bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographics and patterns of care for veterans with colorectal cancer.
Authors: Barnes Tanganyika , Wang Trent P , Zhong Fengming , Chang Victor T , Gonzalez Melanie L. , Paz-Querubin Emma R , Crump Barbara , McPherson Monica , Gandhi Arpita , Kasimis Basil
Published: March 2020

e14124

Background: This study is to analyze demographics and patterns of care for veterans with colorectal cancer. Methods: In an IRB approved protocol, we reviewed the records of pts diagnosed with colorectal adenocarcinoma at a VA Medical Center from 1/1/2003 to 12/31/2007. Demographics including age, sex, ECOG PS, stage, grade, site, CEA, hemoglobin (HGB), liver function tests at diagnosis, treatments and cause of death were reviewed. Results: There were 176 pts with colorectal ca with 112 colon (C) and 64 rectal ca (R) pts. One was a woman and the rest were men. The median age at diagnosis was 71 years (range 45-90). Median survival was 1157 days (5-3256). 95 (54%) pts were dead at this analysis. Median ECOG PS is 0. 160 pts had ECOG PS 0-2, 16pts ECOG 3-4. 4 (2.4%). 4 (2.4%) pts has stage 0, 51 (30.7%) stage 1, 42 (25.3%) stage 2, 35 (21.1%) stage 3, and 34 (20.5%) stage 4. 6 (3.7%) has grade 1, 111 (68.1%) grade 2, and 46 (28.2%) grade 3. Median CEA at diagnosis was 2.9 (0-3117), HGB 12.4 g/dl (6.6-16.7), albumin g/dl 3.98(1.7-4.7), AST 23 units/L (4-107), ALT 20 units/L (8-107), ALKP 77 units/L (37-352), Total bilirubin 0.7 mg/dl (0.1-4.5). 29 pts has liver metastasis at diagnosis. 147 pts (85.4%) received surgical resection. Total 43 pts had adjuvant treatment. 17 pts with rectal cancer had neoadjuvant chemoradiation . 7 pts had down staging and 3 pts had no residual disease after neoadjuvant chemoradiatoion. Total 14 pts had recurrence. 23 pts received palliative chemotherapy when metastatic. 54 of 95 pts (57%) died from cancer progression. Conclusions: This study provides a basis for understanding the epidemiology of colorectal cancer patient in a VA medical center.
Fate of disappeared hepatic metastasis after mFOLFOX6 plus bevacizumab therapy.
Authors: Uetake Hiroyuki , Ishikawa Toshiaki , Sugihara Kenichi
Published: March 2020

e14127

Background: Neoadjuvant and conversion chemotherapy for liver limited metastasis from colorectal cancer (CRC) is a current topic. Minute liver metastasis sometimes disappears on preoperative imaging and intraoperative examination (including contrast enhanced intraoperative ultrasonography (CEIOUS)) after chemotherapy using highly effective regimen, such as FOLFOX or FOLFIRI with molecular targeted agent. We reported a high pathological complete response (CR) rate of resected liver metastasis from CRC after preoperative mFOLFOX6 plus bevacizumab (Bmab) therapy (AACR 2011, abstract #3218), but It is still unclear whether disappeared lesions after chemotherapy need to be removed. Methods: Out of 17 patients with liver limited metastasis from CRC treated with mFOLFOX6 plus Bmab therapy, 9 patients (52%) underwent liver resection after chemotherapy. In 6 of the 9 patients, one or more disappeared lesion(s) after the chemotherapy was not resected and followed up by enhanced CT once every 3 months. Follow up period was 9 to 33 months (22 months in median). Results: Before chemotherapy, 53 liver metastases were detected in the 6 patients. After chemotherapy, 29 (55%) lesions were not detected by preoperative CT or CEIOUS. All the 24 lesion, which were pointed out at the operation, were resected. By histological examination, no viable tumor cell was observed in 12 lesions (50%) among resected lesions. In follow up period, in situ recurrence occurred in 5 lesions (17%) in 4 patients. Three of the 4 patients underwent curative resection of re-detected liver metastases. Conclusions: It was reported that cancer cells remain over 80% of clinically disappeared lesion after conventional chemotherapy. In the present study, only 17% of disappeared lesion after mFOLFOX6 plus Bmab therapy caused in situ recurrence. With this result and a high pathological CR rate of the resected liver metastases after mFOLFOX6 plus Bmab therapy, it is speculated that complete resection for disappeared lesions after this chemotherapy is not always necessary.
Changing prognosis of metastatic colorectal adenocarcinoma (mCRC) 1988-2008 within the general population: Has everyone benefitted?
Authors: Lawrence Yaacov Richard , Golan Talia , Aderka Dan , Shani Adi , Zach Leor , Ben-David Merav A. , Gluck Iris , Rabin Tatiana , Pfeffer Raphael M. , Catane Raphael , Berger Raanan , Symon Zvi
Published: March 2020

