age below 45 years is rare. However, an increasing incidence has been noted in Southeast Asia. It is hypothesized to be a biologically and clinically distinct entity personifying aggressive disease and a worse survival. Data on this subject is scarce from this part of the world and hence our objective was to study the clinical presentation and outcome of early onset sporadic CRC in patients at a single tertiary care center in Pakistan. Methods: Data was collected by a retrospective chart review. 131 patients were found eligible for the period between January 1, 2004 and December 31, 2011. A pre-designed and coded questionnaire was used and analysis was done using SPSS. Cox proportional hazard model was used to compute prevalence ratios. Results: Early onset sporadic CRC accounted for 32% of all CRC treated in the specified time period. Colon and rectal cancers accounted for 55% and 45% of patients respectively. The median age was 35 years (range 16-45 years) and the male to female ratio was 2:1. 74% of patients presented with advanced stage disease [stages III (45%) and IV (29%)]. On comparison, bleeding per rectum, signet ring morphology, stage and grade of tumor were found to be statistically significant for the rectal cancer group on a univariate analysis. 93% of rectal carcinoma patients received appropriate surgery and/or neoadjuvant/adjuvant therapy as opposed to 69% of colon cancers. Median survival was 19 months (range 0-112.5 months). However, Kaplan-Meier analysis revealed a trend towards an inferior survival for rectal carcinoma 2 years after initial diagnosis (p=0.56). Conclusions: Higher incidence of early onset CRC is noted in our population as compared to the western literature. Rectal carcinoma accounts for almost half the patients in this young CRC population. This group was found to have a higher frequency of poor prognostic factors. However, we have noted a similar 2 year survival between the 2 groups, with a trend towards an inferior prognosis with longer followup. It is possible that a larger sample size may have elucidated a statistically significant difference between the two groups.
Comparison of predictors of survival in colon and rectal cancer patients.
Authors: Tang Ying Margie , Okoronkwo Nneoma Olivia , Patel Neal , Chang Victor Tsu-Shih , Wang Trent P , Barnes Tanganyika , Kasimis Basil , McPherson Monica , Crump Barbara , Zhong Fengming
Published: March 2020

e14681

Background: We studied comorbidity and other predictors of survival for patients (pts) with colorectal cancer (CRC) and compared pts with colon (C) vs rectal (R) cancer (ca). Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, Hemoglobin (HGB), and Albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts with C vs R ca. Results: There were 279 men. 191 pts (68.5%) had C ca and 88 pts (31.5%) had R Ca. The two groups were similar for stage, grade, age, HGB, CEA, ALB, and ECOG PS. For R ca pts, Median (M) CCI is 3.7 (0.4-13.9), M CIRS15 2.5 (0-5), M CIRS16 5 (0-13), M CIRS 17 2.0 (0-8), M CIRS18 0 (0-1), M CIRS19 0 (0-1), and M KFI 1 (0-3). For C ca pts, M CCI is 4.3 (0.9-19.6), M CIRS15 3.0 (0-6), M CIRS16 6.0 (0-13), M CIRS17 2.0 (0-9), M CIRS18 0 (0-1), M CIRS19 0 (0-2), and M KFI 2 (0-3). In univariate analysis, stage, ECOG PS, HGB, and ALB were significant survival predictors in R ca pts. Age, stage, grade, ECOG PS, HGB, CCI, CIRS16, CIRS17, CIRS19 and KFI were significant for C ca pts. Other significant multivariate predictors are summarized in the table. R ca pts are more likely to die (P=0.003, HR=0.51). Conclusions: In this larger population of pts with CRC, we confirmed our previous findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 are important independent survival predictors for veterans with CRC. Age, grade, stage, ECOG PS, CCI, CIRS 16 and CIRS 19 are independent predictors for colon ca pts. Only Stage and ECOG PS are independent predictors for rectal ca pts. Rectal ca pts are at increased risk of dying. More research is needed to confirm this. Supported by New Jersey Commission for Cancer Research. [Table: see text]
Association of the polymorphisms of the tandem repeat sequence in the thymidylate synthase gene with tumor stage in colon cancer.
Authors: Aguiar Samuel , Olivieri Eloisa , Carraro Dirce Maria , Mello Celso Lopes , Fanelli Marcelo , Lopes Ademar
Published: March 2020

