bluuebunny/crossref_metadata_2025 huggingface dataset:
Does a common vascular origin confer similar prognosis to malignant tumors of the liver?
Authors: Groeschl Ryan T. , Pappas Sam G , Christians Kathleen K. , Tsai Susan , Quebbeman Edward J , Gamblin T. Clark , Turaga Kiran
Published: February 2017

186

Background: Unlike the ubiquitous hepatic hemangioma, malignant vascular tumors (MVT) of the liver are uncommon and poorly understood. We hypothesized that tumor histology is a predominant factor associated with survival in these tumors.

Methods: Patients with hepatic angiosarcoma (AS), hemangioendothelioma (HE) and its epithelioid variant (EHE), or hemangiopericytoma (HP) were identified using the SEER database (1973-2007). Standardized incidence rates were calculated based on the 2000 U.S. population. Prognostic factors were studied with Cox regression modeling.

Results: We included 297 patients with MVT (207 AS, 28 HE, 56 EHE, 6 HP) with an annual standardized incidence of 3 per million. Patients with AS were likely to be older at diagnosis (median 63 yrs, p = 0.001) and less likely to be female (38%, p < 0.001). All tumors demonstrated metastatic potential, although EHE and AS had the highest rate of regional or distant metastases (75% each, p = 0.05, Table 1). Patients with EHE had the overall longest median survival of 75 (30-183) months (p < 0.001). Surgical resection and transplant did not improve the overall survival of patients with EHE in multivariate models (p = 0.2, 0.9).

Conclusions: Histology is an important factor in determining survival for patients with hepatic MVT. Patients with EHE have the longest OS even in the absence of surgical intervention, whereas patients with AS have shorter survival but appear to benefit from surgery.

[Table: see text]
Clinical significance of circulating tumor cells in blood from patients with advanced or recurrent esophageal cancer.
Authors: Tanaka Motomu , Takeuchi Hiroya , Hiraiwa Kunihiko , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kawakubo Hirofumi , Saikawa Yoshiro , Omori Tai , Kitagawa Yuko
Published: February 2017

19

Background: Circulating tumor cells (CTCs) measured by the CellSearch system in metastatic breast cancer have been reported to correlate with the response to chemotherapy. The purpose of this study was to clarify the clinicopathologic characteristics of CTCs in patients with advanced or recurrent esophageal cancer.

Methods: CTCs from 35 patients with advanced or recurrent esophageal cancer were measured by this system before initiation of a new line of therapy and more than 3 weeks after initiation of therapy. Correlation between CTC counts and clinicopathologic variables was examined.

Results: Of the 35 patients, 14 patients (40%) had recurrent esophageal cancer and 21 patients (60%) had primary advanced esophageal cancer. Their mean age was 65 years (range, 43 to 89 ). Of the 14 patients with recurrent esophageal cancer, measurable lesions included metastasis to lymph nodes, kidney metastasis, liver metastasis, and lung metastasis. With regard to their therapeutic effect, 1 patient (3%) obtained a complete response, 14 (40%) had a partial response, 9 (26%) had stable disease, 11 (31%) had progressive disease. Of the 15 patients with complete response and partial response, the number of CTCs diminished in 8 patients (53%). Of the 20 patients with stable disease and progressive disease, the number of CTCs increased in 16 patients (80%). The change in CTCs tended to correlate with disease progression and chemotherapeutic effect (P=0.07). The survival of patients with >3 CTCs was shorter than that of patients with <3 CTCs both before initiation of a new line of therapy (P=0.026) and more than 3 weeks after initiation of therapy (P=0.003).

Conclusions: This study suggests that measurement of CTCs in advanced or recurrent esophageal cancer patients could be useful as a tool for predicting patients’ survival and monitoring response to cancer therapy.
Patients with liver cancer suitable for sorafenib evaluation registry (LIVER) in Poland.
Authors: Krzemieniecki Krzysztof , Simon Krzysztof , Zieniewicz Krzysztof , Pecilo Pawel
Published: February 2017

194

Background: Due to chronic hepatitis and cirrhosis as main risk factors of HCC – patients in Poland can be treated either by oncologists or by gastroenterologists. As no data exist on HCC patient flow between these specialities, this registry was set up. We also wanted to know the differences in both specialities’ approach to targeted therapies.

Methods: Data of patients treated by oncologists (LIVER 2) and gastroenterologists (LIVER 1) were recorded. Descriptive statistical methods and U-Mann-Whitney and Fisher tests were used.

Results: 478 patients were included into registry from 2009 until the end of 2010. 70% of patients were male. In 42% cases HCC was caused by HCV and in 24% by HBV. LIVER 2 recorded more patients with unknown HCC aetiology than LIVER 1 (35% vs 15%). The HCC diagnosis was made based on CT scan (80%, ns), US scan (74% in LIVER 1 vs 47% in LIVER 2, p<0,0001) or biopsy (72% LIVER 2 vs 48% LIVER 1, p<0,0001). Patients with advanced stage of HCC according to BCLC scale and poor performance status were more frequently seen by oncologists (LIVER 2), similar prevalence in Child Pugh status was observed in both groups (p<0,05 for all). Registry showed differences in frequency of extrahepatic lesions (10% LIVER 1 42% in LIVER 2, p<0,05). Most common co morbidities were diabetes (32%), liver disorders (39%), hypertension (61%), coronary disease (24%). Median AFP level was 100 ng/ml in LIVER 1 and 219 in LIVER 2 (p=0,057). Registry showed that for gastroenterologists reasons to consider sorafenib as next step in therapy was in 47% cases HCC progression, in 51% good performance status and in 55% sorafenib was found as the only one therapy suitable due to contraindications for other treatments. Oncologists consider sorafenib therapy in 56% cases due to HCC progression and in 72% cases due to good performance status. Among patients considered for targeted therapy, approximately 20% presented Child Pugh B status.

