bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized study on lipiodal ethanol mixture (LEM) versus transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC): Report of a preplanned interim analysis.
Authors: Chan Stephen Lam , Hui Joyce , Yeo Winnie , Hui Edwin P. , Mo Frankie , Ma Brigette , Chan Anthony T. C. , Yu Simon
Published: March 2020

e14528

Background: Transarterial injection of LEM produces long-lasting embolization of both arteriolar feeders and peribiliary plexus of HCC leading to infarction of tumor. Our group previously reported the efficacy and safety of LEM for HCC in a phase II clinical trial (Yu et al. J Vasc Interv Radiol. 2008). We initiated a randomized study to compare LEM vs. TACE in HCC. (NCT00467974). Methods: Major eligibility criteria: histologically confirmed HCC; unresectable disease without distant metastases; size ≤15cm; absence of portal vein thrombosis. Consented patients (Pts) were randomized into LEM vs. TACE stratified by tumor size and number. Pts were prospectively followed up and assessed with computed tomography (CT) every 8 weeks. The primary endpoint is overall survival (OS) and secondary endpoints include progression free survival (PFS), RECIST response rate (RR) and toxicity. An interim analysis is planned after recruitment of 70 pts. Results: From 07 to 10, total 70 pts were enrolled. 2 pts withdrew consent and were excluded from the analysis. There were no differences in baseline characteristics between LEM and TACE. Male:Female=53:15; Mean Age=64; Tumor size≤7: >7cm=45:23; Child A:B=55:13. The median follow-up was 2.3 years. The OS of LEM was 25.32 months(m) vs. TACE 22.56m (p=0.38). PFS of LEM was 9.00m vs. TACE 7.8m (p=0.50). Partial response of LEM vs. TACE was 30% vs. 18% (p=0.52); disease control rate of LEM vs. TACE was 80% vs. 70% (p=0.39). Commonest G3 or above toxicities include ALT elevation (LEM 22.2% vs. TACE 9.4%); hyperbilirubinemia (LEM 19.4% vs. 9.4%); pain (LEM 0% vs. TACE 4%). Except pain, there were no differences of toxicities between LEM and TACE after procedure (p=0.04). Conclusions: At interim analysis, LEM showed comparable efficacy and toxicity profile to TACE. A trend of better OS, PFS and RR was observed in LEM arm but statistically insignificant. Further accrual and follow-up is ongoing.
Impact of up-to-seven criteria and neutrophil-to-lymphocyte ratio in liver transplantation for patients who received pretreatment for hepatocellular carcinoma.
Authors: Yoshizumi Tomoharu , Ikegami Toru , Yoshiya Shohei , Motomura Takashi , Mano Yohei , Muto Jun , Matono Rumi , Toshima Takeo , Ikeda Tetsuo , Soejima Yuji , Shirabe Ken , Maehara Yoshihiko
Published: March 2020

e14536

Background: There is currently no consensus on how to manage patients with hepatocellular carcinoma (HCC) while awaiting liver transplantation (LT). The guideline published in UK states that locoregional therapy should be considered for all listed patients with HCC. Living donor LT (LDLT) is a choice for treating HCC patients in organ shortage era. The aim of the present study is to clarify the risk factors of tumor recurrence after LDLT in patients who had received pre-transplant treatments (pre-Tx) for HCC. Methods: One hundred two adult patients (39 females and 63 males) who had undergone LDLT due to end-stage liver disease with recurrent HCC after pre-Tx were enrolled. The primary end-point of this study was HCC recurrence after LDLT. Recurrence-free survival rates after LDLT were calculated. Risk factors of tumor recurrence were identified using univariate and multivariate analysis. Results: The 1-, 3-, and 5-year recurrence-free survival rates were 89.4%, 80.7%, and 78.8%, respectively. Seventy-four of 102 patients underwent pre-Tx more than twice. Moreover, the times of pre-Tx, the interval between the first treatment and LDLT, and the interval between the last treatment and LDLT did not affect the outcome of LDLT. On univariate analysis, the factors affecting recurrence-free survival were exceeding the up-to-seven criteria (p<0.0001), exceeding the Kyushu University criteria (p<0.0001), neutrophil-to-lymphocyte ratio (NLR) > 4 (p=0.0001), Alpha-fetoprotein > 400 ng/ml (p<0.0001), and bilobar tumor distribution (p=0.047). A multivariate analysis identified independent risk factors for post-LDLT tumor recurrence were exceeding the up-to-seven criteria (p=0.001) and NLR > 4 (p=0.002). The 1- and 3-year recurrence-free survival rates in the recipients with exceeding the up-to-seven criteria and NLR > 4 were 30.0% and 15.0%, respectively. Conclusions: The kind or duration of pre-Tx did not affect the outcome of LDLT, but LDLT should not be performed for the patients with exceeding the up-to-seven criteria and NLR more than 4 after pre-Tx for HCC to prevent tumor recurrence.
Comparison of adjuvant chemoradiation to peri-operative chemotherapy for the treatment of resected gastric and gastroesophageal junction adenocarincoma.
Authors: Kim Hae Rin , Kollmannsberger Christian K. , Schellenberg Devin , Cheung Winson , Lim Howard John
Published: March 2020