e14688

Background: Thymidylate synthase (TS) plays an important role in colorectal carcinogenesis and response to 5FU-based chemotherapy. TS expression can be modified due to polymorphisms in the 5'-untranslated region (5’-UTR) of the gene. The aim of this study is to investigate the association between TS polymorphisms with clinicopathological characteristics of colon carcinomas. Methods: we retrospectively studied 89 individuals with high risk stage II (obstruction, T4 stage, presence of lymphovascular invasion or preoperative CEA > 5.0) and stage III patients submitted to curative intent surgery. DNA was extracted from paraffin embedded tumor tissues and sequenced. The polymorphism studied was the variation of the number of the repeated 28-bp sequences (3 or 2 repeats) of the TS gene 5’-UTR. Results: The frequency of the polymorphisms was: 2R2R in 26 cases (29.2%), 2R3R in 36 cases (40.4%), and 3R3R in 27 cases (30.3%). We did not find associations between the frequencies of these polymorphisms and age, gender, presence of lymphovascular invasion, or level of preoperative CEA. We find a significantly higher proportion of T4 tumors between the 3R3R genotype compared with the 2R2R and 2R3R genotypes (OR=2.69; 95% CI: 1.05 – 6.94; p=0.04). By the other hand, a significantly lower proportion of positive lymph nodes were found among patients with tumors presenting the 3R3R genotype, by comparing with the 2R2R and 2R3R subgroup (OR: 0.28; 95%CI: 0.10 – 0.72; p=0.01). Five-year disease free survival and overall survival were, respectively, 81% and 85% among patients with tumors presenting the 3R3R genotype, and 62% and 67% among patients with tumors presenting 2R2R or 2R3R genotypes. These differences were not statistically significant. Conclusions: in this sample, the TS polymorphic tumor genotype 3R3R was associated with lower risk of lymph node metastases in colon carcinomas.
Role of clinical variables for predicting pathologic response to neoadjuvant chemoradiation in locally advanced rectal cancer.
Authors: Taglietti Paula Mendonca , Aguiar Samuel , Amor Divino Paulo Henrique , Begnami Maria D. , Batista Ranyell Spencer Sobreira , Mello Celso Lopes , Lopes Ademar
Published: March 2020

e14691

Background: pathologic response to neoadjuvant chemoradiation is a strong prognostic factor for rectal cancer. Some studies have suggesting a wait and see approach for rectal cancer after clinical complete response to chemoradiation. In this study, we tried to identify clinical predictive factors of pathologic response to neoadjuvant chemoradiation. Methods: we retrospectively reviewed data of 129 patients from a prospective database, treated between January, 2008 and December, 2012. Patients with mid and low rectal adenocarcinoma, clinically staged (MRI) as T3,T4 any N or any T, N+, received pre-operative chemoradiation, which consists in 5040 cGy, concomitant to 5-FU-based chemotherapy. All patients were operated, by radical TME procedures. The clinical variables analyzed were: age, gender, distance from dentate line, cT stage, cN stage, pre-treatment CEA level, NIH toxicity during chemoradiation, endoscopic assessment of response, and interval between the end of radiation and surgery. We investigate associations between these variables with complete pathological response (cPR) and “good” pathological response (gPR), defined as ypT0orT1 N0. Results: the rate of cPR was 20.2%. The rate of gPR was 31.8%. For predicting cPR, only the endoscopic assessment of response showed significant association with cPR. Among 18 patients with complete endoscopic response, 8 (44.4%) confirmed cPR after resection. Among 93 patients with endoscopic findings suggesting residual disease, 14 (15.1%) presented cPR (p=0.008). 55.6% (10/18) of patients with complete endoscopic response still have microscopic residual disease in the resected specimen. For predicting gPR, only the cN staging was significantly associated with ypT0orT1 N0 (23.9% of gPR among cN+ patients against 41.3% among cN0 patients; p=0.038). Conclusions: clinical tools are very poor for predicting pathological response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinomas. Despite endoscopic assessment of response by retoscopy have showed significant association with cPR, the predictive value was weak.
Ovarian metastases in colorectal carcinoma.
Authors: Yucel Idris , Erdem Dilek , Yilmaz Bahiddin , Gonullu Guzin
Published: March 2020

e14697

Background: 5-30 % of all ovarian tumors are metastatic and only 3-14 % of them derive from gastrointestinal tract. The aim of this study is to determine the rate of colorectal cancer patients with ovarian metastases and also to identify the features in the management of these patients. Methods: 972 colorectal cancer patients admitted to our clinic between 01/2001 and 12/2011 were included in the study. Among these patients, only 9 had ovarian metastases. Age, menopausal status, initial symptom, operation status, localisation of colorectal tumor, stage at diagnosis, tumor grade, histopathological type, colorectal tumor-ovarian metastases interval, having synchronous or metachronous metastases, the place of metastases and concurrent metastatic disease were evaluated. SPSS 16 is used. Results: Mean age of patients was 45 years (range between 21-72 years). 66.7 % had premenopausal state. 55 % of them had right colon tumor. 5 patients had stage IV disease. 5 patients had synchronous metastases (55 %). Colorectal cancer-ovarian metastases interval was 6-49 months in the patients with metachronous metastases. Among patients; 5 had right and 1 had left ovarian metastases and 3 had metastases to both ovaries. 2 of 3 bilateral ovarian metastases were derived from right-sided tumors (66.6 %). 7 patients also had metastases to other different parts and most of those had peritoneal involvement (85.7 %). PFS was between 2 and 27 months. At the time of ovarian metastases, 7 patients had high CA 125 levels and 3 had high CEA levels. All patients with high levels of CA 125 during diagnosis continued to have high levels of CA 125 with ovarian metastases. Conclusions: Premenopausal patients seem to have higher risk of ovarian metastases. This study support that examining CA 125 levels in colorectal cancer patients who have abnormal findings in the gynecological examination preoperatively may help not to miss synchronous ovarian metastases.The finding of ovarian metastases should make consideration that the disease is disseminated. Ovaries should be examined preoperatively and it should be kept in mind that CA 125 levels may be a valuable marker in this setting.
Clinical colorectal cancer (CRC) subsets in advanced disease: Patterns of metastatic spread to predict survival.
Authors: Bourlon María Teresa , Carpinteyro-Espin Paulina , Mora-Pineda Mauricio De Jesus , Gamboa-Dominguez Armando , Huitzil-Melendez Fidel David
Published: March 2020

