bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of weekly scheduled irinotecan and capecitabine treatment in advanced colorectal cancer patients.
Authors: Li Wenhua , Li Jin , Xu Jianming , Shen Lin , Liu Tianshu , Guo Wei jian , Zhang Wen
Published: March 2020

e14644

Background: The clinical application of combination therapy of irinotecan and capecitabine is at a standstill due to the consideration on severe diarrhea. The aim of the current phase II study was to explore the optimal administration mode of these two drugs, and evaluate the safety and efficacy of weekly-scheduled XELIRI regimen (wXELIRI) in mCRC pts. Methods: Pts with unresectable, histologically confirmed mCRC were enrolled to receive wXELIRI: irinotecan 90mg/m(2) on Day 1 and capecitabine 1200 mg/m(2) bid on Days 1-5 weekly. Both the first-line pts and second-line treatment pts who failed with FOLFOX or XELOX were eligible. The primary endpoint was rate of Grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and other safeties. Results: From January 2011 to May 2012, totally 43 pts with measurable mCRC were enrolled, 18 of them were male and 25 were female. The median age was 60 yrs (range 32-70). No Grade 4 diarrhea was observed and the rate of grade 3 diarrhea was 4.7%. The most common Grade 3/4 toxicities included leucocyte(11.6%), neutrophile (18.6%), vomiting (4.7%), fatigue (2.3%), hand-foot-syndrome (2.3%) . With a median follow-up of 19.0 months, 23 PFS events were observed. The mPFS for all the 43 pts was 6.1 mons and the mOS was 15.5 mons. For the 31 first-line treatment pts, the mPFS was 7.5 mons and the mOS has not reached. In the second-line treatment group (12 pts), the mPFS was 5.4 mons and mOS was 13.8 mons. Conclusions: The weekly-scheduled irinotecan and capecitabine combination has a low rate of severe diarrhea and acceptable toxicity profile. It could be an alternative regimen for mCRC pts, especially in the second-line setting. Clinical trial information: NCT01322152.
Prognostic significance of presence of any mucinous component in curatively resected stage II and III colorectal cancer patients who received adjuvant treatments: Data from a single tertiary center.
Authors: Dane Faysal , Ozturk Mehmet Akif , Yumuk Perran Fulden , Kocar Muharrem , Besiroglu Mehmet , Atasoy Beste Melek , Telli Ferhat , Kanitez Metin , Aktas Bilge , Turhal Nazim S.
Published: March 2020

e14660

Background: Mucinous adenocarcinoma colorectal cancer (CRC) is defined as presence of more than 50% mucinous component and its prognostic significance is debatable. We analyzed the prognostic importance of positivity of any mucinous component in early stage adenocarcinoma patients who were operated and received adjuvant treatments in a single tertiary cancer center. Methods: Data from charts of early stage CRC patients curatively treated between January 1998-December 2009 in our clinic was retrospectively analyzed. Cases with any degree of mucine presence in final pathology reports were noted (including mucinous adenocarcinomas). Adjuvant treatments were either 5-FU or oxaliplatin based regimens. All rectal carcinoma patients received postoperative radiotherapy. Survival analyses were made by Kaplan-Meier estimator, and independent factors of survival were tested with Cox regression test. Survival data of subgroups were compared with log-rank test. Results: 532 patients (45% female) were analyzed. Median follow-up was 36 months. Median age at diagnosis was 62 years (24-84). Fifty-four percent of patients had rectal primary (n=292). Presence of any mucinous component was found in 94 patients (17.7%). There was a close relation between mucine presence and T stage (p=0.0001) or tumor grade (p=0.0001). There was no statistical relation between presence of mucine and lymphatic invasion, vascular invasion, or perineural invasion. Five-year disease-free survival for mucine (+) and mucine (-) tumors were, 45.7% and 61.4%, respectively (p=0.031). Five -year overall survival of mucine (+) tumors was worse than mucine (-) tumors (65% vs. 74%, p=0.004). Conclusions: Presence of any mucinous component in early stage CRC appears to be an important bad prognostic feature in our patient group, which was not previously reported in the literature to our knowledge. This “context specific prognostic property” of presence of any mucinous component might serve as a stratification factor for further adjuvant CRC studies.
Effect of microRNA-202-3p on cell proliferation and targeting of ADP-ribosylation factor-like 5A in human colorectal carcinoma.
Authors: WANG Qifeng , Du Xiang
Published: March 2020