Conclusions: This is the first detailed HCC registry in Poland covering the different therapeutic area specialists. Patients with more advanced HCC and worse performance status are more frequently treated by oncologists (p<0,05). The data shows need of early HCC detection interdisciplinary system referring patients to the oncologist.
Cost-effectiveness of FOLFIRINOX for first-line treatment of metastatic pancreatic cancer.
Authors: Attard Cheryl L. , Brown Stephen , Alloul Karine , Moore Malcolm J
Published: February 2017

199

Background: The ACCORD 11/0402 trial demonstrates that FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is significantly more efficacious than the current standard of gemcitabine (G) monotherapy in the first line treatment of metastatic pancreatic cancer (mPC). This study assesses for public payers the cost-effectiveness of first-line FOLFIRINOX compared to first-line G in Canadian mPC patients.

Methods: A Markov model was used to estimate how patients progress through the following states: ‘stable’, ‘progressed’, ‘dead’. OS and PFS data were derived from the trial data. Published utility data and Canadian cost data were applied based on time in each state and treatment related adverse event (AE) rates. Costs included first and second-line therapy, monitoring, AE and end of life costs. Costs and outcomes are discounted at 5%. Two separate analyses were made. Analysis 1: Based on trial data (First-line FOLFIRINOX → second-line G versus First-line G → second-line platin-based chemo, G-CSF usage allowed). Analysis 2: Current Ontario Treatment Patterns (first-line FOLFIRINOX → second-line G vs first-line G → best supportive care, no G-CSF usage).

Results: All analyses found that using first-line FOLFIRINOX produced more life years and QALY than treatment strategies that used first-line G. The probabilistic sensitivity analysis results for both analyses support the use of FOLFIRINOX for first-line treatment of mPC. FOLFIRINOX has a greater than 95% and 90% probability of being cost effective at an $80,000 threshold for Analysis 1 and Analysis 2 respectively.

Conclusions: First-line FOLFIRINOX significantly prolongs median OS by more than 4 months over G (11.3 vs 6.8 months, HR=0.57). Given the favorable costs per QALYs, the improvement in clinical efficacy and the limited available treatment options, FOLFIRINOX represents an attractive cost-effective treatment for mPC.

[Table: see text]
MicroRNA analysis of fine-needle aspirates from pancreatic cancer.
Authors: Philip Philip Agop , Saleh Husain , Ali Shadan , Chen Wei , Palazzolo Paulette , Sethi Seema , Sarkar Fazlul H.
Published: February 2017

200

Background: Tissue-based research is a major challenge in localized pancreatic cancer (PC) especially those with locally advanced unresectable or borderline resectable disease. Approximately half of the patients are diagnosed by a fine needle aspirate (FNA) /biopsy of the pancreatic primary tumor with limited tissue available for correlative assays. Micro-RNAs (miRNAs) are biomarkers with the potential to be developed for prognostic and predictive purposes. Moreover, these molecules can facilitate the development of targeted therapies in PC.

Methods: miRNA expression profiling and quantitative real-time PCR (qRT-PCR) were performed from RNA (25-100 ng per patient) extracted from formalin-embedded cell blocks (FFPE) obtained from diagnostic FNA of the pancreas. Expression profiles of miRNAs were compared to those from patients undergoing pancreatic biopsy for non-malignant conditions.

Results: Cell blocks from FNAs from twenty-nine and 15 patients with pancreatic adenocarcinoma and non-malignant conditions were studied, respectively. miRNA profiling demonstrated deregulation of over 228 miRNA. The top 7 were validated by qRT-PCR. The expression of let-7c, let-7f, and miR-200c were significantly reduced in most patients. Conversely, the expression levels of miR-486-5p and miR-451 were significantly elevated. Significant interindividual variations were also noted in expression of certain miRNAs.

Conclusions: FFPE obtained from diagnostic FNA of pancreatic tumor can be a valuable resource to study miRNA expression profiles of multiple miRNAs and undertake qRT-PCR in patients with localized PC and further supports the use of diagnostic FNA in RNA-based translational research. miRNA expression can be developed for use as prognostic and predictive biomarkers in future clinical trials in patients with PC.
Comparative analysis of treatments, utilization, and survival benefit in HCC patients: A real-world analysis of SEER Medicare.
Authors: Shaya Fadia T. , Breunig Ian Michael , Mullins C. Daniel , Pandya Naimish B. , Chirikov Viktor , Seal Brian S. , Hanna Nader
Published: February 2017

214

Background: We explore various treatments at all stages of Hepatocellular Carcinoma (HCC), in a SEER (Surveillance, Epidemiology and End-Results Program) Medicare population and assess their impact on HCC-specific and overall survival.