e14703

Background: Advanced CRC is a heterogeneous disease. Some patients exhibit diffuse metastatic spread while others show selective organ involvement. We aimed to investigate the frequency and survival implications of initial pattern of metastatic spread in a Mexican cohort. Methods: We retrospectively reviewed charts and radiologic images of patients with advanced CRC at our institution from 2004 to 2011. The initial pattern of spread was recorded. Categories depending on the predominant site of involvement were: 1) Locally advanced, 2) Hepatic, 3) Pulmonary, 4) Peritoneal or 5) Diffuse. Survival was estimated by the Kaplan Meier method and Log rank test used to determine survival differences among categories. Results: 179 patients with advanced CRC were identified. Median age was 60yo, 56% were male. Primary tumor location was 50.3% colon, 27.9% rectum, 17.9% recto-sigmoid and 3.4% had synchronous disease. 66% of patients had advanced disease at diagnosis and 34% were recurrent cases. Metastasis at diagnosis involved the liver in 105 (58.7%), peritoneum in 49 (27.4%), lung in 56 (31.3%) and non regional lymph nodes in 36 (20.1%) patients. Notably, 101 (56%) patients had a predominant site of metastatic involvement: locally advanced in 3 (1.7%), hepatic in 51 (28.5%), peritoneal in 21 (11.7%), pulmonary 21 (11.7%) while 78 patients (44%) had disseminated disease. Median overall survival was 15 months (n= 179) and differed according to predefined CRC subsets: 9, 13, 22, 23, and 52 months for peritoneal, disseminated, hepatic, locally advanced and pulmonary spread respectively p=.018 (significant after multivariate analysis). Other factors associated with better survival were female gender p=.040, absence of morbidity from primary tumor p=.27, resection of primary tumor p=.004, recurrent presentation p=.039, and access to 1stline chemotherapy p=.00. Conclusions: Over 50% of patients exhibited selective metastatic spread. Clinically defined subsets correlate with better (pulmonary) or worse (peritoneal/disseminated) survival. This finding might have implications in patient selection for regional therapies and encourage research to find the molecular determinants of this biologic behavior.
Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.
Authors: Quintanilla Guzman Arturo , Luevano Gonzalez Arturo , Rojas Martinez Augusto , Flores Gutierrez Juan Pablo , Gonzalez Guerrero Juan Francisco , Rios Ibarra Clara Patricia , Lopez Chuken Yamil Alonso , Rodriguez Silva Claudia , Ortiz Lopez Rocio
Published: March 2020

e14708

Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).
Diabetes as a predictor of colon cancer prognosis: A single institution based retrospective data analysis.
Authors: Ammannagari Nischala , Patel Anush V. , Bravin Eric N. , Scribani Melissa , Victory Jennifer
Published: March 2020

e14709

Background: Prevalence of Diabetes mellitus (DM) has increased in dramatic proportions globally over last few decades. Several observational epidemiological studies have shown increased risk of colorectal malignancies in patients with DM. However, it is not yet clearly understood if DM can impact the prognosis of colon cancer. Methods: The hospital’s cancer registry was used to identify advanced (stage III or IV) colon cancer cases diagnosed from January 2007 to December 2009. To be included in the study, the patient must have been treated with a 5-Fluoro Uracil based chemotherapy regimen. Retrospective chart review of electronic medical records was used to collect patient characteristics, including diabetes mellitus (DM) status. Kaplan-Meier curves were constructed for disease free survival and overall survival time. These survival curves were compared between diabetics and non-diabetics using the log rank test. Results: A total of 40 subjects met inclusion criteria, with a mean age of 64.6 years. Compared to non-diabetic patients, patients with diabetes had significantly poorer disease free survival (p=0.03). There was no difference in overall survival when comparing diabetic patients to non-diabetics (p=0.47). Conclusions: While taking into consideration that the study was under powered due to the small sample size, this study does raise the possibility that diabetes mellitus might be an important prognostic indicator of colon cancer. Management of diabetes must be emphasized as an integral part of care of colon cancer.
Plasma TIMP-1 in patients with metastatic colorectal cancer treated with first-line oxaliplatin-based therapy with or without cetuximab: Results from the Nordic VII study.
Authors: Tarpgaard Line Schmidt , Guren Tormod Kyrre , Glimelius Bengt , Sorbye Halfdan , Ikdahl Tone , Christensen Ib Jarle , Qvortrup Camilla , Kure Elin , Pfeifer Per , Nielsen Hans J. , Brünner Nils
Published: March 2020

