bluuebunny/crossref_metadata_2025 huggingface dataset:
An experimental MODEL study to investigate the pathogenesis of oxaliplatin-induced liver injury.
Authors: Robinson Stuart M. , Mann Jelena , Manas Derek M. , Mann Derek A. , White Steve A.
Published: February 2017

184

Background: Oxaliplatin based chemotherapy is widely utilized pre-operatively in patients with colorectal liver metastases. Its use is associated with injury to the liver in the form of sinusoidal obstruction syndrome (SOS) the presence of which can have a negative impact on surgical outcomes. The pathogenesis of this condition is poorly understood. Methods: C57Bl/6 mice (n=10 per group) were treated with 5-FU/oxaliplatin/folinic acid chemotherapy (FOLFOX) weekly for 5 weeks or their respective vehicle controls. Animals were culled one week following the final treatment and liver tissue harvested for histological and biochemical analysis. mRNA was extracted from snap frozen liver and subject to genome wide expression analysis the results of which were confirmed using qRT-PCR. To determine the effect of background steatosis on the development of liver injury the experiment was repeated using mice maintained on a high fat diet. To assess the ability of antioxidants to prevent SOS development diet was supplemented with 3% butylated hydroxyanisole (BHA). Results: H&E stained tissue sections confirmed the presence of SOS in all FOLFOX treated animals. Microarray identified changes in expression of over 604 genes in the liver of animals with FOLFOX induced SOS. In particular there was increased expression of genes implicated in oxidative stress (e.g. Metallothionein 1; 22 fold; p<0.001), cell cycle arrest (e.g. p21; 21 fold; p<0.001) and angiogenesis (VEGF-A; 2 fold; p<0.001). Administration of the antioxidant BHA alongside chemotherapy prevented the development of SOS confirming the role of oxidative stress in the pathogenesis of this condition. There was down regulation of a number of genes implicated in fatty acid synthesis (e.g. FASN; 8 fold; p<0.001). In support of this mice maintained on a high fat diet treated with FOLFOX do not develop steatosis unlike those treated with vehicle alone. Conclusions: FOLFOX chemotherapy is specifically associated with SOS and not hepatic steatosis. We have identified some of the molecular pathways involved in the pathogenesis of this condition. Manipulation of these pathways may be of therapeutic potential in preventing the development of chemotherapy-associated liver injury.
Loss of succinate dehydrogenase (SDHB) in midgut carcinoids as a prognostic factor: A new marker of personalized cancer medicine in neuroendocrine tumors?
Authors: De Braud Filippo G. , Pusceddu Sara , Milione Massimo , Buzzoni Roberto , Mazzaferro Vincenzo , Coppa Jorgelina Clara , Damato Angela , Seregni Ettore , Formisano Barbara , Pelosi Giuseppe
Published: February 2017

186

Background: Gene mutations of the succinate dehydrogenase (SDH) complex have recently been involved in the pathogenesis of cancer cells. These mutations often are associated with SDH subunity B loss of activity and overexpression of HIF-1α. The immunoistochemical (IHC) loss of SDHB expression has recently been reported to be a surrogate marker of malignancy in pheocromocytomas and paragangliomas. The aim is the evaluation of SDHB levels expression in advanced midgut carcinoids and investigate its potential role as prognostic marker. Methods: 31 advanced midgut carcinoids were treated in our Istitution, including 24 males and 7 females, aged 55.5 yrs on average (range 19-75). All patients were G1 tumors with stage IV for synchronous liver metastases. 25/31 patients underwent surgical primary resection. IHC evaluation of the SDHB and MIB1 expression were carried out in 20 primary tumors (T) and 19 liver metastases (M). In 11 patients SDHB and MIB1 were tested in both T and M. SDHB was assessed according to the staining intensity scored 1 (low) or 2 (high) on the basis of the internal control represented by normal intestinal cells. Results: Loss of SDHB expression (IHC +1) was detected in 70% of T and in 90% of M. The value of MIB 1 labeling index: 1,3% represent a cut-off for distinguish low or high SDHB expression within these G1 midgut category (MIB 1≥ 1.3, SDHB +1: 90%; MIB 1 <1.3, SDHB +1: 10%). No difference in term of median OS was found between these 2 groups, 113 vs 103 mts respectively. In 11 pts the combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. These findings were inversely proportional to Mib-1 distribution that was 1,54% in metastastic sites and 0.7% in the primaries, respectively. Conclusions: This preliminary analysis suggests a possible correlation between SDHB expression loss, MIB1 increase and biological aggressiveness of advanced midgut carcinoids. A more extensive clinico-biological evaluation is warranted to clarify its relationship with survival and explore the role of SDHB as predictive marker to response of antiangiogenetic agents.
An alternative method to detect peritoneal recurrence of gastric cancer: Clinical application of CT colonography.
Authors: Iwasaki Kenichi , Cho Haruhiko , Watanabe Takafumi , Kuwabara Hiroshi , Hayashi Tsutomu , Shirai Junya , Fujikawa Hirohito , Yoshida Tetsuo , Yoshikawa Takaki , Tsuburaya Akira
Published: February 2017