Methods: Medicare enrollees, older than 65, with an initial diagnosis of a primary HCC between 2000-07 were followed up through end of 2009. Data are from the SEER and linked Medicare databases, with claims generated from Medicare parts A and B. Using multivariate Cox-proportional hazards models, we assessed overall and HCC-related mortality in relation to receipt of treatment/no treatment, adjusting for demographics, general health status (CCI), cancer stage and liver conditions.

Results: Out of the 9054 HCC patients, older than 65, who did not get a liver transplant, 76% were Caucasian, 8% African American (AA), 63% male, and 37% got treatment [12% transarterial chemoembolization (TACE), 12% systemic chemotherapy, 1.5% selective internal radiation therapy (SIRT), 9% external beam radiation therapy (EBRT), 8% surgical resection and 9% ablative therapy]. Treatment was associated with a reduction of overall (HR=0.35, P= <0.001) and HCC-related (0.33, <0.001) mortality. HCC-related mortality was significantly reduced in those getting resection (0.38, <0.001), ablation (0.59, <0.001), TACE (0.76, <0.001), EBRT (0.85, 0.017), or chemotherapy (0.85, 0.013). Significant reduction in overall mortality was seen with resection, ablation and TACE but not with chemotherapy, EBRT or SIRT. No particular treatment was associated with greater mortality reduction in early vs advanced stages. Patients with poor underlying health status (CCI>1) had higher mortality (1.27, <0.001). Alcohol related disease, Hep C, and moderate/severe liver dysfunction were not significantly associated with overall or HCC related mortality. Caucasians and non-African Americans had lower overall mortality (0.87, <0.001).

Conclusions: In HCC SEER Medicare patients, all treatments except SIRT were associated with a significant reduction in HCC related mortality. A limitation of this study is that, through the data, we cannot accurately depict the severity of the disease.
Can we identify patients with cancer at high risk for cachexia? A prospective study in pancreatic cancer (PC).
Authors: Fogelman David R. , Wang Xin Shelley , Hassan Manal , Li Donghui , Javle Milind M. , Katz Matthew H.G. , Overman Michael J. , Varadhachary Gauri R. , Shroff Rachna T. , Wolff Robert A. , Abbruzzese James L.
Published: February 2017

219

Background: Identifying PC patients at high risk for cachexia may allow for early intervention to prevent it. Symptoms such as pain, nausea and anorexia may predict weight loss. Inflammatory cytokines are also associated with cachexia. We evaluated the ability of each to predict weight loss in newly diagnosed PC patients.

Methods: Using the M. D. Anderson Symptom Inventory (MDASI), we assessed baseline symptoms in untreated advanced or metastatic PC patients. The survey assesses severity of symptoms on a 0-10 scale. Baseline serum levels of IL-1a, IL-1b, IGF-1, CXCL-12, CXCL-16, CRP, IL-6, IL-8, VEGF, CEA, and CA 19-9 were measured via ELISA. Using STATA (version 12), we generated multivariable logistic regression models with a backward selection procedure. This allowed us to evaluate all potential univariate correlates with 5% and 10% weight loss at P<.1 to create a multivariate model containing variables of p<.05. Student t-test was used to compare the mean values of cytokines across different strata.

Results: We evaluated 72 patients (33M/39F). Weight loss of >5% or death was observed in 44 patients (62%) and >10% or death in 24 (34%). 61 pts (30M/31F) survived sixty days after the start of treatment with 5% and 10% weight loss seen in 33 (54%) and 13 (21%), respectively. Baseline severe loss of appetite was most strongly associated with weight loss (OR 15.3, p=.005), compared to those with a moderate loss of appetite (OR 4.7, p=.058), nausea (OR 9.4, p=.048), or shortness of breath (OR 7.4, p=.063). Neither diarrhea nor vomiting correlated with weight loss, nor did age, tumor markers, or treatment with platinum drugs, opiates, or erlotinib. Baseline cytokine levels were available for 23 patients. Mean CXCL-16 (p=.05) and IL-6 (p=.045) levels were greater in patients with weight loss. Serum erythropoietin levels may be negatively associated with weight loss (p=0.06). An analysis of the remaining patients’ samples will be available at the meeting.

Conclusions: Both alterations in serum cytokines and specific symptoms may predict the development of cachexia. A more robust analysis of circulating cytokines may allow us to design interventions which prevent or delay cachexia in patients with advanced pancreatic cancer.
Cost-effectiveness of treating patients with advanced progressive pancreatic neuroendocrine tumor with everolimus versus sunitinib in the United States.
Authors: Casciano Roman , Chulikavit Maruit , Perrin Allison , Liu Zhimei , Wang Xufang , Babigumira Joseph , Garrison Louis P
Published: February 2017

226

Background: Everolimus and sunitinib were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). This analysis examines the projected cost-effectiveness of everolimus versus sunitinib in this setting from a US payer perspective.