e14667

Background: MicroRNAs (miRNAs) are small, non-coding RNAs that are strongly implicated in cancer and reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. Methods: Quantitative RT-PCR was used to evaluate miR-202-3p expression in 94 pairs of human primary CRC and adjacent noncancerous tissues (NCT) to determine the clinicopathologic significance of miR-202-3p. Cell proliferation analysis and Xenograft analysis was used to investigate miR-202-3p function in vitro and in vivo.It’s direct target ARL5A was confirmed by Luciferase assay and Western blot. Immunochemistry was performed to reveal endogenous protein level of ARL5A and analysis clinical significance. Results: In this study, miR-202-3p was verified significantly down regulated in 46.7% (44/94) of the CRC tissues when compared to the corresponding noncancerous tissues(NCT). Subsequently, DNA copy number deletion of Pre-miR-202 in 63.2%(24/38) CRC tissue was proved(compared with NCT), which was considered as a main cause of the low expression of miR-202-3p. Cell proliferation analysis and colony formation assay showed that overexpression of miR-202-3p inhibit CRC cell growth in vitro. Xenograft analysis revealed that ectopic expression of miR-202-3p decreased the tumorigenicity of CRC cells in vivo. Consistent with these results, silencing of miR-202-3p resulted in a increased growth ratio of the colon cancer cells. In addition, ADP-ribosylation factor-like 5A(ARL5A) was predicted as potential target of miR-202-3p which was confirmed by Luciferase assay and Western blot. Overexpression of miR-202-3p could reduced the endogenous protein level of ARL5A, whereas silencing of miR-202-3p obviously up regulated ARL5A expression. In human CRC tissues, miR-202-3p expression levels correlated inversely with ARL5A protein levels which was identified as an prognostic factor in this study. Furthermore, knockdown of ARL5A phenocopied the proliferation-inhibiting effect of miR-202-3p. Conclusions: These results indicated that miR-202-3p, acting as a new tumor suppressor in CRC, could decrease cell proliferation via directly targeting ARL5A, a first reported gene related to CRC prognosis.
Neoadjuvant chemoradiotherapy (NACRT) in patients with locally advanced rectal cancer (RC): Results of a phase I/II trial in Japan.
Authors: Koyama Takafumi , Gomi Daisuke , Yukinori Ozaki , Nakamura Yoshiaki , Nagano Masafumi , Mike Makio , Kano Nobuyuki , Oyama Yu
Published: March 2020

e14670

Background: NACRT for patients with RC has been shown to increase the chance of sphincter preservation and local control, and has become the standard of care in stage T3/T4 rectal carcinoma in western countries. NACRT decreases the need for abdominoperineal resection (APR) that results in permanent colostomy and sexual/urinary dysfunction. In Japan, NACRT has not been utilized in RC and its value is unconfirmed. Thus, we performed a phase I/∥study to assess the toxicity and efficacy of NACRT. Methods: Eligibility criteria included histopathologically confirmed locally advanced adenocarcinoma with reasonable PS. Radiotherapy (RT) consisted of 5040 cGy in 28 fractions, and was delivered six times a week to the pelvis with individually shaped portals. Chemotherapy consisted of oral capecitabine (1650 mg/m2/day) or fluorouracil as a continuous infusion (225 mg/m2/day) on each RT day. Surgery was performed within 6-8 weeks after chemoradiation (CRT). Tumor response to CRT was measured using a radiologic scale, called the RECIST, and by pathologic examination of resected specimen. CTCAE v3.0 was used for evaluation of toxicity. Results: Fifty-two patients were enrolled in the study. Forty-nine (92%) patients completed CRT without treatment interruptions: 1 patient had temporary treatment interruption due to toxicity or noncompliance and 3 patienst had definitive treatment interruption. The incidence of Grade 3 lower gastrointestinal toxicity was only 9%. After NACRT, computed tomography showed that 14 patients had PR and 38 had SD. Resection was performed in 48 patients (low anterior resection in 34 and abdominoperineal resection in 14). Surgical resection resulted in R0 and R1 in 44 and 4 patients, respectively. At a median follow-up of 21.5 months (range: 4-69 months), local recurrence or tumor progression occurred in 2 patients and distant metastasis in 7. The median overall survival was 47 months. Conclusions: Our data confirm the safety and efficacy of NACRT using capecitabine/5FU in Japanese patients with locally ARC. We suggest that NACRT is the preferred treatment approach since it can provide increased resectabilility and possibly a superior rate of local control.
Intensive CT scan surveillance for patients who have undergone curative intent treatment for colorectal cancer: The Medstar Washington Hospital Center experience.
Authors: Leventakos Konstantinos , Lu Stanlee Santos , Perry David John
Published: March 2020

e14675

Background: The current ASCO guideline for surveillance after curative intent treatment of colorectal cancer is yearly CT scan of the chest, abdomen and pelvis with every 3-6 months history and physical exam and serial measurement of Carcinoembryonic antigen (CEA). The benefit of doing more intensive CT scan surveillance has not been adequately substantiated. Methods: Data of patients with resectable stage I-III colorectal cancer treated at Medstar Washington Hospital Center from January 2000-June 2012 were retrospectively reviewed. Epidemiologic, histopathologic , surveillance schedule (CT scan and CEA), and survival data were analyzed. Our institutional standard was to obtain CT scans every 3 months for the first year, every 6 months for the second year and then yearly for years 3-5. Results: Thirty-three patients with adequate documentation were included. The mean age of the patients was 59.6 years at diagnosis, 55% were female and 78% ethnically African American. 6% were in stage I, 37% were in stage II and 57% in stage III. CT scan was used in 100% of the patients done with a median interval of 7 months. At follow up, 28 (85%) patients had recurrence at a median of 21.6 months from surgery. 67% had recurrence in the liver. 96% of these recurrences were diagnosed primarily by CT scan and only 1 patient (3%) was diagnosed with MRI of the liver following an elevated CEA with a negative CT scan. Only 50% of patients with recurrence had an elevated CEA. 54% of patients with recurrence were able to undergo curative treatment (resection and/or chemotherapy). Conclusions: In this single institution, retrospective review, CT scan surveillance was utilized more frequently than specified in current ASCO guidelines. CEA screening alone would have missed 50% of patients with potentially curable recurrent cancer. Our data shows that more intensive CT scan surveillance led to earlier detection of recurrences that allowed patients to undergo curative intent treatment. A prospective study is warranted to further support this finding.
UGT1A1*28 polymorphism and vomiting in advanced colorectal cancer.
Authors: El Bastawisy Ahmed El Saied , El-Zeiny Amany , Farid Samar , Bahnasy Abeer
Published: March 2020