19

Background: Peritoneal metastasis (PM) is among the most frequent patterns of recurrence of gastric cancer: however, it cannot be detected by general axial CT or even by PET until it develops to massive ascites or an overt peritoneal mass. CT colonography (CTC) is used to screen for colon cancer, with the advantage that it can provide both colonic and extracolonic information at the same time. Methods: CTC was applied for patients that were suspected to have PM based on their clinical symptoms and general CT findings, without sufficient information to confirm the diagnosis, to detect signs of peritoneal metastasis earlier. PM diagnosis in CTC was defined as the finding of an abnormal deformity of the colonic wall without intraluminal tumor by both the attending doctors and radiologists. Results: Twelve patients suspected of having PM were enrolled in the study. Nine of those patients (75%) were positive for PM by CTC. Abnormal colonic deformities were also identified in other locations other than the lesions detected by general CT in 6 patients. All of the nine patients with positive PM were clinically confirmed to have PM, and had a poorer prognosis (median survival: 252 days). The three patients with negative PM are all alive without recurrence. Conclusions: CTC is thus considered to be a candidate for the early detection of PM. Further study with more patients is therefore warranted.
The natural history and role of surgical cytoreduction and systemic chemotherapy in high-grade mucinous adenocarcinomas of the appendix.
Authors: Overman Michael J. , George Binsah , Taggart Melissa W. , Eng Cathy , Royal Richard E. , Wolff Robert A. , Mansfield Paul F. , Fournier Keith F.
Published: February 2017

199

Background: The natural history, clinical presentation, and impact of cytoreductive surgery (CRS) or systemic chemotherapy for high grade MAA has been poorly studied. Methods: A retrospective chart review of patients (pts) with moderate or poorly differentiated AA was completed from 1994-2010. Radiographic response was assessed semi-quantitatively form physician records and complete cytoreductive surgery (CRS) was defined as a completeness of cytoreduction score of 0 or 1. For CRS and chemotherapy subgroups efficacy endpoints were calculated from date of CRS or first chemotherapy dose, respectively. Results: 288 (136 moderate and 152 poor grade) pts were identified with a median age of 52 years (range: 25-82). Mucinous histology was present in 110 pts (38%) and differed by grade: 55% of moderate and 23% of poor. Stage IV presentation (n=163) occurred in 76% of poor grade but only 35% of moderate grade. Both median OS (4.5 vs. 2.7 yrs, P=0.04) and median OS for the stage IV subgroup (3 vs 1.9yrs, P=0.005) were improved for MAA vs. non-MAA. Moderate compared to poor grade had improved median OS (3.7 vs 1.9 yrs, P=0.002) for Stage IV disease, but this differed by mucinous histology (moderate mucinous 6.2yr vs. poor mucinous 1.6yr, P=0.001; moderate nonmucinous 1.4yr, poor nonmucinous 2yr). 39 MAA pts underwent a complete CRS (30 moderate and 9 poor) with a median time to recurrence of 1.5yrs and median OS of 9.2yrs. Improved OS was seen for pts with a complete CRS compared to pts with an incomplete CRS, P<0.001. 55 MAA pts received systemic chemotherapy (fluoropyrimidine/oxaliplatin in 30, irinotecan-based in 8, fluoropyrimidine-based in 16, and other in 1): median OS of 2.1yr, median TTP of 7.2 months, and radiographic response of 36%. No statistical differences were seen between chemotherapy groups. Conclusions: High-grade MAA represents a heterogenous disease with a statistically worse OS for poor as opposed to moderate histological differentiation. This data does not support the AJCC 7th edition use of a single mucinous high-grade category. The use of systemic chemotherapy appears to be a viable treatment option for these pts and a complete CRS is associated with improved OS.
Prospective phase II trial of GTX in metastatic pancreatic cancer: Laboratory and clinical studies.
Authors: Fine Robert , Lee Yoomi , Sherman William H. , Gulati Anthony Paul , Oberstein Paul Eliezer , Chu Kyung , Tsushima Dawn , Mowatt Kelley B , Schrope Beth , Lee James A , Allendorf John , Chabot John A , Schreibman Stephen M.
Published: February 2017

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Background: We found that in pancreatic cancer (PC) cells, when gemcitabine, docetaxel, capecitabine (GTX) are given in a sequence and time specific manner, it 1) increased Bax, Bak, Fas and decreased Bcl-2 and Bcl-XL expression; 2) increased hENT-1 expression >8 fold, which increased intracellular gemcitabine accumulation by 220%; 3) specifically inhibited MEK to ERK phosphorylation (p-MEK) by >70%. Methods: From this pre-clinical data, we developed the GTX regimen utilizing: capecitabine 750 mg/m2/BID capped at 2500mg/day for days 1-14; on days 4 and 11 gemcitabine at 750mg/m2 given over 75mins (FDR), followed by docetaxel at 30mg/m2. Week 3 is off all drugs. Forty four patients with previously untreated metastatic PC were enrolled and followed until death. ECOG PS was: 0(2%), 1(63%), 2(35%), and median age was 60 (33-72). Over 85% of patients had >3 liver metastases. Results: Median response rate (RR) was 38% with 14% CR in metastatic or primary sites and 40% stable disease using RECIST 1.0 indices. Median PFS was 6.9 months and median OS was 14.5 months. After failing GTX, 80% of patients received our second line synergistic regimen called ICM (irinotecan 80mg/m2 and cisplatin 25mg/m2 on days 1 and 8, and mitomycin C 5mg/m2 on day 1 only, out of a 28 day cycle). The 6, 12, 18, 24, 30 and 36 month survival on GTX was 77, 59, 35, 16, 14 and 7%, respectively. Grade3/4 toxicities were: leukopenia (32%), neutropenia (29%), febrile neutropenia (3%), anemia (12%), thrombocytopenia (12%), diarrhea (5%), HFS (3%), fatigue (8%), and mucositis (8%). GTX inhibited MEK to ERK phosphorylation (P-MEK). We performed IHC (0-4+) for P-MEK in 16 patients and found high P-MEK (3-4+) correlated with an 85% RR while low P-MEK (0-1+) correlated with a 90% rate of PD to GTX. Conclusions: GTX is an effective regimen for metastatic PC with durable RR, PFS, OS rates, and acceptable toxicities. IHC for P-MEK seems to be a good biomarker to identify subsets of patients who will respond to GTX. GTX is a rationally designed regimen derived from lab studies. GTX increases pro-apoptotic and decreases anti-apoptotic proteins, inhibiting MEK to ERK in the MAPK pathway. Clinical trial information: NCT00996333.
Prognostic significance of p53 protein overexpression in localized gastrointestinal stromal tumors of the small intestine.
Authors: Park Young Soo , Kon Young Wha , Ryu Min-Hee , Ryoo Baek-Yeol , Park Hye Jin , Yook Jeong Hwan , Kim Byung Sik , Kang Yoon-Koo
Published: February 2017