Methods: A lifetime Markov model was developed to simulate a cohort of advanced, progressive pNET patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life years (QALYs) gained when treating with everolimus as compared to sunitinib. Absent head-to-head trials, efficacy data were based on a weight-adjusted indirect comparison of the two agents using the respective phase 3 trial data. Disease or health states considered in the model included: stable disease without adverse events, stable disease with adverse events, disease progression, and death. Costs of anti-tumor therapies, symptomatic care drugs, and post-progression therapy were based on wholesale acquisition cost. Other costs including physician visits, tests, infusions, hospitalizations, adverse event costs, and end-of-life care costs were obtained from literature and/or standard sources such as the Healthcare Cost and Utilization Project and Medicare reimbursement rates. Utility inputs were based on a UK time trade-off study. Sensitivity analyses were conducted to test the model’s robustness.

Results: In the base case analysis, the estimated gain of everolimus over sunitinib was 0.448 LYs (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained), which fell within the cost per QALY range for many other widely used oncology drugs. The analysis was sensitive to the uncertainty of the sunitinib trial results; however, a probabilistic sensitivity analysis showed the results were consistent across simulations.

Conclusions: While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies rather than a single head-to-head trial, everolimus is expected to be cost-effective relative to sunitinib in advanced pNET.
Health plan budget impact of introducing everolimus for treatment of advanced progressive pancreatic neuroendocrine tumors in the United States.
Authors: Casciano Roman , Chulikavit Maruit , Sriprasert Michelle , Liu Zhimei , Wang Xufang , Garrison Louis P
Published: February 2017

229

Background: Everolimus was recently approved for treatment of patients with advanced progressive pancreatic neuroendocrine tumors (pNET) based on a clinically meaningful and statistically significant increase in progression-free survival. To understand the financial impact of introducing everolimus into the market, a model was developed to simulate a typical health plan in the United States (US).

Methods: A cross-sectional budget impact model with a one-year time horizon was developed. Disease prevalence and drug usage data were derived from a real-world data source. Costs for anti-tumor therapy and underlying care included concomitant medications, physician visits, treatment infusion, surgical procedures, tests, hospitalizations, and adverse event (AE) management. Resource utilization rates were derived from a physician survey-based resource utilization study; treatment-related AE rates were taken from secondary literature. Drug costs were Wholesale Acquisition Costs (2011). Medical procedure and hospitalization costs were based on Medicare fee schedules for current procedure terminology and diagnosis-related group codes. AE costs were obtained from the literature. The model assessed the initial annual budget impact, under the assumption that everolimus and sunitinib, another recently approved targeted therapy, replace most currently available chemotherapy treatments.

Results: Based on published prevalence rates, for a health plan with 1,000,000 members, an annual count of 12 advanced pNET patients was projected. The model estimated a $22,657 budget increase ($0.0019 per member per month or $0.0227 per member per year [PMPY]). The largest percent increase in budget was associated with anti-tumor treatments; infusions and surgical procedures represented the largest percent decrease in costs. Scenario analyses indicated that increasing the percentage of everolimus use (by reducing that of sunitinib) resulted in a decrease in the overall budget compared to baseline.

Conclusions: Our model predicts that treating pNET patients with everolimus will have a minimal budget impact on US health plans, amounting to about $0.027 PMPY.
Phase I trial of gene-mediated cytotoxic immunotherapy combined with resection for pancreatic adenocarcinoma.
Authors: Shirley Lawrence Andrew , Marsh Christopher , Walker Jon , Coyle Walter , Tahiri Sanaa , Manzanera Andrea G , Aguilar Laura K. , Aguilar-Cordova Estuardo , Chung Vincent M. , Bloomston Mark
Published: February 2017

241

Background: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival is still poor. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug administration. This is the first application of GMCI in pancreatic cancer.

Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into pancreatic tumors via EUS 2 weeks before resection. Patients then underwent attempt at resection. If resection was undertaken, AdV-tk was injected into the resection bed. If resection was not possible, AdV-tk was injected into the primary tumor. The prodrug, Valacyclovir, was given for 14 days after each injection. Postoperative therapy was not protocol-driven.

Results: The study accrued 14 patients with 12 completing therapy: 3 at each of the 4 planned dose levels. One patient died of an unrelated myocardial infarction 2 days after initial injection and one patient dropped out mid-treatment after metastases were found at surgery. Median age was 67 years (range 40-81). Of 12 patients explored, 4 were not resected due to distant metastases (N=3) or locally advanced disease (N=1). Three patients had Grade 3 possibly-related adverse events: 2 abdominal pain and one dehydration with renal insufficiency. There were no dose limiting toxicities and no grade 4 clinical adverse events. Grade 3-4 laboratory abnormalities were AST/ALT, bilirubin, alkaline phosphatase and lipase, all in patients with obstructive jaundice. Post-operative complications included 2 patients who developed abscesses requiring drainage. Six of 12 patients are alive 5-34 months after start of treatment including 5 resected patients and one unresected.

Conclusions: AdV-tk can be safely injected into potentially resectable pancreatic tumors prior to planned resection. Early results are encouraging and justify further evaluation in a Phase 2 study.
Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma?
Authors: Valsecchi Matias Emanuel , Littman Susan Joy , Holdbrook Thomas , Leiby Benjamin , Mitchell Edith P. , Yeo Charles , Brody Jonathan Robert , Witkiewicz Agnieszka
Published: February 2017

246

Background: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.

Methods: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).