e14710

Background: Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a biomarker in patients with metastatic colorectal cancer (mCRC). TIMP-1 inhibits matrix metalloproteinases and has tumor promoting functions. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based but not oxaliplatin-based treatment in patients with mCRC. Based on our prior studies, we here tested the hypothesis that high pretreatment plasma TIMP-1 correlate with short overall survival (OS) and short progression-free survival (PFS) but not response rate (RR) in patients with mCRC included in the NORDIC VII Study in which patients received oxaliplatin-based therapy. Methods: In the NORDIC VII Study patients were randomized to: A) Nordic FLOX; B) Nordic FLOX + cetuximab or C) Nordic FLOX intermittently + cetuximab continuously. Plasma samples for TIMP-1 analysis were available from 426 patients. Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic ELISA. Results: The three study populations were comparable and not different from the total intention to treat population. The median pretreatment plasma TIMP-1 was 269 ng/mL (58-1318 ng/mL). KRAS mutated in 149 patients (35%). There was no interaction between treatment arms and pretreatment plasma TIMP-1 either for PFS (p = 0.16) or OS (p = 0.64). High pretreatment plasma TIMP-1 was associated with shorter PFS (HR=1.22, 1.07-1.39, p=0.003) and shorter OS (HR=1.55, 1.36-1.80, p<0.0001). RR did not correlate significantly to pretreatment plasma TIMP-1 (OR=1.16, 0.91-1.49, p=0.22). Multivariate analysis (TIMP-1, Köhne index, KRAS and BRAF status, CRP, CEA, age, gender) demonstrated that high pretreatment plasma TIMP-1 was not an independent biomarker of PFS (HR=1.06, 0.88-1.28, p=0.52) or OS (HR=1.19, 0.96-1.47, p=0.11). Conclusions: Plasma TIMP-1 is a prognostic biomarker in patients with mCRC treated with 1st line oxaliplatin-based therapy +/- cetuximab. A predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment, and no significant treatment by marker interaction was observed.
Prediction of tumor recurrence by tumor location in stage II and III colon cancer patients through common germ-line variants of genes involved in wnt signaling pathway.
Authors: Zhang Wu , Ning Yan , Yang Dongyun , Wakatsuki Takeru , Stintzing Sebastian , Volz Nico Benjamin , Li Joseph Ethan , Labonte Melissa Janae , El-Khoueiry Rita Elie , Barzi Afsaneh , El-Khoueiry Anthony B. , Kahn Michael , Lenz Heinz-Josef
Published: March 2020

e14714

Background: Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. The Wnt signaling pathway was found to be deregulated in 93% of colorectal cancer (CRC). Tumor recurrence after curative resection is still a major problem in the management of adjuvant CRC, with recurrence rate approximately 30-40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. In this study, our group tested whether gene polymorphisms [TCF7L2 rs7903146, AXIN2 (rs2240308, rs3923087) and P300 (rs7286979, rs220551 and rs5782022)] involved in Wnt signaling pathway could predict the risk of tumor recurrence in stage II and III CRC patients. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 years (range 22–78 years)) with stage II (105 patients) or III (129 patients) colon cancer at the University of Southern California/Norris Comprehensive Cancer Center. The median follow-up was 4.4 years. TCF7L2, AXIN2 and p300 SNPs were determined by PCR-RFLP or PCR-based direct sequence. The primary endpoint of the study was time to tumor recurrence (TTR). Results: In univariate analysis, patients with TCF7L2 rs7903146 TT genotype had significantly longer TTR (median=10.7 months, 95%CI 4.9,10.7 +) compared with those harboring CT (median=3.9months, 95% CI 2.4, 10.7) or CC genotype (median=5.9months, 95% CI 2.8, 11.4+) patients (p=0.042, log-rank test). In multivariate analysis, left-side tumor patients with p300 rs7286979 AA genotype had highest risk of TTR (HR=2.85, 95% CI 1.03,7.89) compared to those carring GA (HR=0.81, 95% CI 0.35,1.84) or AA genotype (p=0.048, Wald test). Conclusions: Our results show that germline polymorphisms profiling of Wnt signaling pathway TCF7L2 rs7903146, p300 rs7286979 may predict tumor recurrence risk in adjuvant colon cancer patients, and may dependent on tumor location. Our exploratory data warrants further validation.
Plasma membrane localization of human equilibrative nucleoside transporter 1 (hENT-1) to predict better outcome of adjuvant gemcitabine in cholangiocarcinoma (CC) patients.
Authors: Brandi Giovanni , Tavolari Simona , Vasuri Francesco , Farioli Andrea , Deserti Marzia , Frega Giorgio , Corbelli Jodi , Barbera Maria aurelia , Pantaleo Maria A. , Di Girolamo Stefania , Biasco Guido
Published: March 2020