e14678

Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, this study tried to investigate correlation with other toxicities like vomiting. Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, group1: patients with no or hetero mutation, group 2: patients with homo mutation. All patients received standard IFL regimen. Primary endpoints were: 1-comparison between the 2 groups as regard vomiting .2-assessement of the incidence of UGT1A1*28 polymorphism. Secondary endpoints were: comparison between the 2 groups as regard: neutropenia, diarrhea, progressive diseases (PD), progression free survival (PFS) and overall survival (OS). Results: 43 cases of advanced colorectal cancer aged between 19 and 68 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow up of 9 months. UGT1A1*28 polymorphism were present in 21 patients (42%) of them 14% are homozygous. Grade (II-III) vomiting was found in 18.9% of group 1 versus 66.7% of group2. (P=0.03).Grade (II-IV) neutropenia were found in 27% of group 1 versus 83.4% of group2. (P=0.01). Grade (II-III) diarrhea was found in 37.8% of patients of group1 and 16.7% of patients with group 2. (P=0.44).20% of group 1 showed PD versus 40% of group 2. (P=0.5).1year PFS was 19% in group 1 versus 0% in group 2. (P= 0.74) while there was a trend towards better OS in group 1 (47% versus 0%). (P= 0.0892). Conclusions: UGT1A1*28 polymorphism is present frequently (42%) in a Caucasian population and is associated with more vomiting and neutropenia.
Choice of sequential biologic therapies in metastatic colorectal cancer (mCRC): A cost comparison analysis for wild-type KRAS mCRC patient population in Brazil.
Authors: Weschenfelder Rui , Buschinelli Caio Timko
Published: March 2020

e14679

Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in Brazil. Metastatic disease affects up to 50% of patients resulting in 5-year survival of less than 10%. Therefore, there is an increasing interest about the best treatment options, mainly regarding biologics and their sequencing across first line (1L) and second line (2L) treatment of mCRC. Modern series show that the probability of a patient receives 1L, 2L and a third line (3L) therapy is approximately 99%, 70% and 40%, respectively. In addition, in 2012, the ML 18147 study demonstrated the benefit of sequential use, 1L and 2L, of bevacizumab (bev) based combination in mCRC and considering this emerging data, it is important to understand the implications in terms of costs for the Brazilian private healthcare system. Methods: A costing tool was developed to compare the sequencing costs of 1L → 2L regimens used for treatment of wild-type KRAS mCRC patients. Dosing schedules were derived from labels, clinical trials and expert opinion. Analysis was performed from a private payer perspective and included drug-acquisition and administration costs only. Sequences in the ML18147 study (1L bev 5mg/kg+FOLFOX → 2L bev 5mg/kg+FOLFIRI and 1L bev 5mg/kg+FOLFIRI→2L bev 5mg/kg+FOLFOX) were compared to another frequently used sequence in Brazil where bev is replaced by cetuximab(cet) in 1L (1L cet 400-250mg/m2+ FOLFIRI → 2L bev 5 mg/Kg + FOLFOX). Results: Average costs per patient per month were Brz 21,285.50 for sequences with bev in 1L and 2L and Brz 24,191.68 when bev is replaced by cet in 1L. The average cost savings per patient for the entire treatment were Brz 28,767 (1L bev 5mg/kg + FOLFOX → 2L bev 5mg/kg + FOLFIRI vs 1L cet + FOLFIRI → 2L bev + FOLFOX) and Brz 29,938 (1L bev 5mg/kg + FOLFIRI → 2L bev 5mg/kg + FOLFOX vs1L cet + FOLFIRI → 2L bev + FOLFOX). Conclusions: Sequential use of bev in 1L and 2L mCRC according to the ML18147 study protocol is less costly compared to another sequence of biologics that starts with cet in 1L followed by bev in 2L. Resources savings with sequential bev have the potential to optimize 3L treatment strategy for wild-type kras mCRC patients in Brazil.
CTLs/regulatory T-cells ratio as a prediction marker of chemotherapy in metastatic colorectal cancer.
Authors: Sasatomi Teruo , Oochi Takafumi , Ogata Yutaka , Akagi Yoshito , Shirouzu Kazuo
Published: March 2020

e14684

Background: Many multiple anti cancer drugs regimens have been established for metastaticcolorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 32 metastatic colorectal cancer patients have been started chemotherapies. Their PBMCs were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3,CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs(CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less thanhalf. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased or stable patients. (P=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Both resectability rate of liver metastatic lesion and early tumor shrinkage rate were higher at the CTL/T reg ratio increased patients group than at the other patients group. Conclusions: We found that the CTL/T reg ratios of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
The study on functions and mechanisms of miR-106b in the metastasis of colorectal cancer.
Authors: Ni Shujuan , WANG Qifeng , Tan Cong , Du Xiang
Published: March 2020