e14143

Background: Between 1991 and 2008 the FDA approved 7 new drugs for the treatment of mCRC. The results of randomized phase III trials, performed on selected (e.g. younger) patient populations, may not reflect net benefit seen within the general population. We therefore performed a population-based survival analysis of patients who initially presented with mCRC. Methods: Survival statistics were extracted from the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with mCRC between 1988-2008. Survival was analyzed using the Kaplan-Meier method and proportional hazard models as appropriate. Exclusion criteria included diagnosis at autopsy, non-adenocarcinoma and unknown histology. Results: The study population consisted of 42,347 patients diagnosed with mCRC from 1988-2008, 52% female. Mean age 67 years; 46% were aged 70 or over. Prognostic variables included race, gender, age, marital status, disease site, surgical resection and year of diagnosis (for all p<0.001). For the entire population median OS improved from 8 months in 1988 to 14 months in 2007. Net improvement in OS was highly dependant upon age: for pts<50 yr OS improved from 9m to 21m; for pts 50-69 yr from 10m to 17m; for pts >=70 yr from 7 to 8m. Conclusions: There has been a continuous improvement in OS of patients diagnosed with mCRC between 1988 and 2008. We could not determine if this was due to new therapeutic agents or improved imaging leading to earlier diagnosis. Little improvement has been seen in patients >70 years age. The disparity in median OS between younger and older patients with mCRC over this period has widened from 2 months in 1988 to 13 months in 2008.
Cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative triple treatment for rectal cancer (CET-CAPOX-RT-Phase-I/II Study): Influence on long-term survival and relevance of biomarkers.
Authors: Liersch Torsten , Conradi Lena-Christin , Sprenger Thilo , Middel Peter , Sülberg Heiko , Rödel Franz , Rüschoff Josef , Beissbarth Tim , Arnold Dirk , Rödel Claus
Published: March 2020

e14162

Background: Preoperative application of cetuximab and radiochemotherapy combined with 5-FU+oxaliplatin (CET-CAPOX-RT-phase-I/II-study) failed to increase the complete remission rate (pCR, primary endpoint) in rectal cancers. Here, we report longterm survival in respect of biomarkers. Methods: In 45 of 53 patients (85%) total mesorectal excision (TME) was performed with curative intention. Disease-/progression-free survival (DFS/PFS) and overall cancer specific survival (CSS) were correlated with clinicopathological findings (e.g. tumor regression grading (TRG), KRAS-, HER-2-, Ki67-, EGFR-, IGF1R-, Src-, PTEN-, Survivin-, XIAP- and thymidylatesynthase(TS)-status). Results: After triple RCT, ypUICC stages were 0 (4x), I (17x), II (10x), III (14x) and IV (7x); RCT-induced T-level- (49%) and UICC-downcategorizing (53%) correlated with major (38% TRG 3-4) versus minor response (62.3% TRG 0-2) (p=0.005 and p=0.02, respectively). During follow-up (63 months) 7/53 patients with M1-status at surgery died. In 45 patients with M0-status no locoregional failure but in 5 patients metastatic recurrences were detected. DFS at 1, 3 and 5 years was 90.7% (CI: 82.5-99.8), 88.3% (CI: 79.2-98.5) and 88.3% (CI: 79.2-98.5); the CSS was 97.6% (CI: 93.1-100), 95.2% (CI: 89-100), and 90.3% (CI: 82-99.8), respectively. Patients with ypN0-status demonstrated better DFS (p=0.027), PFS (p=0.024) and CSS (p=0.016). KRAS mutations (33%) had no prognostic influence but a positive HER-2-status (18%) seemed to be associated with better CSS (p=0.11). High Ki-67-expression (p=0.09) as well as the loss of RCT-induced Survivin-downregulation (p=0.05) correlated with reduced CSS. No prognostic influence was found for EGFR-, IGF1R-, Src-, PTEN-, XIAP- and TS-expression. Conclusions: The disappointing pCR rate of the CET-CAPOX-RT-phase-I/II-study did not translate to poor longterm survival.
Early rise in blood pressure to predict clinical outcomes in metastatic colorectal cancer (mCRC) patients treated with first-line bevacizumab.
Authors: Upanal Nazeerahamad N. , Ackland Stephen P. , Bonaventura Antonino , McElduff Patrick
Published: March 2020

e14166

Background: Bevacizumab (Bev) induced hypertension (HTN) may be a predictive biomarker of anti-tumor activity in patients with metastatic colorectal cancer (mCRC) . We retrospectively assessed if significant rise in blood pressure (SRBP) [ ≥ 20 mmHg ] or any grade of HTN within first 10 weeks of treatment with bev is associated with improved clinical outcomes. Methods: Retrospective review of all mCRC patients, on or off clinical trial, treated with first line chemotherapy plus Bev (5 mg/kg Q2W or 7.5 mg/kg Q3W) at our institution from 2005-2010 was conducted .BP was measured before each treatment and graded according to CTCAE version 3.0.The median follow-up time of eligible patients was 19.6 months. Results: Of 50 patients eligible for the analysis, 20 patients (40%) developed significant rise in BP or HTN (SRH) whereas 30 patients had no change (NRH). There were no statistical differences between the two groups with respect to age, gender, ECOG status, number of sites of metastases, pre-existing HTN (55% SRH,37% NRH ; P=0.251) and first line chemotherapy regimen. Chemotherapy regimens used in SRH and NRH groups were 5-Fluoropyrimidine based (25% vs 23.3%), irinotecan based (40% vs. 36.7%) and oxaliplatin based (35% vs 30%). Four patients (20%) in the SRH group developed SRBP and other patients in this group developed G1-G3 HTN according to CTCAE v3.0.SRH group had improved median progression free survival (15.8 vs 6.2 months ; p<0.001) and overall survival (25.9 vs. 16 months; p=0.005). Overall response rate was higher in the SRH group (75% vs 26.7%; p=0.001). Conclusions: SRH developing within 10 weeks of commencing first line chemotherapy with bev correlates with improved outcomes in mCRC. These data need confirmation in prospective studies.
The morbidity of cytoreduction/hyperthermic intraperitoneal chemoperfusion (HIPEC) in the modern era.
Authors: Haslinger Michelle , Kane John Michael , Francescutti Valerie , Burke Rachel , Skitzki Jospeh J.
Published: March 2020