e14537

Background: Currently there are several accepted peri-operative treatment modalities for the resected gastric (GC) and gastroesophageal junction (GEJ) adenocarcinoma. In the 2008, peri-operative chemotherapy (CRT) using the MAGIC was adopted as the preferred approach to adjuvant chemoradiation with the MacDonald protocol (cXRT) in the British Columbia. An era to era comparison was performed to determine if there were differences in outcomes. Methods: Data from the pharmacy records of patients (pts) referred to 1 of 5 cancer treatment in BC were analyzed from 2001- July 2010. Pts that underwent curative resection for GC or GEJ were only included. cXRT cohort was defined from Jan 2001-Dec 2007, prior to the CRT era. CRT cohort started from Jan 2008-July 2010. Descriptive statistics were used to compare the groups. Survival analysis was performed using Kaplan Meier methods. Results: Table 1 summarizes the patient characteristics. In the CRT arm, there were more males, less pts with a LN ratio >0.2 and shorter median follow-up. 92.1% completed the pre-op chemotherapy and 44.7% completed post-op chemotherapy whereas 73.3% of pts completed cXRT (p<0.05). 1 yr survival was similar between the 2 cohorts. Median overall survival was not reached in the CRT arm and was 64.1 months in the cXRT arm. Conclusions: Delivery of CRT was similar to that in the MAGIC trial. Outcomes of CRT compared to cXRT appears to be similar in this cohort to cohort study with similar 1 yr survival. Pre-operative CRT results in less pts with a LN ratio > 0.2. Further follow-up is needed with respect to relapse and overall survival. Either modality can be considered for peri-operative management of GC or GEJ adenocarcinoma. [Table: see text]
Prognosis significance of HER2/neu overexpression and amplification in patients with curatively resected gastric cancer.
Authors: Zhou Fei , Li Ning , Hua Zhaolai , Xia Lin , Wang Liwei
Published: March 2020

e14539

Background: HER-2/neu targeted therapy has been successfully used in advanced gastric cancer, but the role of HER-2/neu inprognosis of gastric cancer is not yet clear. To investigate the correlation between HER-2/neu expression and amplification and their associations with clinicopathologic outcomes and prognosis in patients with curatively resected gastric cancer. Methods: We constructed tissue microarray blocks containing >70% of gastric cancer tissue and matched adjacent normal gastric tissue for 229 patients. Expression of the HER-2/neu protein in these specimens was analyzed using immunohistochemical (IHC) staining. Amplification of HER-2/neu was also analyzed for the same samples using fluorescence in situ hybridization (FISH). Kaplan Myers curve and Cox proportional hazards model were used to assess the survival. Results: Of the 229 gastric cancer samples, 14.85% were positive for HER-2/neu protein expression that was closely correlated to the Lauren type, degree of differentiation, tumor size, lymph node metastasis and overall survival. Overall, 11.79% of the 229 gastric cancers were positive for amplification of HER-2/neu, which was also closely correlated to the Lauren type, degree of differentiation, tumor size and overall survival. Moreover, Cox proportional hazards model showed that positive expression of HER-2/neu, Lauren type, tumor size, vessel invasion, TNM stage were independent prognostic factor. Both IHC and FISH assays provide an important prognostic factor for gastric cancer with a concordance rate of 96.9%, but IHC was a stronger independent prognostic factor. Conclusions: Expression of the HER-2/neu protein, compared with its gene amplification, was an independent and more sensitive prognostic factor for curatively resected gastric cancer patients.
Description of initial treatment for newly diagnosed metastatic carcinoid (cNET) and pancreatic neuroendocrine (pNET) patients.
Authors: Bobiak Sarah , Choti Michael A. , Benson Al B. , Strosberg Jonathan R. , Bloomston Mark , Bergsland Emily K. , Zornosa Carrie C. , Kulke Matthew , Nakakura Eric K. , Shah Manisha H. , Yao James C.
Published: March 2020

e14542

Background: There is limited descriptive information regarding treatment (tx) patterns for NET from clinic practice data. The primary aim of this analysis was to describe initial tx among NET pts as a first step in understanding tx patterns for NET. Methods: The National Comprehensive Cancer Network (NCCN) Oncology Outcomes Database was queried to identify newly diagnosed pts presenting to 7 NCCN institutions with a confirmed metastatic cNET or pNET diagnosis in 2004 or 2005. Pts with a minimum of 5 years of follow up or confirmed death were included in the analysis. Pt demographics, clinical characteristics, initial tx, and 5-year survival were described. Results: Among 187 cNET pts, 52% were male, median age at diagnosis was 58, and 51% alive. Approximately 58% had a known primary tumor; 65% of which were in the small bowel. Most cNET pts (85%) presented with symptoms, 33% had carcinoid syndrome. Initial tx included surgical therapy in 43%, drug therapy in 41%, and other therapies in 16%. The majority (82%) had imaging prior to treatment, among which 79% had a CT scan and 35% had somatostatin receptor scintigraphy (SRS). The most frequent biomarker test was for CGA (performed in 64 pts, elevated in 53). Of 76 cNET pts receiving initial drug therapy, 82% were treated with a somatostatin analog (SA); others received chemotherapy or targeted therapy. Kaplan-Meier (K-M) curves indicated a 5-year survival of 62% and 56% among pts receiving surgery or drug therapy as initial tx, respectively. Among 104 pNET pts, 61% were male, median age at diagnosis was 54, and 41% alive. Approximately 82% presented with symptoms among which 25% were hormone related. Among the 84% of pts imaged prior to treatment, CT scan was most common (79%) and 38% had SRS. The most common initial tx among pNET pts was drug therapy (56%); 60% received a SA; 31% received chemotherapy. Only 25% underwent surgery as initial tx. K-M curves indicated a 5-year survival of 63% among surgical pts in contrast to 31% for pts whose initial tx was drug therapy. Conclusions: Initial tx among the majority of pts was either surgery or drug therapy. Among cNET and pNET pts receiving drug therapy, 82% (n=62) and 60% (n=35) respectively, received an SA.
Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer (ca).
Authors: Chang Kenneth J. , Senzer Neil N. , Binmoeller Kenneth , Goldsweig Howard , Coffin Robert
Published: March 2020