Results: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, either in univariate or multivariate analyses, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively) (Table 1). Similar results were obtained for DFS.

Conclusions: RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes.

[Table: see text]
Looking for synergy or additivity between 188Re and sorafenib on hepatoma cell lines.
Authors: Pracht Marc , Lepareur Nicolas , Edeline Julien , Lenoir Laurence , Ardisson Valerie , Clement Bruno , Raoul Jean Luc , Boucher Eveline , Garin Etienne
Published: February 2017

247

Background: In case of non resectable HCC, radioembolization and sorafenib (S) are therapeutic options respectively for intermediate and advanced stages. In some other cancers, there is an increase of efficacy when external beam radiotherapy is done concomitantly with systemic chemotherapy or targeted therapies. So we wondered if there could be a synergistic or an additive activity when S is combined with a radionuclide.

Methods: Hepatoma cell lines N1S1 (murine HCC), HepG2 (human hepatoblastoma) and HepaRG (human HCC) were treated with increasing concentrations of rhenium-188 (188Re) or S. On each cell line, we have studied the cellular toxicities of S and 188Re using Tetrazolium dye test, extra-cellular medium LDH level and morphologic analysis. This was done for different dosage of S and 188Re. We measured the lethal concentration killing 25% of cells (LC25) with the results of the Tetrazolium dye test. Secondly, we looked for synergy or additivity on cellular toxicity of these two compounds according to cell lines by combined treatment. Synergy or additivity was estimated with the combination index (CI) method (synergy if CI lower than 1, additivity if CI = 1, antagonism if CI upper to 1) based on the Tetrazolium dye test’s results.

Results: Monotherapy dose-dependent toxicities were observed for all three cell lines with 188Re and for the N1S1 and HepG2 cell lines only with S. Combined treatment with 188Re and S showed synergy on HepaRG and N1S1 cell lines and additivity on the HepG2 cell line.

Conclusions: The additive, and even synergistic, interest of a combined treatment with 188Re and S is demonstrated in vitro (for the first time to our knowledge) on hepatoma cell lines. This results, in particular for the HepaRG cell line (human HCC), could be explained by the down-regulation of the hepatic drug transporters which are responsible for the Sorafenib efflux in case of simultaneous DNA damages due to a radionuclide exposition. This promising approach now needs to be confirmed in vivo.

[Table: see text]
Targeting hyaluronan (HA) in tumor stroma: Interim safety and translational evaluation of pegylated hyaluronidase (PEGPH20) in patients (pts) with advanced solid tumors—A focus on gastrointestinal malignancies.
Authors: Infante Jeffrey R. , Ramanathan Ramesh K. , Borad Mitesh J. , Rosen Lee S. , Korn Ronald , Dychter Samuel Simon , Shepard Harold Michael , Maneval Daniel C. , Jiang Ping , Carson Deborah , Von Hoff Daniel D. , Frost Gregory Ian
Published: February 2017

249

Background: HA, a glycosaminoglycan in the tumor matrix, accumulates in 20-30% of solid tumors and ≥28%, ≥42% and ≥87% of colon, gastric and pancreatic ductal adenocarcinoma (PDA) tumors, respectively. Tumors that accumulate HA can develop high interstitial fluid pressure (IFP) and are resistant to chemotherapy. HA in human PDA is associated with disease progression and poor prognosis. In animal models, PEGPH20 reduced tumor-associated HA, tumor IFP and tumor growth, and increased efficacy of chemotherapy. Pharmacodynamic (PD) activity of PEGPH20 is being evaluated in Phase 1 (Ph1) trials.

Methods: Two Ph1 studies in pts with advanced solid tumors refractory to prior therapy examined the safety, tolerability, PK, PD and MTD of single-agent IV PEGPH20. Dosing in Study 1 was 2x/wk and then reduced to q21d and in Study 2 is 1-2x/wk x 4wks and 1x/wk thereafter with dexamethasone pre-medication regimen. Biomarkers evaluated: Histochemistry to detect depletion of tumor HA, serum HA catabolites, Dynamic Contrast Enhanced (DCE)-MRI and FDG-PET.

Results: In Study 1, the first 3 pts demonstrated musculoskeletal events (MSE; 2 pts dosed with 50 µg/kg 2x/wk, severe; 1 pt dosed with 0.5µg/kg 2x/wk, moderate) not predicted from GLP safety studies. The frequency of drug administration was reduced to q21d and the next 10 pts tolerated ≤1.5 µg/kg. In Study 2, dexamethasone pre-medication regimen was evaluated while dosing at 1-2x/wk. Nine pts were dosed ≤5.0 µg/kg. Doses ≤3.0 µg/kg administered 2x/wk were tolerated with intermittent Grade 1-2 MSE. Activity of PEGPH20 was reflected by increased HA serum catabolites. Pre- and post-dose biopsies from 2 colon pts demonstrated a 23-60% reduction in tumor HA after 4 wks of PEGPH20 dosing. DCE-MRI of PDA and FDG-PET of lung metastases increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 dose and was still apparent after 4 wks of treatment with PEGPH20.