e14685

Background: Emerging evidence has shown that aberrantly expressed microRNAs (miRNAs) are highly associated with tumour initiation, development and progression. However, little is known about the potential role of miRNAs in colorectal cancer (CRC) metastasis. Methods: The miR-106b expression levels in CRC tissues were deteted by quantitative reverse transcription polymerase chain reaction (qRT-PCR) to investigate its relationship with clinical characteristics or survival of CRC patients. Using the CRC cell lines ectopically expressing miR-106b conducted by lentivirus transduction as experimental material, cell culture, cell growth analysis and transwell used to analyze the potential influence of miR-106b on CRC metastasis. In addition, luciferase assays and western blot were used for the target gene study. Results: In this study, we firstly investigate the role and related mechanism of miR-106b in CRC metastasis. We found that miR-106b expression was lower than in CRC compared with their corresponding non-tumorous tissues (P=0.009), and the downregulated miR-106b was negatively associated with lymph-node metastasis. Functional assays demonstrated that overexpression of miR-106b suppressed CRC cell migration and invasion in vitro. In addition, we confirmed that ATAD2 was a direct and functional target of miR-106b. Overexpression of miR-106b in CRC cells could reduce the mRNA and protein levels of ATAD2, whereas miR-106b silencing significantly increased ATAD2 expression. Luciferase assays confirmed that miR-106b could directly bind to 3′ untranslated region of ATAD2. Knockdown of ATAD2 significantly inhibited CRC cell migration and invasion. We further found that ATAD2 was involved in miR-106b-induced suppression of CRC cell migration and invasion. Conclusions: By understanding the functions and molecular mechanisms of miR-106b in CRC, we found mir-106b through targeting ATAD2 inhibited CRC cell migration and invasion. These results suggest that patients with downregulated miR-106b are prone to lymph node metastasis and tumour progression. miR-106b may have a therapeutic potential to suppress CRC metastasis.
Use of VEGF expression to predict for first-line treatment chemotherapy regimen in metastatic colorectal cancer.
Authors: Ozkan Metin , Berk Veli , Deniz Kemal , Karaca Halit , Inanc Mevlude , Bozkurt Oktay , Duran Ayse Ocak
Published: March 2020

e14695

Background: In metastatic colorectal cancer treatment more successful results are achieved by adding anti-angiogenic therapy to the chemotherapy. Over expression of VEGF in colorectal cancer is known to be a poor prognosis factor but its effects on designating the therapy is not clear. In this study, results of the patients receiving FOLFIRI + Bevacizumab or XELOX + Bevacizumab were compared for VEGF expression. Methods: VEGF was assessed immunohistochemically in primary tumors of the 53 metastatic colorectal cancers. Severity and conformity of VEGF expression was evaluated. Results were used to assess the association with the therapy response, progression free survival (PFS) and overall survival (OS). Results: The median age of the patients was 55 (range, 32-79). In combination with bevacizumab 38 patients received FOLFIRI and 15 patients received XELOX. In 30 patients (57%) there was a strong expression of VEGF and in 23 patients (23%) the expression was weak. In the high VEGF expression group, PFS was 11 months in FOLFIRI receiving patients and 8 months in XELOX receiving ones but in low expression group PFS was 8 months in patients receiving either one of the two treatment protocols. In high expression group, PFS in FOLFIRI-bevacizumab combination receiving patients was different and this difference was statistically significant (p=0.009). Overall survival in FOLFIRI receiving patients with high VEGF expression was 26 months and with low VEGF expression it was 16 months (p=0.04). Median OS was not reached in the XELOX receiving patient group. FOLFIRI regime clinical benefit was 58% in high VEGF expression group whilst it was 34% in low expression group. This difference was not statistically significant but it was close to the significance threshold (p=0.06). There was no association between the therapy responses and VEGF expression of the 15 patients who received XELOX. Conclusions: There is no difference in efficacy between the first line chemotherapy regimens of the metastatic colorectal cancer. In this study, in metastatic colorectal patients with over expressed VEGF first line FOLFIRI-bevacizumab combination led to better response and survival rates.
Results of monoclonal antibodies against EGFR-receptors application in patients with metastatic colorectal cancer (mCRC).
Authors: Vladimirova Liubov Yu , Kit Oleg Ivanovich , Nikipelova Elena A , Abramova Natalya A
Published: March 2020

e14701

Background: Monoclonal antibodies against the epidermal growth factor receptor(EGFR)are standard components of treatment in mCRC.This study was designed to evaluate the tolerability and efficacy of the combinations of Panitumumab(P) and Cetuximab(C) with chemotherapy in patients with wild type(WT) KRAS tumors mCRC. Methods: Mutation analysis of KRAS(codons12,13) was done on samples at diagnosis. Key elegibility criteria included measurable mCRC stage IV, ECOG ≤2, adequate liver,kidney and bone marrow function, no brain metastases. P was administered 6mg/ kg 1 day q2w. C was administered 400mg/m² 1day and 250mg/m² q1w. Combination with FOLFOX-6 or FOLFIRI pegimens was allowed. Endpoints include response rate, OS, PFS and safety. Results: Of 38 testable samples there were 21(55.3%) WT KRAS tumors. All of these 21 (13male and 8female) pts were recruited. Mean age was 58.1±12.3. Synchronous metastases had 33.3%(7pts). Majority of pts benefited from anti-EGFR combined with cytotoxic chemotherapy 80.9% (17), mostly FOLFIRI – 57,1%(12).There were23.8%(5) in the 1st line CT, 76.1%(16) in the 2nd line CT. 6 mos of the treatment were analyzed. Overall RR was76.1 %(16) including 6PR(28.5%) and 10SD(47.6%). Med OS= 9.1mo, Med PFS= 4.3mo. 8 pts(38.1%) are alive till the abstract submission. Most common toxicities were:skin rash 2/3Gd.-90.5%(19), xeroderma 2Gd.-42.9%(9),skin itch 1/3Gd.-42.9%(9), paronychia 2Gd. -14.2%(3), purulent psorophthalmia 2Gd.-14.2%(3). All kinds of toxicities were controlled by symptomatic medication if necessary and did not lead to anti-EGFR agents dalay. Besides,diarrhea 1/2Gd.- 66.7%(14), 3Gd.-14.3%(3), neutropenia 1/2Gd.-28.6%(6), 3/4Gd.-9.5%(2), nausea 3/4Gd.- 14.3%(3), vomiting 1/2Gd.- 42.9%(9), fatigue 1/2Gd.-47.6%(10). Conclusions: These results consider significant efficacy of anti-EGFR agents combined with CT in pts with mCRC. Controlled toxicity of the therapy allows to use it widely.
Pathologic response, KRAS status, and bevacizumab: The Bermuda triangle for outcome prediction after hepatic colorectal cancer metastases (HCRM) resection.
Authors: Fanetti Giuseppe , Biondani Pamela , Tessari Anna , Melotti Flavia , Milione Massimo , De Braud Filippo G. , Perrone Federica , Miceli Rosalba , Mariani Luigi , Gevorgyan Arpine , Di Bartolomeo Maria , Pietrantonio Filippo
Published: March 2020