212

Background: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumors (GISTs). p53 alteration has been suggested as an additional genetic change that affects patient outcome in some studies. However there has been few studies in GISTs of the small intestine. The aim of this study was to determine the prognostic significance of p53 alterations in localized GISTs of the small intestine. Methods: We retrospectively reviewed 113 patients with completely resected localized GISTs in the small intestine who were not treated with adjuvant imatinib between 1994 and 2008. Immunohistochemical staining of CD117, CD34, S-100, SMA and p53 were performed in all patients and mutational analyses of c-kit exons 9, 11, 13 and 17 were conducted in 81 (56.6%) patients. Results: The median follow-up after diagnosis was 84 months (range, 40-146 months). Overexpression of p53 were observed in 38 patients (33.6%). p53 overexpression was strongly correlated with high mitotic index (p = 0.01) and higher risk groups based on the National Institutes of Health’s (NIH) risk category (p = 0.019). On univariate analysis, patients with p53 overexpression showed worse recurrence-free survival (RFS, p = 0.003). c-kit mutation status was not a prognostic factor (p = 0.411). Multivariate analysis indicated that p53 overexpression remained as independent poor prognostic factors for RFS (hazard ratio = 2.66, p = 0.026) as well as tumor size and mitosis. The p53 overexpression was marginally associated with poor RFS in the low or intermediate risk groups according to NIH's risk category (p = 0.081). Conclusions: Our results suggest that the p53 overexpression is an independent prognostic factor for RFS in localized GISTs of the small intestine. Additionally, p53 overexpression could be a helpful marker for selecting patients for further treatment in low or intermediate risk group patients.
Adjuvant chemotherapy in patients with resectable cholangiocarcinoma.
Authors: Wirasorn Kosin , Ngamprasertchai Thundon , Khantikaew Narong , Pakkhem Ake , Ungarereevittaya Piti , Jindaprasert Jarin , Sookprasert Aumkhae
Published: February 2017

219

Background: Cholangiocarcinoma patients usually have poor treatment outcome and high mortality rate. The role of adjuvant chemotherapy is controversy. Our study aimed to evaluate benefits of adjuvant chemotherapy in resectable cholangiocarcinoma patients. Methods: A retrospective study included 263 patients who underwent curative resection in Srinakarind university hospital. These patients had pathological report with clear margin (R0) or microscopic margin (R1). Results: There were 138 patients received adjuvant chemotherapy. This group had significantly lower mean age than patients without chemotherapy (57.7 ± 8.5 vs. 60.4 ± 9.0 years, p = 0.01). Level of serum albumin above 3g/dL was more common in adjuvant chemotherapy group than another one (87.7% vs. 79.2%, p = 0.04). Patients who received adjuvant chemotherapy had significantly longer overall median survival time (21.6 vs. 13.4 months, p = 0.01). Patients with combination of gemictabine and capecitabine regimen had the longest survival time (median overall survival time of gemcitabine and capecitabine 31.5, 5-FU and mitomycin 17.3, 5-FU alone 22.2, capecitabine alone 21.6, and gemcitabine alone 7.9 months, p = 0.02). Benefits of adjuvant chemotherapy were likely to be found in patients who had high risk features, i.e. high level of CEA, high level of CA19-9, advanced stage, T4 stage, nodal involvement and R1 margin. Conclusions: Adjuvant chemotherapy may significantly prolong survival time in resectable cholangiocarcinoma patients, particularly the high risk group.
Stereotactic radiotherapy (SRT) for primary and metastatic liver tumors with functional treatment planning.
Authors: Kirichenko Alexander V. , Thai Ngoc , Lappinen Erik , Gayou Olivier , Day Ellen , Kotinsley Katherine , Gott Susan
Published: February 2017