e14172

Background: Critics of cytoreduction/HIPEC for treatment of peritoneal surface malignancies cite high morbidity/mortality in historical published literature. With improved patient selection algorithms based upon recent clinical experience, perioperative morbidity/mortality should be comparable to the treatment of other GI malignancies. Methods: Retrospective data collection on all patients undergoing cytoreduction/HIPEC at a single institution (2 surgeons) from 2003-2011. Patient demographics, perioperative complications, mortality, and survival were analyzed (logistic regression modeling, Kaplan Meier, and Log rank testing). Results: 113 patients (45M/68F; median age 53 years) underwent 124 cytoreduction/HIPEC procedures. Primary tumor histology was colorectal adenocarcinoma (34%), appendiceal DPAM (24%), appendical adenocarcinoma (21%), mesothelioma (10%), and other (11%). 46% of patients received systemic chemotherapy prior to cytoreduction/HIPEC. Median HIPEC time was 12 hours (range 6 to 20 hours). All patients received mitomycin C at first HIPEC with 26% receiving a dose reduction. Median number of GI anastomoses was 1 (range 0-3). Median ICU stay was 1 day (range 0-21) and median length of stay (LOS) was 12 days (range 6-122). Major postoperative complications included wound infection (15%), anastomotic leak (11%), neutropenia (7%), pulmonary (5%), and thromboembolic events (2%). The reoperation rate for complications was 15%. Operative mortality at 30 and 60 days was 0% and 3%, respectively. As a surrogate for complications, LOS >14 days occurred in 24% of patients. Median follow-up was 25 months (1-80 months). Median progression-free and overall survival were 26.3 and 68.5 months, respectively. An anastomotic leak was associated with increased LOS, decreased progression-free survival (15.3 months, p< 0.05) and overall survival (15.3 months, p< 0.005). Conclusions: Despite being stage IV disease, perioperative morbidity/mortality for cytoreduction/HIPEC is comparable to surgical treatment of primary upper GI malignancies. Patient selection and meticulous technique may be critical to avoid anastomotic leaks associated with decreased survival.
Impact on overall survival and disease-free survival of adjuvant chemotherapy after neoadjuvant chemoradiotherapy for rectal cancer.
Authors: Castro Rafael amaral de , Paiva Carlos Eduardo , Saad-Hossne Rogerio , Michelin Odair Carlito , Souza Cristiano de padua
Published: March 2020

e14173

Background: Colorectal cancer is the second most common cancer with 2,4 million people diagnosed. The rectal cancer (RC) is 27% of these cases. Neoadjuvant chemoradiotherapy (NCRT) has become standard but brought controversy in the adjuvant treatment. The objective was to assess the impact of adjuvant chemotherapy after NCRT. Methods: Between mar/96 and Oct/2010, 84 patients received NCRT, and 58 patients underwent resection of the rectum. The NCRT consisted of 5-FU 350mg/m2, D1-D5 (50% of cases) or 5-FU 425mg/m2, D1-D3 (43%) with LV 20mg/m2 bolus in the 1st and 5th week of the 25 sessions of radiotherapy in linear accelerator (total 45 - 50 Gy). When performed, Adjuvant chemotherapy (ADJC) consisted of 5-FU 425mg/m2, LV 20mg/m2, both on D1-D5 for 4 cycles. Evaluation of Overall Survival (O.S) and Disease-Free Survival (DFS) performed using Kaplan-Meier curve in SPSS version 13.0 Results: Of the 58 patients who underwent surgery, 90% were stage II, 51% occurred in the lower rectum and 66% were ECOG 1. Pathologic Complete Response (PCR) was obtained in 25.8% (15) of patients (group 1). Of these, 20% (3) received ADJC. Patients without PCR (group 2) received ADJC in 51% of the cases (22). The mean follow-up was 41 months. Both the DFS (HR: 2.594, 95% CI: 1134-5938, p = 0.024) and OS (HR: 2.615, 95% CI: 1005-6807, p = 0.0488) were higher in patients with PCR independent of the use of ADJC. On the other hand, patient treated with ADJC vs without ADJC, independent of presence of PCR, did not alter DFS (p = 0.74) or OS (p = 0.32). In PCR patients, ADJC do not interfere in the outcome (DFS, p = 0.76; SG, p = 0.73). In group 2 (patients without PCR), the subgroup with ADJC, there was a trend towards better SLD (p = 0.06) and OS (p = 0.06). Those who did not receive ADJC in group 2 had worse SLD (p = 0.011) and OS (p = 0.028) compared with group-1. Conclusions: Adjuvant treatment after NCRT did not increase OS or DFS. Patients without PRC had worse results without ADJC, compared to those with PCR. The first, probably, the subgroup of patients who benefited most from the use of ADJC. PCR improves OS and DFS regardless of ADJC, being perhaps the group that does not deserve ADJC.
Colorectal cancer screening barriers.
Authors: Patel Monaliben , Malin Jessica , Headly Anna
Published: March 2020