e14716

Background: Clinicopathologic factors are insufficient to stratify prognosis after HCRM resection. The identification of prognostic biomarkers is an unmet clinical need. Even if the prognostic role of KRAS mutations in the metastatic setting is controversial, recent data hypothesized a correlation to worse outcome after HCRM resections. This analysis evaluated the correlation between KRAS mutation, pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National Cancer Institute of Milan from 2007 to 2012 following bevacizumab (Bev) (n=30) or cetuximab (Cmab) (n=28) based neoadjuvant regimens. Tumor regression grade (TRG) was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3 for response; TRG 4-5 for scarce/no response. KRAS exons 2 to 4 were sequenced by direct PCR. Results: KRAS missing in 3 pts (1 Bev/2 Cmab), mutated in 23 (42%) vs wild-type in 32 (58%), mutated in 18 (62%) of Bev group vs 5 (19%) of Cmab. Mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). Pathological response higher for KRAS mutant vs wild-type (70% vs 41%; p=0.003 at Chi-square test). At log-rank test, DFS significantly shorter for KRAS mutated vs wild-type (7.6 vs 14.6 months; p=0.05), and for TRG4-5 vs TRG1-3 (8.1 vs 15.3 months; p=0.02), while no difference observed according to treatment. OS data are not mature. Multivariable Cox model for DFS shown in the Table. Conclusions: After Bev-based neoadjuvant treatment, patients with KRAS mutated HCRM and without good pathological response may have the worst outcome after curative resection. [Table: see text]
Iiteglinα4 (ITGα4) rs7562325 polymorphism was associated with better survivals in Austrian but not in Japanese patients with gastric cancer.
Authors: Iqbal Syma , Wakatsuki Takeru , Bohanes Pierre Oliver , Zhang Wu , Gerger Armin , Azuma Mizutomo , Stotz Michael , Yang Dongyun , Ning Yan , Volz Nico Benjamin , Stintzing Sebastian , El-Khoueiry Rita Elie , Labonte Melissa Janae , Li Joseph Ethan , Maus Martin K. H. , Koizumi Wasaburo , Watanabe Masahiko , Barzi Afsaneh , Lenz Heinz-Josef , El-Khoueiry Anthony B.
Published: March 2020

e15009

Background: Integrins mediate cell-extracellular matrix and cell-cell interactions. It has been demonstrated that integrins may play a crucial role in carcinogenesis, progression, and metastasis.Recently, we demonstrated that ITGα4 rs7562325 C/T, ITGβ1 rs2298141, and ITGβ3 rs4642 were associated with outcomes in stage II and III adjuvant colorectal cancer in the US cohort. To apply these results in gastric cancer, we tested whether ITGpolymorphisms could predict outcome in two ethnically and epidemiologically different GC cohorts from Japan and Austria. Methods: Sixty-three (stage Ib-III) Austrian patients and one-hundred and sixty-nine Japanese (stage Ib-IV) with histopathologically-confirmed localized GC (AJCC-6th) were enrolled from 2001 to 2010. Both cohorts were treated with D2 lymphadenectomy based surgery. Results: The median DFS and OS in the Austrian cohort were 4.0 and 4.8 years, while median DFS and OS in the Japanese cohort were 4.8 and 5.8 years, respectively. Adjuvant chemotherapy was conducted 109 (64%) patients in the Japanese cohort, while 14 (22%) patients in the Austrian cohort. Only ITGα4rs7562325 C/T were associated with survivals in the Austrian cohort; patients homozygous T/T (n=10) showed a median DFS of 20.1+ years vs. 2.8 years in patients harboring at least one-C allele (n=53) (HR: 9.18 [95%CI: 1.25-67.5] p=0.029). Similar finding was also seen for OS; patients homozygous T/T showed a median OS of 20.1+ years vs. 4.3 years in patients harboring at least one-C allele (HR: 9.33 [95%CI: 1.27-68.6] p=0.028). In multivariate analysis stratified by stage and gender, this result was conserved in DFS (HR: 9.40 [95%CI: 1.26-69.9] p=0.029), but not in OS (HR: 1.77 [95%CI: 0.87-3.62] p=0.112). These results were consistent with previous our results of adjuvant CRC in the US cohort; however, we could not validate these findings in patients with GC in the Japanese cohort. Conclusions: ITGα4 rs7562325 polymorphism was associated with longer DFS in Austrian patients with GC, not in Japanese patients. Ethnic difference and different implementation rates of adjuvant chemotherapy between Austria and Japan may influence these results.
Impact of virologic factors on recurrence-free survival in HBV-related hepatocellular carcinoma after surgical resection: Post hoc analysis from a prospective study with long-term follow-up.
Authors: Chiang Nai-Jung , Chen Miin-Fu , Hsiao Chin-Fu , Lee Po-Huang , Chen Pei-Jer , Chen Li-Tzong ,   Taiwan Cooperative Oncology Group (TCOG)
Published: March 2020