Conclusions: Ongoing Ph1 studies have shown in vivo activity of PEGPH20 through HA plasma catabolites, tumor HA depletion, DCE-MRI and FDG-PET.
Randomized phase II trial of gemcitabine plus S-1 combination therapy versus S-1 in advanced biliary tract cancer: Results of the Japan Clinical Oncology Group study (JCOG0805).
Authors: Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Takashima Atsuo , Ueno Makoto , Ikeda Masafumi , Hamamoto Yasuo , Ishii Hiroshi , Boku Narikazu , Furuse Junji
Published: February 2017

255

Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial.

Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0 - 1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, iv, days 1 and 8; S-1: 60 mg/m2, p.o., days 1 - 14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1 - 28, every 6 weeks). We assumed that %1-year survival of one regimen is 30% and that of the other regimen is more than 40%. To ensure at least 85% probability of correct selection, 98 eligible pts are required. The decision rule was that the regimen with higher %1-year survival will be considered as more promising regimen.

Results: From February 2009 to April 2010, 101 pts (GB, n=38; IHBD, n=35; EHBD, n=20; AV, n=8) were randomized (GS, n=51; S-1, n=50). For the GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 0.54-1.36]; p=0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29-0.67]; p<0.0001). Grade 3/4 hematological toxicities were more frequent in the GS arm than in the S-1 arm, (percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. Although two treatment-related deaths occurred in the GS arm (pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxicities were infrequent and reversible in both arms.

Conclusions: The GS arm was superior in %1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.
Phase II trial of fixed-dose rate gemcitabine, bevacizumab, and concurrent 30 gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.
Authors: Van Buren George , Ramanathan Ramesh K. , Krasinskas Alyssa M , Smith Ryan , Abood Gerard J. , Shuai Yongli , Potter Douglas M. , Bahary Nathan , Lembersky Barry C. , Zureikat Amer H , Bartlett David L. , Zeh Herbert , Moser Arthur J
Published: February 2017

258

Background: Effective multimodality treatment for localized pancreatic cancer is elusive. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with short-course radiotherapy (RT) and the angiogenesis inhibitor bevacizumab (BEV) would improve margin negative surgical outcomes and complete pathological response rates.

Methods: Multisite phase II trial evaluating all potentially-resectable pancreatic adenocarcinoma without major arterial involvement or portal venous occlusion. Dual primary endpoints included complete pathological response and margin negative resection rates of 10% and 80%. Subjects received FDR GEM on days 1, 15, and 29 combined with BEV (10 mg/kg IV), followed on day 43 by BEV and concurrent 30 Gy RT (3 Gy/fraction) over 10 days. After restaging, subjects underwent laparoscopy and possible resection after day 85. Stopping criteria required continuous monitoring of serious wound complications.

Results: 58 subjects enrolled, of which 29 (50%) had suspected venous involvement. 57 completed treatment without dose-limiting toxicity or delays in surgery. Two grade 4 (3.4%) and 17 grade 3 toxicities (28.8%) occurred. Four patients progressed before surgery. 54 subjects underwent laparoscopy; ten had unexpected carcinomatosis, and one was unresectable. 43 subjects were resected (74%; 33 pancreatico-duodenectomy, 8 distal pancreatectomy, 1 total pancreatectomy, 1 Appleby); 19 (44%) required portal vein resection. Margin negative outcome was achieved in 38 (88%, 95% CI: 75%-96%) with one complete pathological response (2.3%; 95% CI: 0.1%- 12%) and seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival (OS) was 16.3 months (95% CI: 13.9 -22.1) and 21.3 months (95% CI: 15.0-32.9) after resection. Median progression-free survival (PFS) was 5.7 months (95% CI: 3.9-9.1) and 9.9 months (95% CI: 5.7 to 14.1) after resection, with 7 local and 21 distant recurrences.

Conclusions: Combination therapy was well-tolerated and was within statistical design parameters for the primary endpoints despite a significant proportion of borderline tumors.
A phase II trial of gemcitabine and S-1 therapy in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer (JSAP-03).
Authors: Saiura Akio , Ueno Hideki , Kosuge Tomoo , Matsuyama Yutaka , Ishii Hiroshi , Nakao Akimasa , Doi Ryuichiro , Tanaka Masao
Published: February 2017

263

Background: Although anti-tumor effect of gemcitabine (G) and S-1 (S) therapy is high for advanced pancreatic cancer (PC) patients, safety and effectiveness of postoperative GS adjuvant therapy has not been fully examined.

Methods: Eligibility criteria included macroscopically curative resection of invasive ductal PC and no prior chemotherapy. Patients were recruited in 19 institutes. The primary endpoint was overall survival (OS). The patients received G (800 mg/m2/week) intravenously over 30 min on day 1 and S (60 mg/m2/day) orally twice daily from days 1 to 7 every 14 days for 12 cycles.