e14175

Background: Colorectal cancer is the third cause of cancer death in the U.S., yet only 53% of adults over 50 are screened. Rates for minorities and patients without a high school education are lower. Colonoscopy may prevent 65% of cancers; identifying obstacles to screening could save lives. Our objective was to investigate obstacles and improve screening in Camden, NJ, a city that is 95% minority, only half of adults have completed high school, and 44% of families live below poverty level. Methods: In coordination with the American Cancer Society and Horizon Medicaid, we obtained data on Horizon enrollees at a primary care practice of Cooper University Hospital in Camden. All patients 50 and above with no insurance claims for screening in the last 10 years were included. 92 patients met criteria. We attempted to contact each by phone (via interpretation service if Spanish speaking). A standardized template was used to explain benefits of screening, ask for reasons for not having screening, offering transportation to the procedure, and asking if they were willing to have a colonoscopy. Patients who agreed were scheduled for colonoscopy. Results: 92 patients were identified. 30 could not be contacted after 3 attempts. Of 62 contacted, 12 agreed to colonoscopy; 25 stated they had already had screening; and 25 declined. Of 12 who agreed, reasons for not having had screening were: lack of awareness (6 patients, 5 Spanish speaking); not having transportation (3, 1 Spanish); and simply having put it off (3). Of 25 who declined, reasons were: desire to schedule themselves (8); the subject was too uncomfortable (4); mistrust of doctors (1); and being too scared (1). 10 (7 Spanish) gave no reason, and 1 had moved. Conclusions: Obstacles identified to colorectal screening were 1) lack of awareness (50% of patients who agreed to procedure); 2) transportation (25% of patients who agreed); 3) language barriers (83% of those who were unaware of recommendations were Spanish speaking); 4) fear/mistrust (8%); and 5) having lost contact with the system (33%). Efforts toward increasing screening should be targeted accordingly. We acknowledge the ACS and the Walmart Foundation for their participation and support. Findings and conclusions do not necessarily represent the views of ACS and the Walmart Foundation.
Clinical benefit rate (CBR) of panitumumab monotherapy among patients with KRAS wild-type metastatic colorectal cancer (mCRC).
Authors: Kennecke Hagen F. , Lim Howard John , Johal Balvindar Singh , Zulfiqar Muhammad , Speers Caroline
Published: March 2020

e14176

Background: Panitumumab (Pmab) improves progression free survival as first-, second- and third-line therapy for KRAS wild-type (wt) metastatic colorectal cancer (mCRC). Only in the third-line setting is there evidence of benefit of Pmab monotherapy. In this analysis of an exploratory biomarker study of Pmab monotherapy, the clinical benefit rate of Pmab according to previous lines of therapy is described. Methods: Patients (pts) with KRAS non-mutated, measurable MCRC previously treated with or ineligible for oxaliplatin/5-FU and irinotecan were treated with Pmab 6mg/kg IV q2w until progression or toxicity. The primary endpoint is clinical benefit rate (complete (CR) or partial response (PR) + prolonged stable disease (PSD) > = 24 weeks) by RECIST criteria. Results: The study completed accrual and (40) evaluable patients were treated between September 2009 and December 2011 of which 32 were evaluable for the primary endpoint. Median follow-up was 8.8 months, median age was 64.5 years and 90% were ECOG 0/1. Previous therapy was: 5-FU/Capecitabine(C) only in 12 pts, Irinotecan/5-FU/C only in 2 patients, Oxaliplatin/5-FU/C only in 3 pts, Oxaliplatin/Irinotecan/5-FU/C in 23 pts. 22 patients received prior Bevacizumab. Median number of cycles was 8 and 6 pts required a dose modification. There were 7 (22%) PRs and 7 (22%) pts experienced PSD >=24 weeks. Clinical benefit rate (PR+PSD) according to previous therapy was 33% (3/9) for 5FU/C only, 100% (2/2) Oxaliplatin/FU/C only, 0% (0/2) Irinotecan/FU/C only, and 47% (9/19) for Oxaliplatin/Irinotecan/5FU/C. Conclusions: Pmab monotherapy is well tolerated and response rates vary according to previous lines of therapy. Patients ineligible for irinotecan and/or oxaliplatin experience a high clinical benefit rate with single agent Panitumumab and should be considered for such therapy. Updated study results will be presented.
Feasibility analysis of mutational status of advanced colorectal cancer patients and correlation to disease progression.
Authors: Grissom Daniel , Wade Mark , Weis John R. , Boucher Kenneth M. , Sharma Sunil
Published: March 2020

e14177

Background: Mutational Analyses are being increasingly performed on colorectal cancer patients. More efforts are needed to correlate this data to clinical outcomes such as disease prognosis, metastasis, and tumor responsiveness to chemotherapy or targeted therapy. We assessed the mutational status of patients diagnosed with colorectal cancer in the GI oncology clinics of Huntsman Cancer Institute. Methods: We examined 46 patients diagnosed with colorectal cancer that had molecular profiling performed. To determine effectiveness of mutation analysis we compared the time to progression (TTP) of patients in correlation to KRAS or BRAF, PIK3CA and PTEN status. KRAS, BRAF and PIK3CA testing was performed by direct sequence analysis on genomic DNA isolated from a formalin-fixed paraffin-embedded tumor sample. Testing utilized custom primers designed to flank, amplify and sequence codons 12 and 13 in exon 2 and codon 61 in exon 3 of the KRAS gene, codons 464-469 of exon 11 and codon 600 of exon 15 in the BRAF gene located at 7q34, and codons 539-546 of exon 9 and codons 1043-1049 of exon 20 in the PIK3CA gene located at 3q26.3. PTEN expression was determined by immunohistochemistry. H-score of ≤10 was considered PTEN Low. Results: Of the patients reviewed there were 26 male, 20 female with a median age of 59 (23-81). 43 patients had metastatic disease and 3 patients had localized disease. Mutations found were 48% KRAS, 6% BRAF, 13% PIK3CA, 46% PTEN Low, 13% KRAS + PIK3CA, and 28% KRAS/BRAF + PTEN Low. In patients with KRAS/BRAF wild type (n=14), median TTP from diagnosis to starting first chemotherapy for metastatic disease was 365 days as compared to KRAS/BRAF mutant (n=21) of 182 days (p=0.008). This study could not detect any correlation between dual alterations in RAS with PI3 kinase pathway and TTP probably as a function of lower sample sizes. Conclusions: Our data supports association of KRAS and BRAF mutational status to TTP rates in colorectal cancer patients. Substantial numbers of patients have alterations in the PI3-Kinase pathway in combination with the RAS pathway. Continued testing of molecular mutational status is needed in order to improve these predictive models.
Clinical benefit of panitumumab after cetuximab failure in patients with metastatic colorectal cancer.
Authors: Haraldsdottir Sigurdis , Wu Christina Sing-Ying , Rose Jeffrey Scott
Published: March 2020