e15003

Background: The role of adjuvant chemotherapy in CC is controversial and, to date, no standard treatment has been established in this setting. Some institutions offer gemcitabine (GEM) as adjuvant strategy to radically resected CC patients. The efficient uptake of this drug into cells requires the expression and plasma membrane localization of hENT-1. A recent study showed that a high hENT-1 expression closely associated with better survivals in macroscopically (R0 + R1) resected CC patients treated with adjuvant GEM plus S-1. In the present study, we analyzed the relationship between hENT-1 expression/localization and disease free survival (DFS) in CC patients undergone surgery and treated with adjuvant GEM. Methods: A total of 71 CC patients (44 intra-hepatic and 27 extra-hepatic) operated between 2002 and 2011 (46 R0 and 25 R1) and treated with adjuvant GEM (1000 mg/m2, 1-8-15/21 days planned for 6 months) in our institution were enrolled and retrospectively analyzed for hENT-1 expression/localization by immunohistochemistry. Main outcome measure was DFS. Hazard ratios (HR) of relapse and associated 95% confidence intervals (95% CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score (estimated from baseline covariates). Results: 26/71 patients (36.6%) showed a high hENT-1 plasma membrane expression. During a median follow-up of 18.1 months (IQR 9.1–36.2) 49 relapses were observed. Patients with a high expression of hENT-1 showed a reduced risk of relapse (HR 0.50, 95%CI 0.26–0.99, p=0.047). Noteworthy, the effect of hENT-1 appeared to increase across tertiles of duration of gemcitabine-based adjuvant chemotherapy (lower tertile, ≤102 days: HR 0.87, 95%CI 0.30–2.53; middle tertile, 103–170 days: HR 0.68, 95%CI 0.22–2.06; higher tertile, ≥171 days: 0.20, 95%CI 0.04–0.94). Conclusions: High plasma membrane hENT-1 expression was associated with a longer DFS among CC patients. The interaction between hENT-1 expression and duration of chemotherapy deserves further investigations, as it could be useful to tailor optimal GEM-based adjuvant chemotherapies.
Diagnostic discrepancies between second-opinion and referring pathology reports of neuroendocrine tumors.
Authors: Lin Hillary , Longacre Teri A. , Khandelwal Vilay H. , Balise Raymond R. , Kunz Pamela L.
Published: March 2020

e15011

Background: The nomenclature and histologic classification schemes for neuroendocrine tumors (NETs) have historically been heterogeneous and inconsistent. However, clinicians require specific descriptors to determine treatment plans for patients. In 2010, Klimstra, et al. published a set of NET pathology reporting guidelines. Using these guidelines, we undertook a systematic evaluation of discrepancies between referring versus Stanford second-opinion NET pathology reports. Methods: We developed a cohort ofall NET cases seen at Stanford University Hospital between April 1998 and December 2012 with available Stanford and referring pathology reports for the same specimen to identify the discrepancies between their clinical diagnoses. Results: Of 170 cases, histological diagnoses were discrepant in 79% of the reports; 89 (66%) of which were clinically insignificant, and 46 (34%) clinically significant. Stanford used 14 unique terms for histological description, and referring institutions used 49 unique terms. Grade, mitotic index (MI), and Ki67 were among the variables examined; they were not reported (NR) from the majority of cases in one or both reports, yet more likely to be included in the Stanford report. Grade was NR in one or both reports in 152 cases (89%); of the 18 cases reporting grade in both reports, 3 (2%) were discrepant. MI was NR in one or both reports in 128 cases (75%); of the 42 cases reporting MI in both reports, 27 (16%) were discrepant. Ki67 was NR in one or both reports in 153 cases (90%); of the 17 cases reporting Ki67 in both reports, 12 (7%) were discrepant. Reporting was found to improve over time for these variables (five-year blocks from 1998-2012). There was a trend towards improved reporting from academic hospitals (vs. non-academic hospitals) and by Stanford NET pathology experts (vs. general pathologists). Conclusions: Clinically relevant differences were frequently found between Stanford and referring pathology reports for NETs. Future studies of NET pathology discrepancies are warranted to allow additional time for adoption of the 2010 guidelines.
Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor, in combination with gemcitabine in patients with advanced pancreatic cancer.
Authors: Mahesh Sameer A. , Gabrail Nashat Y. , Gandhi Jitendra G. , Khorana Alok A. , Manges Robert , Shah Satish , Thomas Gary W. , Hamdy Ahmed M. , Stevens-Brogan Michelle , Zhou Cathy , Elias Laurence , Loury David , Ramanathan Ramesh K.
Published: March 2020