222

Background: We report on outcomes and toxicity of liver SRT/SBRT based on 3D-CT/SPECT treatment planning with conformal avoidance of well perfused functional normal liver volumes (FNLV). Methods: 51 patients with unresectable metastatic (36) or primary (15) hepatic tumors (65 targets) completed SRT planning with 99mTc sulfur colloid 3D-SPECT/CT to define FNLVs. Various degrees of FNLV retraction as a result of hepatic cirrhosis or systemic or intrahepatic chemotherapy were observed. For conformal avoidance of the residual FNLV, total dose and fractionation were adapted to FNLV constraints. 4D-CT and SPECT-based dosimetry were compared and treatment outcomes and toxicity were analyzed with medium followup 14.5 months (3-36months). Results: The in-field local control rate was 95%, hepatic failure free survival - 88%, hepatic progression free survival - 78% and overall survival - 70%. 25% patients developed Grade ≤ 2 elevation of liver enzymes with no incidence of “classic” radiation-induced liver disease. No patients with hepatic cirrhosis had Child-Pugh score progression. The most common toxicity was Grade ≤ 2 fatigue. For the group, FNLVs were significantly reduced compared to CT-derived NLV (p<0.01) with marked FNLV contraction in patients with Child-Pugh ≥ B cirrhosis, those who completed hepatic resections or received TACE within 2 months prior to SRT. Treatment planning with incorporated SPECT/CT helps to reduce volumes of functionally active liver parenchyma receiving doses above prescription threshold in patients with HCC compared to conventional 4D-CT treatment planning (p<0.01). There was no such correlation for non-HCC patients. Conclusions: 3D-SPECT/CT treatment planning allows identification and conformal avoidance of FNLV from high radiation doses facilitating safety of liver SRT in patients with preexisting liver disease. Outcomes are favorable, however participation in prospective Phase III trial would estimate true value of this method.
Quality of life in a multicenter phase II trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma.
Authors: Serrano Aybar Pablo Emilio , Herman Joseph M. , Zalupski Mark , Kim Edward Jae-hoon , Ben-Josef Edgar , Bekaii-Saab Tanios S. , Wolfgang Christopher Lee , Laheru Daniel A. , Moore Malcolm J. , Dawson Laura A. , Ringash Jolie , Wei Alice Chia-chi
Published: February 2017

226

Background: Pancreatic cancer remains incurable for the great majority of patients afflicted with the disease. The purpose of this study was to evaluate health related quality of life (HRQoL) following neoadjuvant full dose gemcitabine, oxaliplatin and radiation therapy (30 Gy) for pancreatic adenocarcinoma in a multi-institutional Phase-II trial. Methods: Fifty-seven patients were evaluable for the HRQoL component of this trial that consisted of two cycles of neoadjuvant chemoradiation with gemcitabine and oxaliplatin followed by pancreatectomy and two additional cycles of adjuvant chemotherapy. The effects of therapy on HRQoL were evaluated using: EORTC-C30, EORTC-PAN26 and FACT-HEP. Results: There were 20 patients (35%) with untreated resectable and 37 (65%) with borderline resectable pancreatic cancer. Thirty-nine patients (69%) completed two cycles of preoperative chemotherapy and surgery, 26 (40%) underwent a pancreaticoduodenectomy and 9 (14%) a distal pancreatectomy. Twenty-six patients completed postoperative adjuvant therapy. The median age was 64 (range 42-82); patients younger than 65 had a higher global HRQoL score at 6 months (p=0.046) following the initiation of treatment. There was no difference in the HRQoL according to type of operation performed. EORTC-C30 Global HRQoL remained statistically and clinically unchanged compared to baseline levels at all time-points. FACT-Hep Trial Outcome Index and Total score showed a statistically significant but not clinically meaningful decline following cycle 2 of neoadjuvant treatment (p=0.002 and p=0.004), returning back to baseline levels after 6 months. This may in part be explained by a decrease in the functional (p=0.004) and physical (p=0.001) wellbeing, an increase in diarrhea (p=0.044), digestive symptoms (p=0.037) and an increased fatigue (p<0.001). Conclusions: We report that this neoadjuvant chemoradiation protocol did not have a clinical impact on global HRQoL. Overall this regimen was well tolerated with no negative effect on quality of life following the conclusion of treatment. Clinical trial information: NCT00456599.
Preoperative chemoradiotherapy for pancreatic cancer encountered vertebral compression fractures.
Authors: Otani Keisuke , Teshima Teruki , Nishiyama Kinji , Ito Yuri , Kawaguchi Yoshifumi , Konishi Koji , Takahashi Hidenori , Ohigashi Hiroaki , Araki Nobuhito , Ishikawa Osamu , Oshima Kazuya
Published: February 2017

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Background: Preoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer at our institute achieved excellent cure rates, while treated patients encountered vertebral compression fractures (VCFs) frequently. Methods: From January 2006 to December 2011, 220 patients (male/female: 134/86, median age: 66 (range: 33-84)) with resectable pancreatic cancer have been treated with preoperative CRT with GEM. This method consisted of concurrent radiotherapy (50-60 Gy in 25 fractions over 5 weeks) and chemotherapy (GEM 1,000 mg/m2intravenous, weekly for 12-15 weeks, 3 times during 4 weeks). Three-dimensional conformal radiotherapy was used and its fields covered both primary pancreatic tumor and retropancreatic tissues with 50 Gy level. Boost irradiation to the roots of celiac and superior mesenteric arteries with 2.4 Gy/fr using field-within-field technique has been started since 2009. The risk factors for VCF and its causes were retrospectively analyzed for 1,308 Th10-L3 vertebral bodies. Results: Follow-up time from the initiation of CRT ranged from 3.4-73.9 months (median: 17.9). Median overall survival time of these patients was 40.6 months. Radical surgery was completed in 164 patients (75%). Twenty-five patients (11%) diagnosed as VCF (CTCAE v4.0 grade1/2: 12/13) and 22 of them were at 3.6-23 months from CRT. Cumulative incidence rates at 2 years were 18.9% in total, 8.5% in male and 38.4% in female (p = 0.0002). Corresponding rates were 5.1% in age < 60 and 24.9% in age ≥ 60 (p = 0.0107). On their courses 37 de novo VCFs (Th10/11/12/L1/2/3: 2/3/11/13/7/1) were observed at first and 9 patients repeated VCFs near the initial VCFs. Dose-volume factors of each vertebral bodies also significantly correlated with VCF; vertebrae whose mean dose were < 38 Gy/ ≥ 38 Gy developed VCFs in 2.7%/10.0% at 2 years (p < 0.0001), vertebrae whose V30 were < 80%/≥80% developed VCFs in 2.4%/10.6% (p < 0.0001). Conclusions: Besides women and higher age, dose-volume factors of radiotherapy were risk of developing VCF in patients with pancreatic cancer after preoperative CRT with GEM. These findings should be considered to avoid VCFs as late adverse event after CRT for pancreatic cancer, especially in IMRT era.
Treatment-related hypertension (HTN) as a predictive biomarker for clinical outcomes in patients (pts) with advanced pancreas cancer (APCA) treated with bevacizumab (B): A pooled analysis of four prospective clinical trials.
Authors: Martin Ludmila Katherine , Wei Lai , Van Loon Katherine , Iyer Renuka V. , Pant Shubham , Fogelman David R. , Ko Andrew H. , Bekaii-Saab Tanios S.
Published: February 2017