e14178

Background: Panitumumab (Pmab) is a fully humanized monoclonal IgG-2 antibody against epidermal growth factor receptor (EGFR). It was approved by the FDA in September 2006 as 3rd line therapy in metastatic colorectal cancer with disease progression on or following fluoropyrimidine (5-FU), oxaliplatin, and irinotecan chemotherapy regimens. Cetuximab (Cmab) is a chimeric monoclonal IgG-1 antibody and has been on the market since February 2004. It is unclear whether patients who have previously progressed on Cmab will benefit from therapy with Pmab. Methods: This is a retrospective analysis of 13 patients previously treated at OSUMC. The primary aim was to assess clinical benefit rate of Pmab in patients who failed Cmab. Patients were identified through our database from Sep 2006 until Dec 2011. Patient characteristics, length of treatment duration, response rate, and time elapsed from Cmab to Pmab were recorded. Clinical benefit (CR, PR, SD) was assessed by RECIST criteria. CEA was recorded. Results: Median age was 61 years (range 29-80), 8 males and 5 females. One patient had one FU-based line of chemotherapy while 12 patients had two FU-based lines of chemotherapy before starting Pmab. Five patients were KRAS wild-type, 8 were unknown. Five patients got Pmab as a single agent, 6 with FOLFIRI, 1 with irinotecan and 1 with capecitabine. Median time elapsed from stopping Cmab to starting Pmab was 4 months (range 0-25 months). One patient had a partial response to Pmab, 6 had stable disease, 2 had progressive disease and 4 patients did not have imaging studies. CEA decreased in 7 patients with mean decrease of 55% (SD +/- 34%). Median time to progression on Pmab was 5 months (range 1-13 months). Of 3 patients without clinical benefit to Cmab, 2 (67%) had clinical benefit from Pmab. Of 8 with clinical benefit to Cmab, 5 (63%) had clinical benefit from Pmab. Median duration of time from stopping Cmab to starting Pmab was similar for responders (3.5 months) and nonresponders (2.5 months). Conclusions: Our data suggest that Pmab can be given to patients previously treated on Cmab with clinical benefit seen in 2/3 of cases. Of interest, patients who did not have clinical benefit from Cmab did so with Pmab in 2/3 of cases.
Clinical mucositis and intestinal permeability abnormalities in metastatic colorectal cancer patients treated with irinotecan and 5-fluoruracil.
Authors: Gifoni Markus , Lima Roberto Cesar , Lima Aldo Angelo Moreira , Facanha Adriana , Callado Rodrigo Barbosa , Azevedo Carolina , De Albuquerque Ribeiro Ronaldo
Published: March 2020

e14183

Background: The comprehension of the mechanisms involved in the adverse events of the cytotoxic drugs available to treat metastatic colorctal cancer (CRC) is necessary to improve their efficacy and safety. The irinotecan, fluoruracil and folinic acid (IFL) bolus regimen have as its major toxicity issue the complex and multi-mediated gastrointestinal mucositis. Nevertheless, it is difficult to obtain a reliable measurement of the intestinal abnormalities and functional consequences caused by intestinal mucositis, as almost all the clinical data available are reported on a patient symptoms-based scale analysis. Methods: With the lactulose/ mannitol permeability test as the experimental platform, we did a prospective case control study with 25 metastatic CRC patients treated with first line IFL. The primary end point was to compare (Wilcoxon test) the lactulose/ mannitol permeability test before the treatment and the same patients tests at the 15th and 29th day of the first IFL cycle. Blood samples of the same individuals were obtained before the treatment and at 15th day of their first IFL cycle to compare the ELISA serum levels of potentially involved cytokines (TNFα, IL-1β, IL-6, IL-18, IL-18bp e IL-33) (paired t-test). Results: In contrast with the pretreatment controls, the lactulose/ mannitol ratio was significantly (p<0,05) increased at the D15 and D29 in patients taking the first IFL cycle. The mannitol excretion rate was also decreased (p<0,05) at the 29th day. This abnormalities also reserve significant (p<0,05 – Spearman coeficient) correlation with the diarrhea and abdominal pain symptoms (NCI-CTC version 4.0) scale reported by the patients. Otherwise, it has not been possible to demonstrate serum levels differences of the addressed cytokines before and after the treatment. Conclusions: The lactulose/ mannitol permeability test is an objective and reliable tool to measure intestinal permeability abnormalities secondary to gastrointestinal mucositis caused by IFL to metastatic CRC patients.This non-invasive test could bring more objetctive measurement of the functional consequences of this limiting toxicity.
Use of plasma level of 5-fluorouracil to predict the efficacy in patients with advanced gastric cancer receiving first-line capecitabine plus cisplatin.
Authors: Song Weifeng , Cai Xun , Li Xiaoyu , Wang Liwei
Published: March 2020