Results: Fifty-five patients were enrolled in this study. One patient was excluded from the analysis due to no malignant pathology. Remaining 54 patients were analyzed. Deaths were observed in 17 patients (31.5%). Median overall survival was not reached. Estimated 1-year and 2-year OS were 88.9% (95% CI, 76.9-94.8) and 72.1% (95%CI, 58.1-82.2), respectively. Recurrences were observed in 31 patients (57.4%). Estimated 1-year and 2-year disease-free survival were 57.4% (95% CI, 43.2-69.3) and 44.4% (95%CI, 30.9-57.0), respectively. G3 febrile neutropenia was observed in 1.9 % of the patients, whereas the most common adverse reactions were neutropenia (G3/4: 59.2%, G4: 25.9%). There were no G4 adverse events except neutropenia and hyperkalemia (1.9%). G3 adverse events included anemia (3.7%), alanine aminotransferase elevation (3.6%), fatigue (1.9%), nausea (1.9%), vomiting (1.9%) and infection without neutropenia (1.9%). The protocol treatments could not finish in 6 patients due to adverse reactions.

Conclusions: Our phase II results suggest that the postoperative GS therapy is a promising regimen that merits further investigation. Phase III trial of postoperative G versus GS therapy is now going on (JSAP-04).
The natural history and effect of adjuvant therapy on resected AJCC stage I-II lymph node-negative pancreatic cancer.
Authors: McKenzie Shaun , Huang Bin , Tucker Thomas , McGrath Patrick , Jones Dennie V. , Desimone Philip , Evers Mark
Published: February 2017

264

Background: Previous investigation has suggested that early stage, lymph node negative pancreatic adenocarcinoma (PAC) has a relatively good prognosis and adjuvant therapy provides little benefit over surgery alone. The purpose of our trial was to evaluate patients with stage I-II PAC receiving surgical resection to determine their clinical characteristics, overall outcome, and the impact of adjuvant therapy on survival.

Methods: Utilizing the population-based registry data from the Kentucky Cancer Registry (KCR) we identified patients with lymph node negative, AJCC I-II, PAC who underwent pancreatic resection during the years of 1995-2008. Patients were further stratified by receipt of surgery alone versus surgery with adjuvant chemotherapy or chemoradiation. Clinical and pathologic data included patient demographics, tumor characteristics, and lymph node status. Kaplan-Meier and Cox-regression survival analyses were performed.

Results: During the study period, 203 patients meeting criteria were identified from the KCR. Median survival (MS) for the entire cohort was 21.7 months. The majority of patients were >70 years old, Caucasian, had well or moderately differentiated tumors and tumors <5cm. 46% (n=94) and 54% (n=109) of patients had stage I and II disease respectively. When stratified by surgery only (n=119, 59%) versus adjuvant therapy (n=84, 41%), only younger age predicted receipt of adjuvant therapy (p=0.002). Adjuvant therapy provided no benefit over surgery alone regardless of stage (stage I MS: 21.5 vs. 24.7 months, p=0.97 and stage II MS: 24.2 vs. 18.0, p=0.13, respectively). By multivariate analysis, only tumor size >5cm predicted worse survival (HR 2.32, CI 1.21-4.45, p=0.012). Age, stage, adjuvant therapy, differentiation, and lymph node retrieval had no impact on survival.

Conclusions: Our data indicate that the survival for surgically resected early stage, lymph node negative pancreatic adenocarcinoma remains poor and is not improved by the addition of adjuvant chemotherapy. These findings should be considered when designing future adjuvant therapy trials for this deadly disease.
Second interim analysis of GIDEON (Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib): U.S. versus global perspective on patient and disease characteristics, treatment history, and sorafenib use.
Authors: Martin Robert C. G. , El-Khoueiry Anthony B. , Goldenberg Alec , Venook Alan Paul , Mantry Parvez , Gholam Pierre Michel , McGuire Brendan , Sanyal Arun , Geschwind Jeff H. , Marrero Jorge A.
Published: February 2017

278

Background: GIDEON is a global, prospective, noninterventional study of patients (pts) treated with sorafenib (SOR) for unresectable hepatocellular carcinoma (uHCC). Regions evaluated included US, Europe, Japan, Asia Pacific, and Latin America. Detailed regional data were presented by Kudo et al (ILCA 2011, abstr 0-030). Data from the second US interim analysis are compared to global results.

Methods: Eligible pts had uHCC and were treated with SOR. Demographics, disease etiology, treatment history, and SOR dosing were compared in a descriptive, preplanned subgroup analysis.

Results: Global and US safety populations comprised 1571 and 313 pts, respectively. In the US, hepatitis B was less common (18% vs 37% global) whereas hepatitis C was more frequent (53% vs 32% global). Alcoholic liver disease etiology was higher in US pts (41% vs 29% global). US pts were diagnosed with later-stage disease, but fewer US pts had documented BCLC and Child-Pugh status. Fewer US pts had an ECOG PS 0 at start of SOR (28% vs 40% global). Rates of prior surgery and locoregional treatment were similar in US (11% and 49%, respectively) and global pts (19% and 55%, respectively). US pts treated with TACE (n = 116) underwent fewer TACE procedures (≥3: 13.8% vs 38.9% global); most (59%) TACE-treated pts in the US received 1 treatment. In US vs global pts, median time from prior surgery to start of SOR was 10 months (range 1-61) vs 14 months (range 1-181) and median time from last TACE to start of SOR was 3.2 months vs 3.1 months.

Conclusions: Disease characteristics and treatment patterns for pts with uHCC in the US differ from those in the global population. US pts enrolled in GIDEON (ie, receiving SOR) have differing etiologies of liver disease and have a greater proportion of hepatic dysfunction, likely accounting for worse performance status.