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Background: Phase III studies of B in unselected APCA pts have been negative. Recent data suggest subsets of pts may benefit from B, but no validated predictive biomarkers exist for B efficacy in APCA. The pathogenesis of B-related HTN (B-HTN) is not well understood, but studies suggest association between B-HTN and improved clinical outcome in various advanced solid tumors. We conducted a pooled analysis of raw data from 4 prospective clinical trials to evaluate that predictive role of B-HTN in APCA. Methods: Relevant raw data were collected from 4 multi-institution single-arm phase II trials of GEM-based doublet chemotherapy + B as 1st line treatment of APCA. Pts were grouped according to B-HTN of any grade (Group 1) and no B-HTN (Group 2). Clinical outcomes including OS, TTP, ORR, and DCR (disease control rate = ORR + SD >16 weeks) were compared between Group 1 and 2. For pts in Group 1, outcomes were also compared according to CTCAE HTN grade (1-2 vs 3-4). Results: 166 pts (85 M, 81 F) with median age 55 (31-85) were included. Group 1= 37 pts (Grade 1-2 HTN, N=18; Grade 3-4 HTN, N=19), Group 2 = 129 pts. Demographics were similar except % stage 4 (92% group 1, 100% group 2, p=0.01). Results are summarized in the Table. Group 1 had significantly prolonged mOS and mTTPand improved ORR and DCR vs Group 2. There was no difference in outcome according to HTN grade. Conclusions: B-HTN of any grade may be an important pharmacodynamic biomarker for B in APCA. This subset of pts could benefit from B and identification of characteristics that predict development of B-HTN may aid in future pt selection for B therapy in APCA. Future prospective studies may consider pharmacodynamic titration of B to grade > 1 HTN to potentially maximize B efficacy. [Table: see text]
The feasibility of R0 resection of locally advanced pancreatic cancer (LAPC) encasing major visceral arteries (T4 lesions) using arterial resection and reconstruction: Short- and long-term outcomes.
Authors: Genyk Yuri , Barzi Afsaneh , El-Khoueiry Anthony B. , Matsuoka Lea , Sutton Vanessa , Buxbaum James , Iqbal Syma , van Dam Jacques , Selby Rick , Lenz Heinz-Josef
Published: February 2017

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Background: LAPC is found in about 40% of patients with pancreatic cancer at initial presentation. Tumors involving major visceral arteries are commonly deemed unresectable. In this study we analyzed the feasibility of R0 resection of LAPC encasing major visceral arteries using arterial resection and reconstruction. Methods: The following data were collected prospectively following pancreatic resection with vascular reconstruction in patients with LAPC: age, gender, operative details, post-operative complications, chemotherapy and/or radiation therapy and overall and disease free survival. Patient survival was calculated utilizing Kaplan-Meier survival probability estimates. Results: From Dec., 2002 to Sep., 2012, 12 patients with LAPC (8 males and 4 females, median age 58.5 yrs (range: 51–78 yrs)) underwent pancreatic resection with concomitant resection and reconstruction of major visceral arteries in our institution. The arterial involvement included celiac artery (n=8), and superior mesenteric artery (n=4). Resections included pancreatico-duodenectomy (n=8), distal pancreatectomy (n=3), and total pancreatectomy (n=1). Management of the arterial involvement included: resection of celiac axis without reconstruction (n=2), resection and reconstruction of one artery (n=6), two arteries (n=3) and three arteries (n=1). R0 resection was accomplished in 9, R1 in 2, and R2 in 1 patient. One patient (8%) died peri-operatively from pulmonary thromboembolism. Chemo- or chemo-radiation therapy was not protocolized. To date, 5 patients are alive and disease free at 7, 9, 11, 23 and 117 months, and 1 patient is alive with recurrence at 107 months. Six-month patient survival was 75% and median overall survival (MOS) was 19 months. Conclusions: The MOS in this patient population with systemic therapy is around 9 months. Although the sample size in our study is limited, observed MOS of 19 months is encouraging and provides the opportunity to reconsider the contraindications to surgical management of such patients with T4 LAPC. Timing of perioperative chemotherapy will be evaluated in a prospective trial.
A phase I study of DENSPM (N1, N11-diethylnorspermine) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Goyal Lipika , Supko Jeffrey G. , Berlin Jordan , Blaszkowsky Lawrence Scott , Carpenter Amanda , Heuman Douglas M. , Stuart Keith E. , Cotler Scott , Senzer Neil N. , Berg Carl L. , Clark Jeffrey W. , Hezel Aram F. , Ryan David P. , Zhu Andrew X.
Published: February 2017