e14508

Background: Capecitabine is an oral 5-Fluorouracil prodrug that provided prolonged high levels of 5-FU within tumor cells and has improved efficacy and tolerability compared with protracted infusion 5-FU. The aim was to assess the value of plasma level of 5-Fluorouracil predicting the efficacy and safety in patients with advanced gastric cancer receiving first-line capecitabine plus cisplatin. Methods: The clinical data from 113 advanced gastric cancer patients receiving capecitabine plus cisplatin in Shanghai first people hospital from September 2006 to December 2009 were retrospectively collected. Fluorouracil plasma concentrations were examined at each cycle. The relationships between Fluorouracil plasma concentration and overall survival, progress free survival, response rate were determined by statistical analysis. Results: The mean plasma concentration was 24.8ug/L. We divided the patients with high mean 5-FU plasma concentration (> 25ug/L) into group A (n=59) and patients with low mean 5-FU plasma concentration (< 25ug/L) into group B (n=54). Median OS was 14.4 months in the group A and 9.6 months in the group B (HR= 0.36, p=0.000). Median PFS was 8 months in the group A and 4.9 months in the group B (HR= 0.37, p=0.000). The objective response rate was 55.9% for group A and 33.3% for group B (p=0.023). COX multivariate analysis showed that high 5-FU plasma concentration was an independent prognostic factors for improved OS (p=0.000) and PFS (p=0.000). All toxicities occurred more frequently in group A than group B. The grade 3/4 mocositis and hand-foot syndrome were significantly increased in group A compared with group B (19% vs 9%, p=0.08; 22% vs 8%, p=0.036). Conclusions: In advanced gastric cancer, high 5-FU plasma concentration might predict efficacy and toxicities for capecitabine plus cisplatin chemotherapy.
Sensitization of hepatocellular carcinoma (HCC) to tigatuzumab (CS-1008), a humanized anti-DR5 antibody, by sorafenib and its derivative SC-49.
Authors: Chen Kuen-Feng , Chen Hui-Ling , Shiau Chung-Wai , Liu Chun-Yu , Tai Wei-Tien , Ichikawa Kimihisa , Chen Pei-Jer , Cheng Ann-Lii
Published: March 2020

e14516

Background: Previously, we have shown that sorafenib sensitizes HCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Here, we report the effects of sorafenib and SC-49, a sorafenib analog, on sensitizing HCC cells to tigatuzumab, a novel antihuman death receptor 5 (DR5) antibody. SC-49 is a sorafenib derivative that is devoid of kinase inhibition activity. Methods: HCC cell lines (Huh-7, PLC5, and Hep3B) were treated with tigatuzumab and/or sorafenib or SC-49 and analyzed in terms of apoptosis and signal transducers. Effects of tigatuzumab and SC-49 on HCC xenograft tumor growth were also evaluated. Results: Our data indicated that sorafenib, as well as SC-49, down-regulated the phosphorylation of signal transducers and activators of transcription 3 (p-STAT3) at Tyr 705 and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cycin D1, in tigatuzumab-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to tigatuzumab in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of sorafenib or SC-49 on tigatuzumab-induced apoptosis, indicating that inhibition of STAT3 mediates the effects of the combination. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and tigatuzumab on p-STAT3 and apoptosis, whereas co-treatment of tigatuzumab and SC-49 increased the activity of SHP-1, suggesting that SHP-1 mediated the combinational effect of tigatuzumab and SC-49 in HCC. Moreover, the in vivo combination of tigatuzumab and SC-49 inhibited HCC xenograft tumor growth. Conclusions: Sorafenib, SC-49 and tigatuzumab induce apoptosis and inhibit tumor growth in HCC through SHP-1-dependent STAT3 inactivation.
Association of the simultaneous expression of ephrin B3 receptor and E-cadherin in Barrett's adenocarcinoma with favorable clinical staging.
Authors: Schauer Matthias , Stoecklein Nikolas , Baldus Stephan , Feith Marcus , Hoelscher Arnulf , Kroepil Feride , Budach Wilfried , Matuschek Christiane , Boelke Edwin , Knoefel Wolfram Trudo
Published: March 2020

e14527

Background: In intestinal epithelium tyrosine kinase receptor Ephrin B3 maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Ephrin B3 is linked to colorectal cancer initiation, overexpression of Ephrin B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Ephrin B3 in esophageal adenocarcinoma we analysed the simultaneous expression of Ephrin B3 and E-cadherin in healthy esophagus and Barrett’s carcinoma. Methods: Simultaneous expression was investigated in samples of 141 patients with Barrett’s carcinoma and of 20 healthy esophagi. For analysis immunhistology and quantitative PCR was used. Results of healthy squamous epithelium, Barrett’s metaplasia and staging specific esophageal adenocarcinoma were correlated. Results: A significantly reduced E-cadherin mRNA activity in adenocarcinoma compared to dysplasia could be detected. Immunhistological activity of E-cadherin and Ephrin B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when Ephrin receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Ephrin B3 showed a significant inverse correlation to tumorstage. Conclusions: We present first evidence of the tumor suppressor activity of Ephrin B3 receptor in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma-sequence, the infiltrative growth pattern and the development of lymph node metastases.
RSF-1/HBXAP to predict prognosis in HBV-related hepatocellular carcinoma patients after curative resection.
Authors: Xu Yang , Fan Jia , Anders Robert , Guan Bin , Zhu Qingfeng , Shih Le-Ming
Published: March 2020