e14546

Background: T-VEC is an investigational, immune-enhanced oncolytic herpes simplex virus type I that selectively replicates in solid tumors. This was an open-label, dose-escalation study of T-VEC administered by endoscopic ultrasound (EUS)-guided fine needle injection (FNI) for advanced pancreatic ca. Methods: Eligibility criteria included ≥ 18 yrs old, ECOG 0-2, pathologically confirmed pancreatic ca with measurable disease (tumors ≥ 1 cm dia), and failure or unable to receive standard tx. T-VEC was administered at wks 6, 12, 18 to a single pancreatic tumor in 4 cohorts (C), 3 pts each enrolled sequentially (extended dosing allowed in pts thought to have benefit): C 1: 1 dose of 104 PFU/mL then 2 of 105 PFU/mL; C 2: 1 dose of 105 PFU/mL then 2 of 106 PFU/mL; C 3: 1 dose of 106 PFU/mL then 2 of 107 PFU/mL; C 4: 1 dose of 106 PFU/mL then 2 of 108 PFU/mL. 2 doses/pt were required for enrollment to the next C. A C could be expanded to 6 if 1 related DLT occurred. If 2 DLTs occurred, dose escalation was stopped. Endpoints were safety and activity as assessed by CT tumor dia changes from screening. Results: 17 pts were enrolled in C 1-3 given at least 1 dose of T-VEC; 65% were men; median age 54; 76% white, ECOG 0-1 82%. C 4 was not opened because of early study termination (not related to safety). 7/17 (41%) received all 3 planned doses and 8 (47%) had at least 1 post-dose CT scan. Only C 3 showed a median decrease in injected tumor dia with 2/4 pts achieving substantial tumor reductions (-36% and -33%). 3 pts (in C 1and C 3) showed decreases in the dia of ≥ 1 uninjected tumors (in liver, pancreas, kidney, and chest); 1 pt had disappearance of a nonmeasurable tumor in the liver. A dose trend was not observed for reductions of uninjected tumors. Most common AEs were ascites (47%), dehydration (41%), anemia, abdominal pain, constipation, and nausea (each 35%), and vomiting (29%). 2 pts (12%) had a grade 5 AE, both considered unrelated to T-VEC. Conclusions: EUS-guided FNI of T-VEC in advanced pancreatic ca, at initial doses of 104 to 106 PFU/mL followed by up to 107 PFU/mL, was feasible and tolerable. Evidence of biologic activity was observed. Future studies should be conducted in pts with less advanced disease, to allow sufficient time to receive multiple doses before PD.
Bevacizumab plus temsirolimus as second-line treatment for advanced hepatocellular carcinoma (HCC).
Authors: Chelis Leonidas , Deftereos Savas , Xenidis Nikolaos , Amarantidis Kiriakos , Hamalidou Eleni Kyrillos , Dimopoulos Prokopios , Michailidis Prodromos , Christakidis Evagelos , Mimidis Kostantinos , Pitsiava Dimitra , Karayiannakis Anastasios , Kakolyris Stylianos
Published: March 2020

e14567

Background: The mTOR pathway has a central role in HCC not only in the tumor growth but also in the insulin driven hepatocarcinogenesis and is reported activated in 40-50% of HCC patients. Temsirolimus is an mTOR inhibitor with proven efficacy in renal cell carcinoma. The angiogenesis inhibitor bevacizumab has shown promising activity in HCC. Sorafenib represents the only drug with proven efficacy in HCC but currently there is no standard 2nd line treatment for patients who progress on sorafenib. Therefore, we performed a phase II study to determine the activity of a bevacizumab plus temsirolimus combination in second-line HCC. Methods: Patients who had progressed on sorafenib were eligible. Other eligibility criteria included ECOG PS 0-2 and Child- Pugh score A. The combination consisted of bevacizumab 10 mg/Kg plus temsirolimus 25 mg (total dose) given i.v. biweekly. After the enrolment of the 1/3 of the preplanned 40 patients (n=13) an interim analysis had to be performed to evaluate biologic activity. Biologic activity was defined either as a partial response by RECIST criteria or a > 50% decline in AFP in at least 2 of 13 patients. An expanded panel of possible biomarkers of response including VEGF, HGF, FGFb, TSP-1 and others, were measured at baseline. Results: The median age of the first 13 patients was 67 years (53-79 years) . The patients performace status was 0 (n=3), 1 (n=4) and 2 (n=6) and 11 of 13 patients had extrahepatic disease. Four patients had radiographic partial responses and five patients had > 50% reduction in AFP. Seven patients (53,8%) showed bioactivity. It is of note that two of them experiencing durable and long lasting partial remissions of 20 and 16 months respectively are still on treatment. One patient developed reversible posterior leycoencephalopathy syndrome (Grade 4 ) and one grade 4 hypertension. Grade 3 non-hematologic toxicities included hyperglycemia (n=3), hyperlipidemia (n=2), diarrhea (n=2) and infection (n=2). Conclusions: The combination of bevacizumab plus temsirolimus is well tolerated with encouraging activity. The study's preplanned criteria for activity have been met and the study continues accrual.
A multicenter random assignment phase II study of irinotecan and flavopiridol versus irinotecan alone for patients with p53 wild-type gastric adenocarcinoma (NCI 8060).
Authors: Janjigian Yelena Yuriy , Tang Laura H. , Shibata Stephen , Kelsen David Paul , Segal Michal , Cheng Catherine , Schwartz Gary K. , Doyle L. Austin , Shah Manish A.
Published: March 2020