e15032

Background: To investigate the impact of virologic factors on recurrence of post-operative hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a prospective study population with long-term follow-up. Methods: 183 patients who had participated an adjuvant trial with detectable HBV DNA and of genotype B and/or C and negative for anti-hepatitis C antibody were included. All analyses were censored upon Dec 30st, 2010. Results: The genotype distribution was B in 99 (54.1%), and C or mixed B+C (C/B+C) in 84 (45.9%). Genotype C/B+C infected patients had significantly higher incidence of HBeAg-seropositivity, high baseline HBV viral load, elevated serum ALT level, and underlying cirrhosis than patients with genotype B infection. The median time-to-recurrence (TTR) was 94.9 months and 33 months for genotype B and C/B+C infected patients, respectively (p=0.0495), and that for viral titer <104 and ≥104 copies/mL was 129.8 and 39.9 months, respectively (p=0.059). Tumor size >5 cm (p=0.008), presence of venous invasion (p=0.007) and moderately or poorly differentiation (p=0.039) were adverse prognostic factors for TTR in multivariate Cox’s regression analysis, but neither HBV DNA titer nor genotype. Of patients with tumor size ≤5 cm, HBV genotype C/B+C and baseline HBV viral load ≥104 copies/mL are significant adverse prognostic factors for TTR. On the other hand, microvascular invasion but not viral factor was prognostically significant for tumor size >5 cm subpopulation. Compared with patients with neither genotype C/B+C infection nor baseline viral load ≥104 copies/mL, the relative risk for TTR of patients with either and both of the virological risk factors was 2.581 (p=0.068) and 3.384 (p=0.019), respectively, for the entire study cohort. Conclusions: HBV genotype and baseline viral load are associated with risk of recurrence in post-operative HCC, especially in patients with tumor ≤5 cm. Adjuvant anti-viral therapy may be more likely benefit to curatively resected small HBV-related HCC patients, which is currently tested in TCOG1206 trial.
Doxorubicin drug eluting beads transcatheter chemoembolization (DEB TACE) in patients with large hepatocellular carcinoma (HCC): Overall survival and a multivariate analysis (MVA) of prognostic factors.
Authors: Prajapati Hasmukh J. , Spivey James R. , El-Rayes Bassel F. , Kauh John S. , Kim Hyun Sik
Published: March 2020

e15033

Background: To investigate the prognostic factors (PFs) associated with survival after DEB TACE in patients (pts) with at least > 5cm sized index HCC (iHCC). Methods: Consecutive pts with at least > 5cm sized iHCC, who received DEB TACE over last 82 months, were studied. Median overall survivals (mOSs) were analyzed according to different parameters from 1st DEB TACE. Kaplan Meier estimator by log rank test and Cox proportional Hazard model (for MVA) were used survival analyses using v20 SPSS. Results: 332 DEB TACEs (mean 3, medium 2) were performed in 112 pts (mean 62.1 years, SD 12), who had at least >5cm sized iHCC (mean 9.5 cm, SD 3.7). MOS from diagnosis and DEB TACE were 14.3 months (m) and 9.4 m respectively. MOS were 31.9 m, 11.1 m and 2.8 m in pts who received > 4, 2-4 and a 1 DEB TACEs respectively (p<0.001). Etiological factors for HCC were hepatitis C virus (54.4%), hepatitis B virus (12.5%), chronic alcoholism (7.1%), other causes of chronic liver disease (17%) and unknown with no chronic liver disease (9%); mOS were 8.8 m, 4.4 m, 5.8 m, 27 m, and 9.4 m respectively (p=0.01). MOS in pts with Child-Pugh Class A (58.9%), B (34.8%) and C (6.3%) were 17.2 m, 5.8 m and 1.6 m respectively (p<0.001). MOS in pts with BCLC stage B (17%), C (69.6%) and D (13.4%) were 20.9 m, 9.4 m, and 3.4 m respectively (p=0.003). 46.4% of pts had portal vein thrombosis (PVT) with mOS of 5.4 m vs. 17.1m in pts without PVT (p=0.006). Pts with serum alfa feto protein (sAFP) level>400 ng/dl (43.7%) had mOS of 5.4 m vs. 16.6 m in pts with sAFP<400ng/dl (p=0.008). 32.1% of pts received sorafenib systemic chemotherapy; mOS were 13.3m vs. 7.6m who did not receive the sorafenib (p=0.2). Pts with >5 HCCs (20.5%) had mOS of 5.4m vs. 13m in pts who had <5 HCCs (p=0.009). The following variables were independent significant PFs of survival on MVA: Child-Pugh class, etiology, number (no) of DEB TACEs, presence of vascular invasion and ECOG PS. Conclusions: Higher number of DEB TACE treatments correlates independently to improved OS in patients with at least >5cm sized index HCC. Other independent PFs of survival were etiology, Child-Pugh class, no of HCC tumors, ECOG PS and PVT.
Patterns of recurrence after neoadjuvant docetaxel, cisplatin, and 5FU combined with resection and extended lymphadenectomy for locally advanced esophagogastric adenocarcinoma.
Authors: Ferri Lorenzo , Alcindor Thierry , Ades Steven , Aloraini Abdullah , Vanhuyse Marie , Asselh Jamil , David Marc , Thirlwell Michael P.
Published: March 2020