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Background: DENSPM, a synthetic analog of the naturally occurring polyamine spermine, offers a novel approach for treating HCC by inducing polyamine depletion and inhibiting cell growth. The objectives of this multicenter phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), and preliminary antitumor activity of DENSPM in HCC. Methods: Forty-four patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤ 3, and Karnofsky score ≥ 60% were enrolled in a dose escalation study of DENSPM given intravenously on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m2 was escalated at a fixed increment of 15 mg/m2 until the MTD was identified. A sensitive LC-MS/MS assay with a 6.4 nM limit of quantitation was developed and validated to characterize the plasma PKs of DENSPM. Results: Thirty-eight patients (male 79%; median age 61years; Child A 84%; Asian 5%; ≥1 prior systemic therapy 45%) received at least one dose of DENSPM. The most common adverse events (AEs) were fatigue (53%), nausea (34%), diarrhea (32%), vomiting (32%), anemia (29%), and increased AST (29%). The most common grade 3/4 AEs were fatigue/asthenia (13%) and increased AST (13%), hyperbilirubinemia (11%), renal failure (8%) and hyperglycemia (8%). The MTD was 75 mg/m2and was not directly associated with major treatment-related safety concerns. DENSPM plasma levels decreased very rapidly during the initial 60 min post-infusion. The total body clearance, 66.7±35.8 L/h/m2 (mean±SD) for the initial dose was comparable to that in solid tumor patients with normal to near normal hepatic function. However, drug concentrations ≥10 nM persisted for several days after dosing and remained detectable in samples obtained before day 12 dosing in 11/16 (68.8%) patients. No responses were seen but 9/27 (33.3%) evaluable patients achieved stable disease. Conclusions: DENSPM toxicity was dose dependent, the 75 mg/m2 MTD was relatively well-tolerated, and the PK behavior was favorable. Nevertheless, the study was terminated early because of insufficient evidence of clinical benefit in HCC patients. Further evaluation of DENSPM as a monotherapy for HCC does not appear to be justified. Clinical trial information: NCT00081900.
Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.
Authors: Ikeda Masafumi , Shiina Shuichiro , Nakachi Kohei , Mitsunaga Shuichi , Shimizu Satoshi , Kojima Yasushi , Ueno Hideki , Morizane Chigusa , Kondo Shunsuke , Sakamoto Yasunari , Tateishi Ryosuke , Asaoka Yoshinari , Koike Kazuhiko , Arioka Hitoshi , Okusaka Takuji
Published: February 2017

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Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.
Analysis of patterns of failure and prognostic factors in resected extrahepatic bile duct cancer: Implications for postoperative adjuvant radiotherapy.
Authors: Kim Jae-Sung , Koo Tae Ryool
Published: February 2017

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Background: This study is aimed to analyze the patterns of failure and evaluate the prognostic factors in the patients with extrahepatic bile duct cancer (EBDC) for the potential role of postoperative adjuvant radiotherapy (PORT). Methods: We retrospectively reviewed the medical records of 106 patients with EBDC who received curative intent surgical resection. The definitions of tumor location were as follows: proximal EBDC (n = 29) from the confluent portion of the bilateral hepatic bile ducts to the junction of cystic duct, and distal EBDC (n = 77) from the junction of cystic duct to intrapancreatic portion. Nine patients underwent adjuvant chemoradiotherapy or chemotherapy. Results: The median follow-up time was 24 months for the surviving patients. Forty patients experienced locoregional failure (LRF) initially; 13 (45%) with proximal EBDC and 27 (35%) with distal EBDC. The hepatoduodenal ligament (HL) and tumor bed were the most common LRF sites. Distant metastasis (DM) occurred in 10 patients (34%) with proximal EBDC and 15 patients (19%) with distal EBDC. The liver was the most common organ of DM. In the multivariate analysis, perineural invasion (PNI) and postoperative high carbohydrate antigen (CA) 19-9 were associated with poor LRPFS. Conclusions: Both proximal and distal EBDC showed remarkable proportion of LRF. Because the HL and tumor bed are where routinely covered by PORT, it can be speculated that the addition of PORT can improve LRPFS in these patients. Especially PORT needs to be considered in patients with PNI and postoperative high CA 19-9 to improve locoregional control.
Phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy for resectable pancreatic cancer.
Authors: Fan Katherine Y. , Wild Aaron Tyler , Laheru Daniel A. , Pawlik Timothy M. , Zheng Lei , Le Dung Thi , Tran Phuoc T. , Dholakia Avani Satish , Kumar Rachit , Ellsworth Susannah G. , Hacker-Prietz Amy , Rasheed Zeshaan , De Jesus-Acosta Ana , Weiss Matthew , Makary Martin , Cameron John L. , Hruban Ralph H. , Fishman Elliott K. , Wolfgang Christopher Lee , Herman Joseph M.
Published: February 2017