[Table: see text]
Smoking and binge drinking among cancer survivors: The forth Korean national health and nutrition examination surveys (KNHANES IV, 2007-2009).
Authors: Han Mi Ah , Oh Myeung Guen , Park Jong , Ryu So Yeon , Choi Seong Woo
Published: February 2017

28

Background: This study aimed to describe the prevalence of smoking and binge drinking among cancer survivors in Korea, and to compare these rates with those of two control groups: individuals without a history of cancer but with other chronic diseases, and individuals without a history of cancer and without other chronic diseases.

Methods: The study is a cross-sectional analysis of 37,878 adults ≥20 years old who participated in the Forth Korean National Health and Nutrition Examination Surveys (KNHANES IV, 2007-2009). The prevalence of smoking and binge drinking were assessed and compared to two control groups. Logistic regression analyses were performed to determine the likelihood and predictors of current smoking and binge drinking.

Results: The prevalence of smoking and binge drinking were 9.6% and 6.6% among cancer survivors, respectively. Cancer survivors showed lower smoking rate compared with both control groups after adjusting gender, age, marital status, education, income and health insurance. Survivors’ smoking and binge drinking did not vary substantially by the clinical factors assessed.

Conclusions: In our study, the smoking rate was significantly low in cancer survivor compared with both control groups. This result suggested that cancer survivors were more likely than individuals without a cancer history to obtain good health related behavior.
Use of probe-based confocal laser endomicroscopy (pCLE) in the diagnosis of cholangiocarcinoma.
Authors: Wysocki John D. , Newby Celeste , Joshi Virendra
Published: February 2017

281

Background: Despite technologic advances in endoscopy and new cytologic techniques, cholangiocarcinoma is a challenging diagnosis for the endoscopist and oncologists. Current sampling techniques include cytology brushing, biopsy, and fine needle aspiration but are limited in their sensitivity. Confocal laser endomicroscopy (CLE) is a relatively new modality that offers in-vivo imaging of the gastrointestinal tract with microscopic detail in living cells.

Methods: This was an observational study of 10 patients with indeterminate biliary strictures who were evaluated with ERCP, cholangioscopy, and CLE to determine the sensitivity and specificity of tissue biopsy compared to virtual biopsy using this new technology, CLE. All cases were confirmed to be cholangiocarcinoma by histopathology. Fluorescein 10% was used as a contrast agent.

Results: The 10 ERCP cases that were reviewed demonstrated biliary strictures that were suspicious for malignancy based on history and clinical presentation. Nearly all initial brushings and traditional biopsies were inconclusive. Subsequent ERCP and cholangioscopy with CLE imaging was performed. The biliary architecture was concerning for malignancy according to the Miami Criteria. Images were reviewed by 2 independent physicians. Every case demonstrated thick bands >20 µm and dark clumps of glands. Bright vessels ( >20 µm) with tortuosity were visualized in seven cases. Other findings include reticular networks of dark bands and small, fine branching bands <20 µm, but these patterns were infrequent.

Conclusions: 1.CLE is a novel tool to investigate indeterminate biliary strictures and potentially diagnose cholangiocarcinoma in conjunction with other diagnostic modalities during the initial ERCP and cholangioscopy. 2. Our early experience found sensitivity 90% , specificity of 100% , NPV 90% 3. CLE gives the opportunity to obtain en-vivo targeted biopsies during cholangioscopy as well as reduce repeat procedures and cost.
Conditional survival probability of patients with resected pancreatic adenocarcinoma.
Authors: Mishra Mark Vikas , Champ Colin Eamon , Showalter Timothy Norman , Keith Scott W. , Anne Pramila R. , Bar-Ad Voichita
Published: February 2017

284

Background: The purpose of this study is to evaluate conditional survival (CS) probabilities for patients with resected pancreatic adenocarcinoma (PC) amongst patients who have survived ≥1 more year(s) after diagnosis.

Methods: Patients with resected PC from 1998-2008 were identified from the Surveillance, Epidemiology and End Results Database. Data on patient, tumor and treatment characteristics were extracted. Overall survival (OS) rates were calculated using the Kaplan-Meier method. A multivariate analysis (MVA) at different time points from survival was performed to determine independent prognostic factors associated with all-cause mortality hazard ratios (HRs) using Cox proportional hazards models.

Results: A total of 4,883 patients with resected PC were identified. Fourteen percent of patients had Stage IA/B disease, 23% Stage IIA, 53% Stage IIB, and 2% Stage IIIA, and 6% with unknown stage. The 1-, 3-, and 5-year survival estimates for patients at diagnosis were 67%, 29%, and 21%, respectively. One, 3- and 5-year survival probabilities conditional upon number of years already survived are shown in table 1. Prognostic factors significantly correlated with improved OS at the time of diagnosis on MVA include: earlier stage, younger age, later year of diagnosis, white race, female gender, and residence in a high income district (p < 0.05). After already surviving 3 years following diagnosis, younger age was the only prognostic factor correlated with improved OS (p<0.05).

Conclusions: CS estimates provide additional prognostic information that may be used to counsel PC patients on how their prognosis may change over time. Further research utilizing prospectively-collected data is warranted to help determine recommended follow-up intervals and benchmarks for future clinical trials.

[Table: see text]