e15044

Background: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a highly effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophago-gastric junction (EGJ). However there is ongoing debate whether chemotherapy alone provides adequate local or regional control. We hypothesized that DCF combined with enhanced local surgical control would result in a low rate of local or regional recurrence. Methods: A prospective entered database of all esophageal/EGJ ADC pts resected at a high volume referral center was reviewed for cases treated with neoadjuvant DCF (Docetaxel 75mg/m2, Cisplatin 75mg/m2, 5FU 750mg/m2x120 hrs CIV) Q3weeks x3, followed by en-bloc resection with extended lymphadenectomy (D2). Follow up included physical exam Q3m x 2 yrs then Q6m, and endoscopy and CT chest/abdo/pelvis performed Q6 m. Recurrence was defined as: Local = biopsy on endoscopy; Regional = regional lymph nodes; Distant = distant organ or non-regional lymph nodes. Data presented as Median (Range). Results: Of 281 pts in the database, 89 (75%male, 63yrs(24-80)) underwent pre-op DCF and resection for locally advanced ADC (cT3 93%;cN+ 73%) of the EGJ (51%) or distal esophagus (49%) from 3/07-10/12. After overall follow-up of 37(6-72) months, 37 (42%) have recurred at 15(6-33) months. Sites of recurrence include Distant only in 29/37, Regional only in 5/37, and Regional and Distant in 3/37. First site of distant recurrence was peritoneum (14/37), liver (10/37), non-regional lymph nodes (10), brain/ovary/pleura (2 each), and bone(1). No patient had local recurrence alone. 3/5 patients with regional recurrence underwent salvage chemoradiotherapy and are alive without disease at 36 months (30-47) after recurrence. Conclusions: En-bloc resection with extended lymphadenectomy after DCF for locally advanced ADC of the esophagus and EGJ is associated with a low rate of local and regional recurrence. As vast majority of recurrences are distant, our data supports the notion that efforts to improve outcomes in these pts should concentrate on enhancing systemic, rather than local, therapy.
Expression of stem cell markers in pancreatic ductal adenocarcinoma and clinical relevance.
Authors: Andrikou Kalliopi , Faloppi Luca , Loretelli Cristian , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano
Published: March 2020

e15058

Background: Emerging evidence has suggested that malignant tumors are heterogeneous and that are composed of a small subset of distinct cancer cells (usually defined by cell surface marker expression) that are responsible for tumor initiation and propagation, termed cancer stem cells. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. It was found that human pancreatic cancer has shown a population of cancer stem cells that have aberrantly activated developmental signaling pathways, are resistant to standard chemotherapy and radiation, and have up-regulated signaling cascades that are integral for tumor metastasis. The aim of our study is to investigate the prognostic implication of cancer stem cell markers in pancreatic ductal adenocarcinoma. Methods: In 43 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of CD 24, CD44, CD133, CD166, OCT3/4, LGR5. Results: At univariate analysis patients with an overexpression of CD44, CD133, OCT3/4 showed a worse prognosis in terms of overall survival (respectively: p=0.031; p=0.014; p=0.001). At multivariate analysis OCT3/4 resulted to be independent factor influencing outcome (HR=0.23). Patients with overexpression of all factors seem to have a worse OS compared to patients expressing only two, one or none (8.6 vs. 15.6 vs. 18.0 vs. 59.9 mts; p=0.006). Conclusions: Our data suggest that the presence of cancer stem cells could be linked with tumor aggressiveness and patients’ survival. This finding could drive therapeutic decision towards less or more intensive treatment.
Cdc7 inhibition as a novel approach for pancreas cancer therapy.
Authors: Frattini Mark G. , Regales Lucia , Santos Ruth , Carrillo Diana
Published: March 2020

e15059

Background: Pancreatic cancer is the fourth leading cause of cancer death in the USA. In 2012, 43,920 people will be diagnosed and 37,390 people will die of this disease. 95% of tumors reveal loss of the p16 protein, a regulator of the G1 to S phase transition. Cdc7 is a conserved kinase required for the initiation of DNA replication, is a target of the S-phase checkpoint, and has a role in controlling the DNA damage response. Downregulation of Cdc7 kinase activity resulted in slowing of S-phase and cell cycle arrest followed by accumulation of DNA damage. Cdc7 has been shown to be over-expressed in many different tumors including the majority of solid and liquid tumors. In our laboratory a novel natural product small molecule inhibitor (MSK-777) has been identified, developed and shown to be efficacious in cell based cytotoxicity assays and multiple animal models of cancer. Methods: We have examined the efficacy of Cdc7 kinase inhibition as a therapeutic approach for pancreatic cancer by examining the sensitivity of MSK-777 in Capan-1, BxPC3, and PANC-1 cell lines. These cells were treated with MSK-777, control (DMSO), or hydroxyurea and collected for viable cell counts, fluorescence-activated cell sorting (FACS), and western blotting. Results: Cell viability analyses revealed that MSK-777 had a dramatic effect after 24 hours, reducing cell viability to less then 20% in BxPC3 cells. FACS results demonstrated that MSK-777 exposure resulted in cell cycle arrest at G1/S in Capan-1 and PANC-1 cells by 48 hours while BxPC3 cells showed a significant sub-G1 population by 24 hours, indicating apoptotic cell death. Western blotting showed that in BxPC3 cells phosphorylation of the mini-chromosome maintenance 2 protein (Mcm2) disappeared by 24 hours, indicating inactivation of the helicase that unwinds the strands of DNA during replication. Western blots of Capan-1 and PANC-1 cells showed lower levels of phosphorylated Mcm2 by 48 hours. Conclusions: We are currently examining the efficacy of MSK-777 in mouse models of orthotopically injected pancreatic cancer cells. Based on these collective results, inhibition of Cdc7 kinase activity with MSK-777 represents a novel and promising therapy for this deadly disease.
Assesment of SOX-17 gene promoter hypermethylation in hepatocellular carcinoma.
Authors: Chelis Leonidas , Balgouranidou Ioanna , Koukaki Triantafyllia , Michailidis Prodromos , Christakidis Evagelos , Xenidis Nikolaos , Amarantidis Kiriakos , Trypsianis Grigorios , Kakolyris Stylianos
Published: March 2020