e15014

Background: Tissue factor (TF) up-regulation is associated with increased tumor invasiveness and progression, worsened prognosis and increased thromboembolism (VTE). Activation of protease activated receptors by TF:FVIIa complex leads to increases in IL-8, VEGF and other invasiveness promoting factors. PCI-27483 (P), a selective FVIIa inhibitor, reduced pancreatic adenocarcinoma (PCa) xenograft growth in mice at doses producing 2.5 - 3.0 x PT changes. Methods: Escalating doses of P combined with gemcitabine (G) targeting peak (2 hr post) INR = 3.0 was studied in Phase I preceding randomization to G+P at the determined dose vs. G alone in Phase II. Eligible patients (pts) had measurable locally advanced or metastatic PCa, ECOG PS 0-1, and normal PT/aPTT, and no history of VTE. G was given IV at 1 G/m2 q wk X3 every 4 wks, and P was self-administered SC bid continuously. Tumor evaluation including spiral CTs were performed at baseline and q 8 wks. Results: In phase I, 8 pts were enrolled and the targeted INR was attained at 1.2 mg/kg. In phase II, 34 patients were randomized, 16 to G and 18 to G+P. The randomized arms were well balanced; overall 88% had metastatic disease; most had liver involvement. Among pts randomized to P+G, mean ± SD 2-hr post injection INR was 3.1 ± 1.2 on D8 and 2.8 ± 1.0 on D22 (n=13). P dosing was continued for up to 96 wks; mean ± SD: 17 ± 24 wks. Dose reduction to maintain target INR was required for 6 pts. Overall tolerability and safety of G+P was similar to that of G, with a higher incidence of mostly low grade bleeding events and decreased Hgb. Efficacy measures of G vs G+P pts were not significantly different (Table). Conclusions: PCI-27483 +G was well tolerated at doses of P up to 1.5 mg/kg bid. The safety profile of the combination was consistent with that expected of each agent. While the clinical endpoints were not achieved in pancreatic cancer, the targeted inhibition of the coagulation cascade was achieved. Clinical trial information: NCT01020006. [Table: see text]
Quantitative detection of intraabdominal floating tumor cells and clusters using flowcytometry in patients with peritoneal carcinomatosis.
Authors: Kitayama Joji , Kamei Takao , Emoto Shigenobu , Yamaguchi Hironori , Ishigami Hironori
Published: March 2020

e15027

Background: Peritoneal metastasis (P) is the most life-threatening types of metastasis in patients with gastrointestinal cancer. Although the presence of tumor cells in peritoneal cavity is evaluated with microscopic observation by pathologists (Cy) or detection of mRNA of tumor specific molecules, no reliable method is available to quantify the accurate volume of tumor cells. Methods: Acsites or peritoneal lavages were recovered from 72 patients who underwent abdominal surgery for gastrointestinal cancer. In patients who received intraperitoneal (IP) chemotherapy for peritoneal metastasis, 40 samples were obtained from subcutaneous intraperitoneal access port during the course of chemotherapy. In those 112 samples, cells were recovered by centrifugation, fixed and immunostained with mAbs to CD45 and to CD326 (EpCAM). Using FACS analysis, CD326(+)CD45(-) and CD45(+)CD326(-) cells were determined as tumor cells (T) and leukocytes (L), respectively, and T/L ratio was calculated. Results: In 72 patients with surgery, Median (M) of T/L ratio of the P(+) patients was 15.3% (0%-751.3%), which was significantly higher than P(-) patients (M=0%, 0%-2.1%, p<0.001). In P1 patients, 50 samples which was determined as positive cytology (Cy+) showed higher T/L ratio as compared with 33 samples with Cy (-) (M=23.0%, 0.3%-751.3% vs M=0.53%, 0%-3.5%, p<0.0001). In 17 patients who underwent IP chemotherapy, T/L ratio was markedly decreased after chemotherapy (M=75%, 0.2%-339.0% vs M=0.16%, 0%-35.0%, p<0.0001) and the response was more sensitive than Cy. Moreover, the MST of the 21 P1 patients who showed T/L ratio less than 10% at initial examination was 459 days, while MST of 8 P1 patients whose CT/L ratio was more than 10% was 188 day (p<0.0012). Conclusions: T/L ratio measured with flowcytometry well reflects the total volume of intraperitoneal tumor cells and could be a reliable biomarker to predict the prognosis as well as effectiveness of IP chemotherapy in P1 patients in gastrointestinal cancer.
The management of dysphagia in esophageal adenocarcinoma patients undergoing neoadjuvant chemotherapy: Can invasive tube feeding be avoided?
Authors: Cools-Lartigue Jonathan , Jones Daniel , Zourikian Taline , Rousseau Mathieu , Spicer Jonathan , Eckert Eleanor , Alcindor Thierry , Ferri Lorenzo
Published: March 2020