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Background: Amplification and overexpression of the EGFR gene and surface protein have been described in up to 80% of pancreatic tumors, making EGFR an attractive target in developing new adjuvant therapy for pancreatic adenocarcinoma (PDAC). Inhibition of EGFR has been suggested to provide additive activity when combined with capecitabine and radiation. Here we evaluate the antitumor activity and toxicity profile of erlotinib combined with adjuvant chemoradiotherapy (CRT) and chemotherapy. Methods: 50 patients with resected stage I/II PDAC were enrolled in a phase II trial of adjuvant erlotinib and capecitabine administered concurrently with IMRT (50.4 Gy), followed by 4 cycles of erlotinib and gemcitabine. Results: Median length of follow-up was 18.2 months (IQR, 13.8-27.1). Seventy-nine percent of tumors were of the pancreatic head, 85% had nodal involvement, and 17% had positive margins. Median RFS was 15.6 months (95% CI, 14.1-17.1), local RFS 21.1 months (95% CI, 17.1-25.1), and OS 24.4 months (95% CI, 17.1-31.6). Local recurrence was only observed in 19% patients and synchronous recurrence in 8%. Patients with maximum tumor diameter of ≤3 cm showed superior RFS (17.9 vs. 14.0 months; P=0.049), as did patients with cutaneous reaction to erlotinib (16.3 vs. 9.3 months, P=0.021). Superior OS was associated with less than median (32.3U/mL) pre-CRT CA19-9 values (28.2 vs. 19.0 months, P=0.012). During CRT, 31% patients experienced grade 3 toxicity and 2% grade 4, while 31% patients required a treatment break/stopped treatment early. During post-CRT chemotherapy, 35% patients experienced grade 3 toxicity and 8% grade 4, while 30% required a dose reduction. Conclusions: Results of this phase II trial suggest erlotinib combined with standard adjuvant CRT and chemotherapy provides excellent local disease control and reasonable tolerability compared with existing adjuvant regimens. Patients with maximum tumor diameter of ≤3 cm, cutaneous reaction to erlotinib, and less than median pre-CRT CA19-9 values appear to especially benefit from this new adjuvant regimen. Clinical trial information: NCT00962520.
Usefulness of FDG-PET in the evaluation of tumor response to proton beam therapy for locally advanced pancreatic ductal adenocarcinoma.
Authors: Shirakawa Sachiyo , Matsumoto Ippei , Terashima Kazuki , Shinzeki Makoto , Asari Sadaki , Goto Tadahiro , Mukubo Hideyo , Tanaka Masaki , Yamashita Hironori , Iwasaki Toshimitsu , Ishida Jun , Okazaki Taro , Kido Masahiro , Takahashi Masanori , Takebe Atsushi , Fukushima Kenji , Ajiki Tetsuo , Fukumoto Takumi , Ku Yonson
Published: February 2017

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Background: Evaluation of tumor response to radiation therapy in pancreatic ductal adenocarcinoma (PDA) using conventional radiological tests is difficult due to generally small size and inflammatory or fibrotic changes of radiated tissue. Although increasing evidence has shown that 18-F-fluorodeoxyglucose-positoron emission tomography (FDG-PET) can assess functional changes in various tumors, available data in PDA with radiation therapy is scarce. In this study, we investigated the role of FDG-PET in long-term monitoring tumor response to proton beam therapy (PBT) for PDA. Methods: Thirty-four locally advanced PDA patients with pre- and post-PBT FDG-PET data were included in this study. Local tumor responses by computed tomography (CT) and FDG-PET were defined as below: response group in CT (complete response: CR, partial response: PR, stable disease: SD, progressive disease: PD) was defined according to Response Evaluation Criteria in Solid Tumors, but only evaluation of primary tumor; and in FDG-PET, CR was defined as disappearance of FDG uptake, PR as decrease, SD as unchange, and PD as increase, compared to pre-PBT data. We evaluated tumor response at three different time points: 0-3, 3-6, and 6-12 months after PBT. Also serum CA19-9 values were evaluated. Results: Radiation doses were 50.4-70.2 GyE and 28 (82%) patients received concomitant chemotherapy. During the follow-up period (median 19 months), a total of 90 FDG-PET tests were performed. At the first time point, SD was noted in 90% (9/10) of patients by CT, whereas CR or PR in all by FDG-PET. At the second point, 39% (7/18) of patients demonstrated PR by CT, whereas 91% CR or PR by FDG-PET. Two patients with PD by FDG-PET were diagnosed as SD by CT, while one patient with PD by CT was diagnosed as PR by FDG-PET. At the third point, four patients with PD by FDG-PET were diagnosed as PR or SD by CT. Serum CA19-9 values supported FDG-PET findings. In four of 14 patients with serial FDG-PET, the maximum effects were noted at the second point. Conclusions: Serial FDG-PET can detect changes in local tumor response to PBT for PDA earlier and more sensitively than CT. Of note, there is the risk for false positive in early post-PBT FDG-PET.
Effect of the addition of platinum to gemcitabine on outcome in patients with advanced pancreatic cancer who progress on gemcitabine: A comprehensive analysis of published trials.
Authors: Rahma Osama E. , Liewehr David J. , Steinberg Seth M. , Duffy Austin G. , Greten Tim F
Published: February 2017