e14586

Background: Preclinical studies demonstrate that tumors wild-type for p53 (p53wt) are refractory to irinotecan relative to non-functional or mutant p53, and that sequential therapy with flavopiridol, a cyclin dependent kinase inhibitor that inhibits homologous recombination and DNA repair, and irinotecan overcomes p53 mediated drug resistance in vivo. This phase II study is designed to assess cell cycle mediated drug resistance in p53wt gastric cancer, and test the hypothesis that administration of flavopiridol following irinotecan can overcome resistance to irinotecan. Methods: Pts with advanced p53wt (≤ 20% nuclear IHC staining using D07 antibody) gastric adenocarcinoma and disease progression on non-irinotecan chemotherapy regimen were randomized in 2:1 fashion to irinotecan 100 mg/m2 followed 7 h later by flavopiridol 60 mg/m2 administered over 1h or irinotecan 100 mg/m2 administered weekly on a 2 week on/1 week off schedule. Response assessment is performed every 2 cycles and the primary endpoint is 3-month progression free survival (PFS). Pre- and post-treatment biopsies were obtained for molecular assessments of p53 mediated drug resistance. Results: To date 30 of 55 patients screened were p53wt (54%), 19 pts were randomized to receive irinotecan + flavopiridol (n=13) and irinotecan (n=6). Median characteristics of 19 evaluable patients: age 61 (44 to 76), KPS 80% (70 to100), 13 male, 1 prior regimen (1 to 2). The common treatment emergent toxicities were anemia (Grade 2/3 21%), neutropenia (grade 2/3 31%, grade 4 .05%), nausea (grade 2/3 21%) and fatigue (grade 2/3 37%). With irinotecan + flavopiridol 1/13 (8%) confirmed partial response was seen and 5 month disease stabilization in 3/13 (23%) patients. No responses were seen with single agent irinotecan. The median PFS was similar, 1.6 mos irinotecan + flavopiridol vs 1.3 mos in irinotecan group (p=0.21). Conclusions: 54% of gastric cancers are p53wt. Correlative tissue analysis including p53 sequencing, p21, Rad51 is ongoing. Due to lack of activity with irinotecan alone, an amendment to a single arm irinotecan + flavopiridol study is planned.
Somatostatin receptor (SSTR) expression and proliferative index (Ki 67) in 100 patients (pts) with gastroenteropancreatic neuroendocrine tumors (GEP-NETs): Clinical-pathological correlation.
Authors: O'Connor Juan Manuel , Pesce Veronica , Mendez Guillermo Ariel , Bestani Claudia , Marmissolle Fabiana , Giacomi Nora , Belli Susana , Domenichini Enzo , Chacon Matias , Zamora Victor , Cabanne Ana , Roca Enrique Luis
Published: March 2020

e14598

Background: Somatostatin receptor expression (SSTR), mainly subtypes 2 and 5, is a feature of well differentiated GEP-NETs. Such expression has a prognostic and predictive value for the use of somatostatin analogs.Ki 67, present during the cycle phases (G1, S, G2 y M) is a nuclear antigen associated with cell proliferation. The correlation between both clinical and pathological factors is under active investigation in patients with GEP-NETs. Methods: An analysis including 100 patients in the database of the Argentum Group was performed. Consecutive patients were included during the 2006-2007 period. In all cases, a centralized revision of the sample was conducted for diagnosis confirmation.The study of SSTR receptors in tissue and Ki67 was conducted using IHQ.The Kaplan-Meier method was used to analyse survival. Log-rank test was used for the comparative analysis of the variables of interest. Results: The expression of at least one of the SSTRs 2 (a) or 5 was found in 86% and 62% of cases respectivevly in this population. The univariate analysis showed significant differences in the expression of SSTR2 (a) but not in the expression of SSTR 5.The expression of the proliferative index (Ki 67) was associated with significant differences in relation to OS at 5 years, 84% (Ki 67 under or equal to 2%), 66% (Ki 67 between 3 and 15%) and 13% (Ki 67 over 15%). The OS at 5 years in patients with SSTR 2/5 positive and Ki 67 under 2% was 86%, 64% in pts. with SSTR 2/5 positive and Ki 67 over 2% and 20 % in pts. with SSTR 2/5 negative, independent Ki 67 (p .0023). Conclusions: The expression of at least one of the SSTRs 2 (a) or 5 was found in 86% and 62% of cases respectivevly in this population. In the population with GEP-NETs under study, a subgroup of patients with a better prognosis was identified in association with the expression of SSTR 2/5 and Ki67 below 2%. The assessment of SSTR 2(a) and 5 in tissues, together with the study of the proliferative index are a useful tool for prognosis assessment in these patients.
Prognostic value of epidermal growth factor receptors (EGFR) on overall survival of gastric cancer patients.
Authors: Jácome Alexandre A. A. , Wohnrath Durval R. , Scapulatempo Neto Cristovam , Carneseca Estela C. , Nunes Joao Soares , Viana Luciano S. , Serrano Sergio Vicente , Santos José Sebastião
Published: March 2020

e14599

Background: The human EGFR family is involved in the pathogenesis and progression of several solid tumors. However, there is no consensus about the prognostic role of HER2 expression and of other members of EGFR family in gastric cancer patients. The aim of this study was to evaluate the prognostic value of members of the EGFR family in gastric cancer. Methods: Retrospective study with 201 patients with gastric and esophagogastric junction (EGJ) adenocarcinoma stages 0 to IV (AJCC 6th edition) who underwent primary tumor resection between January 2006 and December 2008 at Barretos Cancer Hospital, Barretos, São Paulo, Brazil. Tissue from primary tumors were analyzed by tissue microarray technology. IHC scores 0 and 1+ were classified as negative and scores 2+ and 3+ as positive, both for membrane and cytoplasmic expression of HER1, HER2, HER3 and HER4. The HER2 scoring system for gastric cancer was used for classification. Correlations between receptor expression and clinicopathological characteristics were performed according to the chi-square test. Survival analysis was calculated according to a parametric Weibull model with a mixture model incorporating long-term survivors. Multivariate analysis of prognostic factors was performed by a regression model incorporating long-term survivors with the Weibull distribution. Results: Membrane expression of HER1, HER2 and HER4 were 9%, 17% and 15%, respectively. No membrane expression of HER3 was observed. Cytoplasmic expression of HER1, HER3 and HER4 were 45%, 62% and 24%, respectively. Expression of HER2 and HER3 correlated with intestinal-type histology (p: 0.001 and p < 0.001, respectively) and advanced age (p: 0.011 and p: 0.008, respectively). According to a regression model adjusted for age, surgical radicality, surgical modality, Laurén histology, adjuvant therapy, TNM stage and receptors expressions, only TNM stage showed prognostic influence. Conclusions: Expression of HER2 and other members of EGFR family did not have influence on the overall survival in the gastric cancer population studied. The elaboration of a systematic review with meta-analysis or a prospective study could help elucidate this controversial issue.
Surgical resection and its relationship to survival for recurrent hepatocellular carcinoma after living donor liver transplantation.
Authors: Ikegami Toru , Shirabe Ken , Yoshizumi Tomoharu , Morita Kazutoyo , Toshima Takeo , Muto Jun , Yoshiya Shohei , Uchiyama Hideaki , Soejima Yuji , Maehara Yoshihiko
Published: March 2020