e14538

Background: Remodeling and spacing factor 1(Rsf1, or HBXAP) was demonstrated consistent overexpression in several solid tumors and could be a prognostic marker, while its role in hepatocellular carcinoma (HCC) is still unclear. We try to illustrate the prognostic significance of RSF1 and its mechanism in HBV related HCC patients. Methods: RSF1 expressions were detected in tumor tissue microarrays of 254 HCC patients who underwent curative surgical resection during 2/2004 to 12/2005. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. The effects of RSF1 on cell proliferation and migration were tested in RSF1 knockdown and inducible HCC cells. Related genes were screened by cDNA Microarray and then confirmed by qRT-PCR and werstern blot. Results: RSF1 expression in HCC tissues was significantly related to replase of tumor in HCC patients after curative resection, and significantly related to MMP9 and HBV infection. Knockdown (or over-express) of RSF1 in HCC cells significantly inhibited (or enhanced) HCC proliferation and invasion in vitro. RSF1 controlled the expression of MMP9 in HCC cells. Conclusions: RSF1 up-regulates MMP9 and predicts poor prognosis in HBV related HCC patients after curative resection.
Prognosis of adenosquamous carcinoma of the pancreas: A matched case-control study.
Authors: Imaoka Hiroshi , Yamao Kenji , Hijioka Susumu , Hara Kazuo , Mizuno Nobumasa , Tanaka Tsutomu , Kondo Shinya , Tajika Masahiro , Ogura Takeshi , Obayashi Tomohiko , Niwa Yasumasa , Shimizu Yasuhiro
Published: March 2020

e14540

Background: Adenosquamous carcinoma of the pancreas (ASC), which accounts for only 1-4% of exocrine pancreatic malignancies, is a variant of pancreatic ductal adenocarcinoma (PDAC). However, the prognosis of ASC is still unclear because these reports were based on only case studies and small surgical series with early stage cancers. The purpose of the present study was to clarify the prognosis of ASC using a matched case-control study. Methods: Pathological and clinical records of ASC cases between 2001 and 2011 in our institution were examined. All ASC cases were diagnosed pathologically by a surgical or endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimen. First, to examine the efficacy of EUS-FNA for the diagnosis of ASC, the pathological findings of EUS-FNA were compared with the surgical findings in the resected cases of ASC. Next, to clarify the prognosis of ASC, the clinical characteristics of ASC were evaluated. As a control group, PDAC cases matched with ASC cases by sex, age, pretreatment ECOG-PS, location, initial therapy, and the AJCC TNM staging for pancreatic cancer were also included in this study. Results: Of the 914 cases of pancreatic neoplasms, 28 cases of ASC were identified (3.06%), and 56 cases of PDAC were matched as controls. Of 28 cases of ASC, 6 cases underwent curative resection, and 22 cases were unresectable. Of the 6 resected cases of ASC, 5 cases were diagnosed preoperatively by EUS-FNA (κ, 0.83; positive predictive value [PPV], 100%). Overall survival (OS) was significantly worse for ASC than for PDAC, with a hazard ratio (HR) of 1.94 (95% CI, 1.07 to 3.51; p=0.026; median 8.38 months vs. 15.75 months). Of the 22 unresected cases, the OS of ASC was significantly worse than that of PDAC, with an HR of 2.39 (95% CI, 1.27 to 4.51; p=0.007; median 4.67 months vs. 12.36 months). Conclusions: In the present study, EUS-FNA had a high PPV for the diagnosis of ASC, and ASC was found to be more aggressive than PDAC.
Factors associated with octreotide LAR use among elderly patients with carcinoid syndrome: A population-based analysis.
Authors: Shih Ya-Chen T. , Xu Ying , Leary Colleen , Yao James C.
Published: March 2020

e14549

Background: Octreotide LAR is indicated for the treatment of carcinoid syndrome, diarrhea related to VIPoma, and may delay tumor growth in neuroendocrine tumors (NETs). The pattern of octreotide LAR use in clinical practice has not been well documented. Methods: Using the SEER-Medicare database, we identified patients diagnosed with NETs from July 1999 to Dec 2007. We then excluded those patients with poorly differentiated histology, under age 65 at diagnosis, enrolled in HMOs, and who did not have continuous Part A & B enrollment within 12 months of diagnosis. We further identified patients with potential indication for octreotide LAR use as those having two or more claims indicating carcinoid syndrome, flushing, diarrhea, or malignant islet cell neoplasm within the first year of NETs diagnosis, with the first claim occurring within 6 months of diagnosis. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR use. Multivariate logistic regression analysis was performed to ascertain factors associated with octreotide use; covariates included age, race, region, comorbidity score, urban/rural status, tumor characteristics, neighborhood socioeconomic status and year of diagnosis. Results: Of the 2000 NETs patients with potential indication for octreotide LAR use, 478 (23.9%) were started on octreotide LAR within 6 months of diagnosis. Multivariate analysis showed that older age (≥ 80) (OR=0.61, 95 CI=0.44 – 0.86), southern region (OR =0.67; 95% CI =0.44 – 1.00) and tumor of undetermined grade (OR=0.71, 95% CI=0.52 – 0.98) were associated with lower odds of octreotide use while the odds was positively associated with advanced stage and more recent diagnosis years. By primary site, no clear pattern was identified. Conclusions: Our analyses suggest only a small (< 25%) fraction of patients with eligible diagnoses are receiving indicated therapy with octreotide LAR. Further studies and improved education are needed to improve the management of carcinoid syndrome.
A prospective phase II trial of a S-1/cisplatin-based chemoradiotherapy for locoregionally advanced esophageal cancer.
Authors: Cho Byoung Chul , Chang Hyun , Lee Yong Chan , Kim Dae Joon , Yun Mi Jin , Shin Sung Kwan , Kim Hyun Ki , Kim Han Sang , Lim Sun Min , Kim Joo-Hang
Published: March 2020