e15034

Background: Neoadjuvant chemotherapy is an accepted standard for locally advanced esophago-gastric adenocarcinoma. However the dysphagia frequently associated with this condition may interfere with patient tolerance of neoadjuvant chemotherapy. Surgical or endoscopic invasive tube feeding (ITF), including stents, is a commonly employed strategy to maintain nutritional support however it can cause significant morbidity in its own right. We sought to determine if an approach of careful dietary counseling and fast-tracked neoadjuvant chemotherapy can obviate the need for ITF. Methods: Pts undergoing neoadjuvant chemotherapy (DCF or ECF Q3 weeks x3 or FLOT Q2weeks x4) for locally advanced (cT3 and/or N+) esophageal or EGJ adenocarcinoma at a single institution from 3/07-9/12 were identified from a prospective database. All received dietary counseling and were closely monitored for signs/ symptoms of malnutrition with serial (baseline/pre-surgery) Body Mass Index (BMI), albumin, dysphagia scores (DS: 0 best - 4 worse), and quality of life (FACT-E). We assessed the response of dysphagia and nutritional status to neoadjuvant treatment and the need for ITF. Data presented as median (Interquartile Range) or median (±SD), paired t-test or Wilcoxon signed ranks test determined significance (*p=0.05). Results: Of 130 patients undergoing neoadjuvant chemotherapy 78 had dysphagia scores of 2 or greater, most of whom received DCF (91%). Overall the dysphagia improved in 75/78 (96%) from a DS of 3 (2-4) to 0 (0-1)*. This was associated with an increase in FACT-E QoL scores (117±23 to 140±20)*. Weight (Kg)(70±22:69±24), BMI (24.5±8 to 23.9±7), and Albumin (40±5 to 37±4) were maintained. Only one patient required a stent, and none a jejunostomy, or gastrostomy. Conclusions: Appropriately timed neoadjuvant chemotherapy with a highly effective regimen rapidly restores normal swallowing, maintains nutritional status, and obviates the need for stenting or invasive tube feeding in patients with significant dysphagia from esophageal adenocarcinoma.
Oxaliplatin, irinotecan, bevacizumab followed by docetaxel, bevacizumab in inoperable gastric cancer: Final efficacy results of a multicenter phase II trial (AGMT Gastric-3) of the arbeitsgemeinschaft Medikamentöse tumortherapie (AGMT).
Authors: Woell Ewald , Keil Felix , Thaler Josef , Gruenberger Birgit , Hejna Michael , Eisterer Wolfgang , Fridrik Michael A. , Romeder Franz , Greil Richard
Published: March 2020

e15041

Background: We could show efficacy of oxaliplatin and irinotecan as well as oxaliplatin, irinotecan and cetuximab in previous trials.Time to progression however was short suggesting acquired chemotherapy resistance.To address this problem sequential chemotherapy combined with bevacizumab is investigated in the presented Gastric-3 trial. Methods: Oxaliplatin 85 mg/m2 and irinotecan 125 mg/m2 are administered biweekly (q2w) for the first three months followed by docetaxel 50mg/m2 q2w for subsequent three months. Chemotherapy is combined with bevacizumab 5 mg/kg q2w which is administered until progression. Primary endpoint is response rate. 40 patients (pts.) with histological proven unresectable and/or metastatic gastric adenocarcinoma treated in a first-line setting are evaluated. Median age: 62.5 years PS 0: 26 pts., PS 1: 12 pts., missing: 2 pts.,single metastatic site: 25 pts., multiple metastases: 13 pts., missing: 2. Results: Frequently reported adverse events (more than 20% of pts.) were predominantly grade 1 or 2 and included diarrhea (72.5%), nausea (65%), emesis (50%), abdominal pain (50%), fatigue (47.5%), polyneuropathy (40%), neutropenia (25%), hypokalemia (22.5%), hypertension (22.5%). Grade 3 and 4 toxicities included neutropenia (25%), diarrhea (12.5%), ileus/subileus (10%), hypokalemia (7.5%), leucopenia (7.5%), anemia (5%), meningiosis carcinomatosa (5%). Objective response rate after 3 cycles was available in 31 patients: CR 1/31 (3.2%), PR 48.4%, SD 35.5%, PD 12.9%. After 6 cycles there were 14 evaluable patients with CR 2/14 (14.3%), PR 42.9%, SD 35.7% and PD 7.1%. Median progression free survival was 32 weeks, median overall survival was53 weeks. Progression rate or death was 34/40 (85%), mortality 29/40 (72.5%). Maintenance therapy was given in 12/40 pts. (30%). Median time on maintenance therapy was 17 weeks, range (2 – 77). Conclusions: The combination of oxaliplatin and irinotecan with bevacizumab followed by docetaxel with bevacizumab is feasible and active in advanced gastric cancer. Clinical trial information: 2008-006128-79.
Correlation of prognosis with the gradually increased Golgi protein 73 expression in the progression of benign liver diseases to precancerous lesions and hepatocellular carcinoma.
Authors: Wang Yijun , Shan Shigang , Gao Yingtang , Zhang Qin , Wang Fengmei , Jing Xiang , Du Zhi
Published: March 2020

e15050

Background: Serum golgi protein73 (sGP73) is a novel biomarker for hepatocellular carcinoma (HCC). However, there are few reports on the pattern of GP73 expression in the progression of benign liver diseases to precancerous lesions and HCC. This study aimed to investigate GP73 expression and it correlation with clinicopathologic parameters. Methods: Tissue GP73 (tGP73) levels were detected in specimens of group A (n=186) including HCC (n=62), peritumoral tissue (PTL) (n=43), high/low-grade hepatic atypical hyperplasia (AH) (n=32/2), chronic hepatitis B (CHB) (n=42) and normal controls (NC) (n=5) by immunohistochemistry, and GP73 expression in group B (n=159) and group C (n=16) were detected by RT-PCR and Western blot respectively. sGP73 levels were detected in subjects of group D (n=287) by ELISA. Results: GP73 expression increased gradually from NC, CHB, PTL to high-grade AH and HCC at both protein and mRNA levels (P<0.05), while sGP73 in HCC group was lower than in liver cirrhosis (LC) group (P<0.001). Both tGP73 and sGP73 levels were negatively associated with tumor size and TNM stage, and tGP73 levels were positively associated with tumor differentiation. The high-tGP73 group showed significantly better overall and disease-free survival than low-tGP73 group (P=0.008, P=0.018). Multivariate analysis revealed that the tGP73 level was an independent prognostic factor for HCC, but not sGP73. Conclusions: GP73 increases gradually in the progression ofbenign liver diseases to precancerous lesions and HCC. This expression pattern suggests the regulatory mechanism of GP73 is related to the progression of chronic liver diseases. Furthermore, a high level of tGP73 is a favorable prognostic factor for HCC.
An assessment of the impact of geographic variation on resection rates and survival for early-stage pancreatic adenocarcinoma.
Authors: McDowell Bradley D. , Smith Brian J. , Button Anna M , Howe James R. , Chrischilles Elizabeth A. , Mezhir James J.
Published: March 2020