e14602

Background: Although liver transplantation offers excellent recurrence-free survivals for treating hepatocellular carcinoma (HCC), cases with recurrent diseases usually result in miserable outcomes. In this study, the indication and efficacy of surgical resection for the recurrent diseases after living donor liver transplantation (LDLT) for HCC. Methods: A total of 153 recipients, who underwent LDLT for HCC between 1997 and 2011, were included. The endpoints analyzed were survivals from time of LDLT and from the time of recurrence. Results: Twenty-three patients had recurrence of HCC after LDLT. The mean period until the initial recurrence after LDLT and the mean duration until death after the initial recurrence were 17.1 months (n=23) and 17.4 months (n=16), respectively. A univariate analysis showed that gender (p<0.01) des-gamma-carboxy prothrombin <300 mAU/ml (p=0.02), interferon therapy (p=0.02), early posttransplant tumor recurrence (p<0.01), and eligibility for a surgical resection (p<0.01) all had a beneficial impact on survival from tumor recurrence. Other factors at LDLT including Milan criteria, tumor number, tumor size or alpha-fetoprotein had no impact on the survival after recurrence. Multivariate analysis showed eligibility for a surgical resection (odds ratio 12.3, p<0.0199 and des-gamma-carboxy prothrombin <300 mAU/ml (odds ratio 5.3, p=0.04) were the independent beneficial factors on survival from tumor recurrence. Surgical resection was performed in 12 patients for the initial recurrences at lung (n=5), peritoneum (n=2) lymph nodes (n=2), liver (n=1), bone (n=1) and adrenal gland. The 2-year survival rate after recurrence in the patients surgery was indicated or not indicated was 72.2% and 18.2%, respectively (p<0.01). Conclusions: Surgical therapy could be useful for patients who experience a recurrence of HCC after LDLT to improve their outcome, when such treatment is available.
Interventional oncology for older patients with liver and kidney malignancies.
Authors: Monfardini Lorenzo , Orsi Franco , Bonomo Guido , Vigna Paolo Della , Monfardini Silvio
Published: March 2020

e14607

Background: Less invasive procedures, such as those provided by interventional oncology are often offered to older patients(pts) believing that the benefits outweigh the drawbacks for non-fit vulnerable older pts, but reports in the English literature are very few. The purpose of this study was then to provide information on results and complications of interventional oncology procedures in pts with liver and kidney cancer older than 70 years ,analysing the incidence of complications, loco regional responses and duration of hospital staying and to compare these findings with those of pts younger than 70. Methods: Prospectively collected data on all pts that underwent liver bland arterial embolisation (BAE) with or without radiofrequency ablation and kidney radiofrequency ablation (RFA) at the Interventional Radiology Unit of the European Institute of Oncology, were analyzed comparing incidence of complications, loco regional responses and duration of hospital staying for pts older and younger than 70 years. Results: From April 2007 to March 2011 163 pts (109 males and 54 females) , 66 (40.5 %) older and 97 ( 59.9 %) younger than 70 years were treated with interventional oncology procedures. Of these 56 had an hepatocarcinoma,76 liver metastases and 31 a kidney cancer. The ASA score was homogeneously distributed in older and younger patients. The overall complication rate in patients older than 70 was 4.5 % (3/66) and in younger 3,1 % (3/97), without a significant difference (p=0.69). In pts older than 70 years mean hospitalization was 2.3 nights (36 were inpts for 2 nights, 8 for 3 and 3 for 4) while in the 81 younger pts the mean hospitalization was 2.2 nights (67 were inpts for 2 nights, 12 for 3 and 2 for 4). Objective response rates were 52.8% in older versus 46.3% in younger pts (p=0.55). Conclusions: Our study has confirmed thatliver BAE even followed by RFA and renal RFA in older liver and renal cancer pts are as safe and effective as in younger ones. Age alone should then not be considered as a risk factor in selected older pts.
Effect of a novel CDX2 splice variant on tumorigenicity in gastroesophageal junction adenocarcinoma xenografts.
Authors: Witek Matthew , Waldman Scott A , Snook Adam , Schulz Stephanie
Published: March 2020