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Background: Pancreatic cancer is one of the deadliest cancers with an estimated 5 years survival rate of 5%. Until recently gemcitabine had been considered the first line treatment for locally advanced or metastatic disease. Although many chemotherapy regimens have been used there is no standard of care for second line therapy. The aim of this analysis was to identify superior regimen in the second line setting. Methods: We conducted a general search on PubMed for “second line therapy in advanced pancreatic cancer”. We limited our search to trials published in English from 2000 through 2012. Studies presented as abstracts in major meetings were also included. Trials that used targeted therapy other than erlotinib were excluded. We compared in an exploratory fashion the RR, PFS and OS of BSC and each of the following regimens to the rest of the treatments: 5FU+platinum, gemcitabine+platinum, taxol, erlotinib. In addition, we compared the combinations of platinum with either 5FU or gemcitabine. Finally, we explored the trend of these treatments outcomes over time. Results: Forty-four trialswere identified, of which 34 trials (T) met the inclusion criteria treating 1503 patients (N). There was a trend toward an improved overall survival with treatments (T: 33; N: 1269) compared to BSC (T: 2; N: 234) only (P= 0.013). The combination of gemcitabine and platinum (T: 5; N: 154) was the only regimen that showed a trend toward superior outcomes compared to the other regimens (T: 28; N: 1115) in terms of RR and PFS (P= 0.006 and 0.059, respectively). However, there was no difference in overall survival (P= 0.10). When compared to 5FU+platinum (T: 12; N: 450) the regimen of gemcitabine+platinum (T: 5; N: 154) showed only a trend toward significance in terms of improved RR (P= 0.030) with no difference in PFS or OS (P= 0.60 and 0.22, respectively). Overall, there was a trend toward a worse RR and PFS with no change in OS over the past 13 years. Conclusions: The combination of gemcitabine and platinum may provide a valid second line option in patients with locally advanced or metastatic pancreatic cancer who progress on gemcitabine.
Ablation for hepatocellular carcinoma: Validating the 3-cm breakpoint.
Authors: Groeschl Ryan Thomas , Gamblin T. Clark , Turaga Kiran
Published: February 2017

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Background: Although many previous studies on ablation outcomes for hepatocellular carcinoma (HCC) have dichotomized tumor size around a 3cm cutoff to determine prognostic significance, a growing number of reports describe excellent outcomes for larger tumors. To address the sensibility of this somewhat arbitrary 3-cm cutoff, we stratified patients by 1cm tumor size intervals and hypothesized that disease-specific survival (DSS) would not vary significantly between adjacent groups. Methods: Patients treated with local ablation for T1 HCC (≤8cm) were identified from the Surveillance, Epidemiology, and End Results database (2004-2008). Log-rank tests were used to compare DSS curves of adjacent study groups, and multivariable Cox proportional hazards models were used adjust for confounding variables. Results: There were 1,093 patients included in the study (26% female, median age: 62 years). The 3-year DSS was significantly lower in patients with 3-4cm tumors compared to 2-3cm tumors (58% vs 72%, p=0.002, Table). In adjusted models, DSS did not vary significantly between any size intervals up to 3cm. Patients with 3-4cm tumors, however, had a poorer prognosis compared to patients with 2-3cm tumors (hazard ratio: 1.60, 95% confidence interval: 1.18-2.18, p=0.002). DSS also fell significantly when tumor size increased from 5-6cm to 6-7cm (53% vs 21%, 0.006). Age and alpha-fetoprotein levels were also independently predictive of DSS in most multivariable models; however, the presence or absence of cirrhosis was not predictive in any models (smallest p=0.382). Conclusions: This study defends the use of a 3cm breakpoint when studying outcomes after ablation for HCC. Although some have advocated that ablation is more successful in cirrhotics, we found no evidence for this in our study. [Table: see text]
Characteristics and outcomes of patients with advanced hepatocellular carcinoma treated on phase I trials.
Authors: Subbiah Ishwaria Mohan , Janku Filip , Tsimberidou Apostolia Maria , Naing Aung , Kaseb Ahmed Omar , Hong David S. , Subbiah Vivek , Hess Kenneth R. , Akmal Owais , Falchook Gerald Steven , Kurzrock Razelle
Published: February 2017

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Background: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapies. With that purpose, we analyzed the outcomes and prognostic factors of such pts treated on phase I trials w an emphasis on locoregional and targeted agents. Methods: We reviewed the records of 100 consecutive pts referred to the Phase I Clinical Trials Program from March 2004 and assessed characteristics, types of clinical trials, progression-free survival (PFS), overall survival (OS) and oncogenic mutations. Results: Of 100 referred pts, 39 were not treated mainly due to poor performance status (n=22). Of 61 treated pts (49 male, 12 female, median age 60yrs), median # of prior therapies was 3 (range, 0-8). There were no treatment-related mortalities. One pt on a sorafenib regimen had g3 hand foot syndrome unresponsive to dose reduction. A 2nd pt developed a L-sided visual blurriness after 5 days on a sunitinib regimen; CT showed a small R parieto-occipital hemorrhage, possibly related to therapy. Of 61 treated pts, 7 (11%) had stable disease (SD) > 6 months, 4 (7%) partial response (PR), on protocols combining bevacizumab+sorafenib, pazopanib+everolimus, or single-agent novel oral multikinase inhibitor of VEGFR2-TIE2, or hepatic arterial infusion (HAI) of paclitaxel or oxaliplatin w IV bevacizumab. Median PFS on Phase I trials was 2.2 months vs. 4.4 months and 4.1 months for their 1st- and 2nd-line FDA-approved therapy (p 0.019). In univariate analysis, the presence of ascites, portal hypertension, cirrhosis, serum sodium, albumin, and poor Royal Marsden Hospital (RMH) prognostic score were associated with shorter PFS and OS (p < 0.05). On multivariate analysis, independent factors of shorter OS were Caucasian race (p = 0.031), cirrhosis (p = 0.016), serum sodium (p = 0.0013), and poor RMH prognostic score (p = 0.0015). Molecular analysis in progress will be updated. Conclusions: Phase I therapy offer a reasonable therapeutic option for patients with advanced HCC. The RMH prognostic score was validated in this population. The SD > 6 months/PR rate of 18% was observed with regimen of multikinase inhibitors with mTOR inhibitors and HAI therapy.