e15052

Background: Pancreatic resection is the only known curative option for pancreatic adenocarcinoma. Resection has been previously reported to be underutilized in patients with early stage disease. To develop a better understanding of this issue and control for treatment selection factors, we examined the relationship between geographic area resection rates and survival in patients with stage I/II pancreatic cancer. Methods: We queried Surveillance, Epidemiology, and End Results (SEER) data for patients with stage I/II cancer of the pancreatic head diagnosed from 2004-2009. We excluded patients with less than 3mo survival. Resection rates were calculated within Health Service Areas (HSAs) across all 18 SEER regions. Resection rate was defined as the number of patients who had an operation divided by the total number diagnosed with early stage pancreatic cancer. Multivariate Cox regression was used to estimate the overall survival effect of HSA rates while controlling for age, gender, marital status, poverty level, education, and AJCC stage. Results: 8,323 patients with stage I (n=1,454) and stage II (n=6,869) disease were analyzed. Pancreatectomy was performed in 476 patients (32.7%) with stage I disease and 3,846 (56.0%) with stage II disease. HSA resection rates were arranged into five groups (quintiles) which ranged from 42.7 to 65.7% (Table). Across the quintiles, median overall survival increased from 11 to 14 months, suggesting a positive association with resection rate. Multivariate analysis revealed that for every 10.00% increase in resection rate, the risk of overall death decreased by 5.26% (p<0.001). Conclusions: Patients with early stage pancreatic cancer who live in areas with higher resection rates have longer average survival times. Because geography should not influence treatment response, we conclude that efforts to raise resection rates should increase survival times in patients for whom there is uncertainty about the risk/benefits of resection. [Table: see text]
Phase II trial of nemorubicin hydrochloride (N) in combination with cisplatin (cDDP) administered by intra-hepatic artery (IHA) in patients (pts) with hepatocellular carcinoma (HCC): Final results.
Authors: Izzo Francesco , Vogl Thomas J. , Gadaleta-Caldarola Gennaro , Middleton Mark R. , Valle Juan W. , Hammerstingl Renate , Gadaleta Cosmo D. , Martignoni Marcella , Petroccione Anna , Mariani Mariangela , Davite Cristina , Fiore Francesco
Published: March 2020

e15061

Background: N is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and toxicity of N administered by IHA in combination with cDDP to unresectable HCC pts. Methods: The study was in two HCC pt populations: advanced risk (ARP) (CLIP 2, bilirubin ≤ 2.5 mg/dL, portal vein thrombosis [PVT] admitted) and intermediate risk (IRP) (CLIP 0-1, bilirubin ≤ 1.5 x ULN, no PVT). Treatment was repeated every 4-6 wks for a maximum of 6 courses, if acceptable toxicity and no disease progression occurred. A single-arm, Simon’s Minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria, critical numbers of responses to reject H0were ≥ 6/29 evaluable pts and ≥ 11/33 evaluable pts in ARP and IRP, respectively). Results: Thirty-seven ARP pts (27 evaluable) and 42 IRP pts (33 evaluable) were enrolled. The median number of cycles was 3 in both ARP (range 1-13; dose 400 mcg/m2 nemorubicin and 60 mg/m2 cDDP) and in IRP (range 1-6; dose 600 mcg/m2 nemorubicin and 60 mg/m2 cDDP). The trial was successful in ARP with 8 successes/27 evaluable pts (RR 30%): 7 partial responses (PR), 1 downstaging and 8 minor responses (MR)/ disease stabilization (SD) > 3 months. The IRP did not meet the efficacy criteria:2 CR, 5 PR and 13 MR/SD > 3 months (7 responses/33 evaluable pts; RR 21%). Overall, the main Grade 3-4 hematological and biochemical toxicities in ARP/IRP were thrombocytopenia (28/58%), neutropenia (26/60%), aspartate aminotransferase (25/31%), alanine aminotransferase (14/23%) and bilirubin increase (17/21%). The most frequent adverse events (any Grade ≥ 20%) were fatigue (38%), nausea (35/29%), and vomiting (24/26%). Conclusions: The trial was successful in ARP but not in IRP; IHA infusion of N with cDDP showed promising activity in both IRP and ARP with a well tolerated regimen. These encouraging results warrant further investigation in HCC, specially in multinodular type. Clinical trial information: 2005-000731-26.