e14619

Background: Patients with locally advanced adenocarcinoma of the gastroesophageal junction (GEJ) that undergo aggressive neoadjuvant chemoradiation therapy followed by an extensive oncologic resection have a 25-50% risk of developing locoregional recurrences and/or distant metastases. There is an unmet need for biomarkers that predict tumor behavior following neoadjuvant therapy that can be used to direct future therapy. CDX2, an intestine-specific transcription factor that regulates proliferation and differentiation, is ectopically expressed by epithelial cells lining the GEJ during intestinal metasplasia and retained by adenocarcinomas. To date, CDX2 has not been shown to contribute to the tumorigenic potential of GEJ adenocarciomas limiting its use as a predictive or prognostic marker. Methods: CDX2 mRNA from GEJ tissues were sequenced. Wild type and splice variant transcripts and proteins were analyzed by Western blot, RT-PCR, luciferase assays, and fluorescent IHC. In vitro and in vivo proliferation assays were performed with OE19 cells retrovirally transduced to over-express either GFP or CDX2/AS. Results: We identified a novel splice variant of CDX2, CDX2/AS (alternative splicing) encompassing a protein in which the 85 carboxyl-terminal residues in CDX2 are replaced with a 45 residue domain enriched in arginine and serine. CDX2 and CDX2/AS were concomitantly expressed in adenocarcinomas arising from the GEJ. CDX2/AS localizes to nuclear matrix associated foci with splicing factors in contrast to CDX2 that exhibits a diffuse nuclear expression pattern. CDX2/AS did not activate promoters of putative CDX2-dependent genes but inhibited CDX2 transcriptional activity. Over-expression of CDX2/AS in the GEJ adenocarcinoma cell line OE19 did not impact its growth in vitro but did significantly increase its tumorigenicity in nude mice. Conclusions: We discovered a CDX2 splice variant with dominant-negative properties that increases the tumorigenic potential of GEJ adenocarcinoma xenografts. Further investigation examining the relationship between CDX2/AS expression and human tumor characteristics will determine its value as a prognostic and/or predictive biomarker.
The cost-effectiveness of transarterial chemoembolization treatments.
Authors: Shaya Fadia T. , Breunig Ian Michael , Hanna Nader , Chirikov Viktor , Seal Brian S. , Mullins C. Daniel
Published: March 2020

e14626

Background: Transarterial chemoembolization (TACE) is often a treatment for patients precluded from surgery. TACE recipients may get ≥1 TACE treatment, yet little is known about the cost-effectiveness of such additional TACEs. Methods: The study population includes 1,095 Medicare patients with a 1st diagnosis of 1ry HCC in 2000-07 who got TACE, or both TACE+ablation (LD) where one occurred prior to any other treatments. Patients were studied through end of 2009, in SEER-Medicare A-B. Stratifying by ablation, Cox proportional hazards models were built to assess the impacts of successive TACEs on all-cause/HCC-mortality, adjusting for clinical (cancer stage, underlying health status, liver conditions) and demographics. Average HCC-related Medicare costs (US$2,011) attributed to additional TACEs was estimated with generalized least squares, obtaining incremental cost effectiveness ratios (ICERs) and 95% confidence intervals, controlling for systemic chemotherapy and radiation therapy in the follow-up period. Results: Cancer stages 1, 2, 3, and 4 represented 34%, 16%, 19%, and 5% of the 1095 patients, respectively: 26% unstaged, 68% male, 71% Caucasian, 6% African American, and 17% Hispanic. 474 non-LD TACE patients had one TACE, 218 two, 93 three, 70 ≥four. Among LD patients, 121 got 1 TACE, 58 two, 34 three, 27 ≥four. In non-LD patients, further reductions in all-cause/HCC mortality were associated with the 2nd (HR .76, p<.01; HR .78, p=.045) and 3rd (HR .68, p<.01; HR .61, p<.01) TACE, but not the 4th; only the 3rd TACE further reduced mortality risk in LD patients (HR .48, p=.01; HR .34, p .01). For non-LD patients, using HCC mortality, the 2nd TACE was attributed to $19,969 per life year (LY) added, 95%CI $8,634, $31,303, the 3rd $10,290/LY ($2,815, $17,764); using all-cause mortality, the 2nd $27,813/LY ($15,943, $39,684), the 3rd ICER was statistically N.S. All ICERs were N.S. for LD patients. Conclusions: Additional TACEs provide survival benefit for HCC Medicare patients in clinical practice. However, that benefit may decrease after the 3rd exposure, which is more cost effective than a 2nd one. Additional TACEs may be confounded if ≥4 TACEs are intended to treat biologically aggressive disease.
Prognostic significance of autophagy-related proteins expression in resected pancreatic cancer.
Authors: Won Hye Sung , Ko Yoon-Ho , Cho Young-Seok , Jeon Eun Kyoung , Lee Myung Ah
Published: March 2020

e14634

Background: Autophagy is a critical intracellular pathway for removal of aggregated proteins and damaged organelles. The aim of this study was to explore the contribution of autophagy-related proteins on clinical outcomes of patients with resected pancreatic ductal adenocarcinoma (PDAC). Methods: The expression of five autophagy-related proteins in the PDCA tissues of 73 patients was evaluated by immunohistochemistry using a tissue array method. In addition, clinicopathological characteristics and survival were compared with the expression of autophagy-related proteins. Results: Of the 73 patients, autophagy-related proteins expression frequencies were 49.3% (36/73) for ATG5, 63.9% (46/72) for Ambra 1, 47.9% (35/73) for Beclin-1, 83.3% (60/72) for LC3B, and 69.9% (51/73) for Bif-1. The correlation between the expressions of autophagy-related proteins was statistically significant in all protein pairs. Advanced T stage was marginally associated with a higher number of protein changes (p = 0.059). Multivariate analysis revealed that Beclin 1 overexpression or increases in alteration of autophagy-related proteins were independently associated with poor prognosis (hazard ratio 5.365, p=0.001 and hazard ratio 5.270, p=0.022, respectively). Conclusions: The acquisition of autophagy-related proteins is associated with poor clinical outcome in PDCA. The awareness and inhibition of autophagy offer a potential therapeutic target for PDCA.
Demographic and prognostic factors in ampullary adenocarcinoma: A retrospective review of 74 sequential cases undergoing multidisciplinary management between 1997 and 2009.
Authors: Marsh Robert de Wilton , Pandey Romy , Bentrem David J. , Baker Marshall , Ding Xian , Stocker Susan , Brown Eric , Talamonti Mark
Published: March 2020