e15063

Background: SRY-box containing gene 17 (SOX-17) is implicated in the WNT/β-catenin pathway and acts as a tumor suppressor gene inhibiting the transcription of activated β-catenin. WNT oncogene plays a crucial role in liver carcinogenesis and has been shown to correlate with poor survival and aggressive behavior in hepatocellular carcinoma (HCC). Silencing of SOX-17 gene through promoter hypermethylation results in WNT overexpression. Tumor-related cell free DNA (cfDNA), circulating in the blood of cancer patients can be used for the detection of methylation status of several genes. Therefore, we examined SOX-17 methylation in the blood of HCC patients and correlated it with the outcome. Methods: Patients diagnosed with HCC were eligible. cfDNA from 87 patients (N=87) was isolated from 200 μL serum before any treatment. After DNA extraction, all samples were subjected to a sodium bisulfite conversion reaction. Methylation specific polymerase reaction (MSP) for SOX17 promoter methylation was performed using specific primer pairs for both the methylated and unmethylated promoter sequences. Results: According to BCLC staging system, our patients were staged as A=5 (5.6%), B=15 (17.2%), C=67 (77%) respectively. SOX-17 methylation was detected in 58 (66.7%) patients while 29 (33.3%) had a non-methylated gene. The methylated form of the gene was significantly correlated with an impaired performance status (PS) of 2-4 (p=0.021) and with extrahepatic spread of the disease (p=0.036). No correlation was detected for stage, Child-Pough score of cirrhosis, or underlying cause of HCC. The overall survival (OS) was 14 months for the non-methylated and 5 months for the methylated gene, respectively (p= 0.0062). Sixty three patients received sorafenib as 1st line treatment. The OS was 15 months for patients with the non-methylated and 6 months for patients with the methylated gene, respectively (p= 0.012). In the multivariate analysis for OS, SOX-17 methylation status along with PS remained significant (p=0.04) Conclusions: Assessment of SOX-17 promoter hypermethylation in the peripheral blood is feasible. SOX-17 gene methylation is a frequent event in HCC and seems to correlate with a poorer outcome.
Pharmacodynamic separation (PDS) of gemcitabine (Gem) and the epidermal growth factor receptor (EGFR) inhibitor erlotinib (E) in patients (Pts) with advanced pancreatic cancer: Phase II results.
Authors: Semrad Thomas John , Lenz Heinz-Josef , Gong I-Yeh , Tanaka Michael S. , Eddings Courtney , Mahaffey Nichole , Mack Philip C. , Beckett Laurel , Lara Primo
Published: March 2020

e15073

Background: Continuously dosed E given concurrently with Gem results in only a modest survival improvement in pts with advanced pancreatic cancer. Preclinical data suggest that there is antagonism between chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) when these are delivered concurrently due to cell cycle effects. Work by our group and others has shown that EGFR TKIs induce cytostasis due to G1 arrest, which reduces subsequent cell cycle phase-dependent activity of chemotherapy. We tested a PDS approach for E + Gem as a means of overcoming the hypothesized negative interaction of EGFR TKIs and chemotherapy. Methods: Pts with measurable, previously untreated locally advanced unresectable/metastatic pancreatic cancer with adequate organ function and PS 0-2 were eligible. Tumor tissue was collected for molecular studies. PDS Regimen: Gem 1000 mg/m2 IV days 1, 8, 15, and E 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. Primary endpoint was PFS; secondary endpoints included response rate (RR) and safety. To have 80% power at 5% significance, 70 pts were planned to detect an increase of PFS from 3.75 to 5.25 months. The study was terminated due to funding considerations. Results: 30 pts enrolled with median age 67 years (range 46-84); PS: 0 (23%), 1 (47%), and 2 (30%); locally advanced (13%) & metastatic (87%). Median PFS was 2.07 months (95% CI; 1.87 – 5.50 months). Median OS was 5.67 months (95% CI; 2.83 – 11.87 months). Median cycles completed were 2 (range 0-8). Two pts withdrew consent in the first cycle without progression and were not evaluable for response. RR was 11% (3 PRs); DCR was 46%. Grade 3/4 adverse events occurred in 63% of pts; the most common were neutropenia (23%), fatigue (13%), anemia (10%), thrombocytopenia (10%), rash (10%), nausea (10%), and diarrhea (10%). Conclusions: Although Gem and E in a PDS dose-schedule was feasible & tolerable in pts with advanced pancreatic cancer, no signal for increased efficacy was seen (compared to historic controls) in this molecularly unselected cohort. Correlative studies to identify potential molecular biomarkers of benefit are ongoing and will be presented. Clinical trial information: NCT00810719.