e14559

Background: Concurrent chemoradiation has similar efficacy as surgery for esophageal cancer. Phase II trial was carried out to evaluate the efficacy and safety of chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer. Methods: Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1 to 14 and 22 to 35) and cisplatin (day 1 and 22) with concurrent radiotherapy (50.4 Gy total: 1.8 Gy/fraction). Esophagectomy was performed between week 12 and 18 as determined by the specialist multidisciplinary team meeting. Results: Sixty patients were enrolled between March 2008 and August 2011. Of the 60 patients entered, 59 patients were eligible. Clinical stage was ≥T3 in 28 patients (47%) and N1 in 43 patients (73%), with squamous cell carcinoma histology in 57 patients (97%). Fifty-four patients (90%) completed the planned treatment. After the chemoradiation, clinical tumor response rate was 62.7%. The primary grade 3/4 toxicities included neutropenia (24%) and esophagitis (8.5%). All three patients died during chemoradiation (two from pneumonia and one from gastrointestinal origin septic shock). Twenty-five patients (42%) underwent esophagectomy following chemoradiation and 15 (60%) achieved complete pathologic regression. At the median follow-up duration of 34.6 months, the estimated overall survival and progression-free survival rate at 2-year was 56.5% and 45.9%, respectively. Conclusions: Concurrent chemoradiation with S-1 and cisplatin showed an encouraging activity with high complete pathologic regression. Survival data was promising compared with historical data with 5-FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.
A phase II trial of JX-594, a targeted multimechanistic oncolytic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Heo Jeong , Breitbach Caroline , Cho Mong , Hwang Tae-Ho , Kim Chang Won , Jeon Ung Bae , Woo Hyun Young , Yoon Ki Tae , Lee Jun Woo , Burke James , Hickman Theresa , DuBois Kara S , Longpre Lara , Patt Richard H. , Kirn David H.
Published: March 2020

e14566

Background: JX-594 is a targeted oncolytic vaccinia virus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ ras pathway activation. Direct oncolysis plus GM-CSF expression is accompanied by tumor vascular disruption and anti-tumoral immunity (Reviewed in Nat Rev Cancer 2009). JX-594 was well-tolerated intravenously (IV) (Nature 2011) and intratumorally (IT) (Lancet Oncol 2008). Complementary anti-tumor effects are predicted with JX-594 followed by sorafenib due to acute vascular disruption effects with JX-594 and anti-angiogenic effects with sorafenib. Methods: Treatment-refractory HCC patients received JX-594 for three weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib. An IT boost dose of JX-594 at Week 12 was optional. The primary objective of the study was to determine the safety of JX-594 followed by sorafenib in patients with advanced HCC. Secondary objectives include disease control rate (DCR) based on mRECIST and/or Choi response criteria at Day 6 (optional), Day 25 (after JX-594 only), 6 and 12 weeks. Results: Twenty (20) patients were treated in this study; fifteen (15) were refractory to sorafenib. The sequential treatment regimen was well-tolerated. Transient flu-like symptoms (Grade 1-2) and transient leukopenia (lymphopenia, neutropenia) were the most common adverse events following JX-594 therapy. Sorafenib toxicities were consistent with the expected toxicity profile. At the time of this interim analysis, thirteen patients were evaluable for radiographic response by Choi criteria (mRECIST pending). After JX-594 alone at Day 25, 10 of 13 evaluable patients (77%) had Choi tumor responses (range 19-48% reduced enhancement). Following subsequent sorafenib therapy, 11 of 13 patients (85%) had Choi responses at Week 6-12, including 9 of 10 (90%) sorafenib-failure patients. Conclusions: JX-594 was well-tolerated and associated with Choi tumor responses following IV and IT injections in patients with advanced HCC. Subsequent sorafenib was associated with the expected toxicity profile. Further trials of JX-594 in HCC patients are warranted.
Fluorodeoxyglucose positron emission tomography for evaluating early response during neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.
Authors: Lin Chia-Chi , Hsu Chih-Hung , Tzen Kai-Yuan , Cheng Jason C. , Lee Jang-Ming , Wang Hsiu-Po , Huang Pei-Ming , Hsu Feng-Ming , Chen Wei-Wu , Huang Ta-Chen , Cheng Ann-Lii
Published: March 2020

e14576

Background: To determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could differentiate between responding and non-responding locally advanced esophageal squamous cell carcinoma (ESCC) early in the course of neoadjuvant chemoradiotherapy (CRT). Methods: Patients (pts) with T3 or N1M0-1a (AJCC, 6th Ed) ESCC first received a 21-D cycle of induction chemo (paclitaxel 70 mg/m2 D 1, 8; cisplatin 30 mg/m2 D 1, 8; fluorouracil 2000 and leucovorin 300 mg/m2 24-hr D 1, 8). This was followed by concurrent CRT (paclitaxel 35 mg/m2 1-hr D 1, 4 /wk, cisplatin 15 mg/m2 1-hr D 2, 5/wk, and radiotherapy 2 Gy D 1-5 /wk) (Lin CC, et al. Ann Oncol 18:93,2007). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated. In pts for whom esophagectomy was not feasible, concurrent CRT was continued to a dose of ≥60 Gy. Serial FDG-PETs were performed before and 14 days after start of induction chemo. Pathologic response (PR) was defined as no or microscopic residual disease. PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of SUV in distinguishing between PR and non-PR. Results: Of 65 pts (M:F = 60:5, median age 55, range 39-71) with locally advanced (M0:M1a = 58:7) ESCC enrolled from March 2008 to December 2011, 40 pts underwent esophagectomy and 26 pts were pathologic responders. The median SUV decrease 14 days after the start of therapy was 75.8% for pathologic responders and 30.1% for non-responders (p <0.05). In ROC analysis, the area under the curve was 0.70 (95% CI = 0.55-0.86). Using a 35% SUV decrease cutoff value, PET correctly identified 24 of 26 responders (sensitivity 92%) and 8 of 14 non-responders (specificity 57%). The corresponding positive and negative predictive values were 80% and 80%, respectively. Conclusions: A 35% SUV decrease 14 days after the start of induction chemo is significantly associated with PR, but its accuracy in detecting non-responders is too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant CRT in pts with locally advanced ESCC.