e14642

Background: Ampullary adenocarcinoma represents 1% of GI cancers but accounts for almost 30% of Whipple operations at major centers. Prognosis falls between that of pancreatic and duodenal cancer, but demographic and prognostic factors are not well delineated. Methods: Retrospective review, with patient consent, of an IRB approved common surgical database at two academic institutions. This includes all cases operated on for ampullary adenocarcinoma between 1997 and 2009. Demographics and factors with potential relevance for prognosis by literature review were examined via Kaplan Meier and/or Cox models. Results: 74 cases were identified: 50 had conventional and 22 pylorus preserving Whipple procedures with 2 unresectable cases. Demographics: 38 males, 36 females; 64 Caucasian, 6 African American and 4 others; age 23-83, median 63.08 years. Tumor characteristics: Tis -1, T1-10, T2-22, T3-27, T4-12, Unknown-2; N0-35, N1-38, Unknown-1; pre-existing adenomas in 37 (50%). Tumor markers: CEA 2/34 and CA 19-9 16/37 tested were abnormal. Adjuvant therapy given (chemo and/or chemoRT): 33/74. Status: 34 patients alive and 41 deceased with a median follow-up of 22 months. Factors associated with poor outcome: Perineural invasion (PNI) p = 0.02; Pre-existing adenoma p = 0.001; Weight loss of 10 lbs or more p = 0.01; RBC transfusion in the OR p = 0.001. Factors not statistically prognostic: T stage, lymph nodal status, lymphovascular invasion, jaundice, CEA or CA 19-9 values and absence of adjuvant therapy. Pancreaticobiliary versus intestinal subtype was assessed by H and E staining but one third of cases were indeterminate, and while these appeared to have a worse prognosis, IHC will be performed for accurate classification and determination of significance. Conclusions: This dataset describes the demographics of patients treated for ampullary adenocarcinoma over 12 years and identifies PNI, weight loss, pre-existing adenoma and transfusion in the OR as adverse factors. These prognostic factors (and potentially histologic subtype) should be considered in patient care and future study design.
Definitive chemoradiotherapy with capecitabine and cisplatin in elder patients with squamous cell esophageal carcinoma.
Authors: Xing Ligang , Zhang Jiandong , Wang Fuli , Liu Fengjun , Yu Xinshuang , Song Meijuan
Published: March 2020

e14643

Background: The purpose of this study is to investigate the feasibility and efficacy of concurrent or sequential chemoradiotherapy (CRT) with capecitabine and cisplatin in elderly patients with squamous cell esophageal carcinoma. Methods: 75 patients elder than 70 years with histologically proven squamous cell esophageal carcinoma were retrospectively reviewed. 40 patients were treated with concurrent CRT (CCRT) consisted of two cycles of intravenous cisplatin and oral capecitabine during and after radiotherapy. 35 patients were treated with sequential chemoradiotherapy (SCRT) as two cycles of capecitabine plus cisplatin before and after radiotherapy. The response rate, overall survival (OS), progression free survival (PFS) and toxicity were compared between two groups. Results: The response rate in the CCRT group was significantly higher than those in the SCRT group (82.5% vs 60.0%, p=0.023). The median OS time and PFS time of the CCRT group were significantly longer than those of the SCRT group (OS: 30.5 vs. 15.7 months, p=0.01; PFS: 25.4 vs. 11.6 months, p=0.014). The acute toxicities was more frequent in the CCRT group than SCRT group, but the grades 3 and 4 acute and late toxicities were similar in the two groups. Conclusions: It suggested that both CCRT and SCRT with capecitabine and cisplatin are tolerable and effective in elderly patients with esophageal squamous cell carcinoma. Concurrent CRT might be superior to sequential chemoradiotherapy.
A prospective, nonrandomized phase II/III trial of definitive chemoradiation, with or without cetuximab, in advanced esophageal squamous cell carcinoma.
Authors: Chen Yongshun , Wang Jianhua , Wu Xiaoyuan , He Chunyu , Wang Wen , Liu Jinsong , Guo Wei , Tan Bo , Wang Yanxia
Published: March 2020

e14645

Background: Chemoradiotherapy is the standard treatment option for patients with esophageal cancer unsuitable for surgery, but the majority of patients will die of their disease, most commonly with local tumor progression/recurrence. We initiated this study to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and radiation for patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: A total of 127 patients with clinical stage II–IVa disease were selected to receive combined-modality therapy consisting of cetuximab (400 mg/m2/wk week 1, then 250 mg/m2/wk week 2-8), paclitaxel (45 mg/m2/wk) and cisplatin (20 mg/m2/wk) in weeks 2-8 with 59.4 Gy of radiation (Group A, n = 29) versus the same chemoradiotherapy schedule but without cetuximab (Group B, n = 98). Results: At the time of this analysis, 27 and 88 patients were available for evaluation of response and survival in Group A and B respectively. In Group A, 20 patients (74.1%) achieved complete response (CR) and 7 (25.9%) achieved partial response (PR), resulting in an objective response rate (ORR) of 100%. The 1- and 2-year progression-free survival (PFS) was 91.2% and 85.1%, the median PFS was not reached. No association between tumor EGFR expression and response or survival was found. In Group B, 33 patients (37.5%) achieved CR, 51 (58.0%) achieved PR and 4 (4.5%) had stable disease, thus the ORR was 95.5%. The 1- and 2-year PFS was 89.0% and 50.5%, with the median PFS of 24.3 months. The difference in PFS between the two groups was statistically significant (p = 0.011). Treatment-related toxicities were generally grade 1 or 2. The most common toxicities were rash (89.3%), followed by neutropenia (71.4%) and esophagitis (60.7%) in chemoradiation-plus-cetuximab group. Adverse events were most often neutropenia (81.8%) and esophagitis (76.1%) in chemoradiation group. Locoregional failure rate was 3.7% and 15.9% in Group A and B, respectively. Conclusions: Cetuximab can be safely administered with chemoradiation and may prolong progression-free survival for Chinese patients with ESCC.
L-asparaginase loaded red blood cells (RBC) in pancreatic cancer: A phase I clinical study.
Authors: Godfrin Yann , Liens David , Andre Thierry , Adenis Antoine , Joly Florence
Published: March 2020

e14650

Background: L-asparaginase (L-asp) efficacy is based on sensitivity of tumoral cells to asparagine deprivation due to a lack of asparagine synthethase (ASNS). However its use is hampered by significant toxicities of which allergic reaction, coagulation disorders and pancreatic impairment take a prominent place. Deficiency in ASNS and therefore potential sensitivity to L-asp treatment has been reported in multiple tumor cell lines including pancreatic cancer, however tentative to use L-asp in solid tumor, and especially in pancreatic cancer is reported in the literature but all attempts so far have failed due to toxicity. Recently, a new formulation of L-asp loaded inside RBC (GRASPA) has shown a very promising safety profile in leukemic patients. Methods: GRASPANC is the first phase I clinical study with GRASPA in patients with pancreatic carcinoma. Primary objective was to find the Dose Limiting Toxicity (DLT) of this cell-based formulation in this setting. Secondary objectives were to assess overall safety profile and activity (defined as serum asparagine depletion) of GRASPA. Patients with non resectable, relapsed pancreatic cancer were included by cohort of 3 and treated with one injection of increasing dose (25, 50, 100 or 150 IU/kg) of GRASPA. An independent Safety Monitoring Board assessed toxicities at the end of follow-up of each cohort to decide for next dose. Results: Twelve patients were included between Dec 2009 and Feb 2011 by 3 centres in France. Mean age was 60.4 years (min: 42.6; max: 71.9) with 9 Male and 3 female. No limiting toxicity has been found up to the GRASPA highest dose (150 IU/kg) planned in the study and the DLT was not reached. No specific other unexpected non limiting toxicity was evidenced. In addition, at all doses GRASPA was shown to be effective at depleting serum asparagine with a trend toward longer activity with increasing dose. Conclusions: Preliminary conclusion is that the dose of 150 IU/kg of GRASPA is safe and appears suitable for further clinical development in patients with pancreatic carcinoma. In order to maximise potential efficacy of this new therapy, selection of patients should be made according to their screening for a none or low expression of ASNS in their tumour cells.
Intensive up-front treatment versus a sequential approach in advanced gastric cancer patients: Does first-line matter?
Authors: Bittoni Alessandro , Scartozzi Mario , Pistelli Mirco , Galizia Eva , Del Prete Michela , Giampieri Riccardo , Faloppi Luca , Bianconi Maristella , Maccaroni Elena , Cascinu Stefano
Published: March 2020

e14663

Background: The definition of the standard chemotherapy regimen for advanced gastric cancer is still a matter of debate. A recent meta-analysis suggested that the addition of a third drug to a doublet regimen should be considered the state-of-the-art strategy to improve overall survival. Aim of our analysis was to retrospectively assess whether an intensive, three-drugs, front line approach could be comparable to a sequential (two-drugs front line then second line) in terms of RR (response rate), PFS (progression free survival) and OS (overall survival) in advanced gastric cancer patients. Methods: Patients with metastatic gastric cancer who have received a first-line combination chemotherapy with a two or three-drugs regimen were included in our analysis. We divided our patients into two groups, A and B, based on the first line chemotherapy administered (group A=three drugs; group B= two drugs). Results: A total of 390 patients were eligible for our analysis. 211 patients (54%) received three chemotherapeutic agents (group A) and 179 patients (46%) received a two drugs regimen as first-line combination chemotherapy (group B). The 2 groups of patients resulted comparable for all known prognostic factors of clinical relevance. RR for group A and B was 46.5% and 28%, respectively (p=0,0007), median PFS was 7.12 months in group A and 3.96 months in group B (p<0,0001). No significantly difference resulted for the median OS of patients in the two groups (13 months for group A and 11.8 months for group B; p= 0.962). Conclusions: The addition of a third drug to a doublet chemotherapy regimen appeared more active in terms of response rate and PFS. However median OS resulted comparable. On this basis, a triplet regimen may represent an optimal choice, particularly when response and PFS are relevant treatment endpoints. Nevertheless the use of a sequential approach may also represent a reasonable strategy for patients unwilling or unable to undergo a more intensive treatment without compromising OS.
Analysis of new N descriptors on prognosis of esophageal cancer with positive lymph nodes in a Chinese population.
Authors: Xu Yaping
Published: March 2020

e14678

Background: The 7th edition of the American Joint Committee on Cancer / Union International Against Cancer (AJCC/UICC) TNM staining system for esophageal cancer (EC) has been published. N descriptors are now divided into N0, N1, N2 and N3. In this study, we aimed to validate the prognostic ability of the new N staging system in patients with resectable EC and positive lymph nodes, and evaluate whether the new N staging system can help the decision-making for postoperative adjuvant therapy in this population. Methods: From 2002 to 2008, patients with stage T1-4N1-3M0 EC who underwent esophagectomy were retrospectively analyzed. EC was classified according to the new N staging system. Kaplan-Meier method and Cox regression analysis were employed to compare overall survival (OS). Results: A total of545 patients met the inclusion criteria: 346 (63.5%) received esophagectomy alone, 199 (36.5%) received esophagectomy and adjuvant radiotherapy, and 36.1% (197/545) received esophagectomy and adjuvant chemotherapy. Univariate analysis and multivariate analysis revealed significant difference in OS among patients with EC at different N stages (p<0.001). Significant difference in OS was also present among patients receiving radiotherapy (p<0.001) and those undergoing chemotherapy (p<0.001). Subgroup analysis indicated that postoperative adjuvant therapy did not significantly affect the OS among patients with EC at different N stages. Conclusions: Our results validated the prognostic ability of new N staging system. N descriptor is an independent prognostic factor in patients with resectable EC who were positive for lymph nodes. Further studies are required to clarify the role of new N staging system in the decision-making for postoperative adjuvant therapy in this population.