Intrahepatic Cholangiocarcinoma Treated with Transarterial Yttrium-90 Glass Microsphere Radioembolization: Results of a Single Institution Retrospective Study.

PURPOSE: To evaluate the efficacy and safety of transarterial yttrium-90 glass microsphere radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review of 85 consecutive patients (41 men and 44 women; age, 73.4 ± 9.3 years) was performed. Survival data were analyzed by the Kaplan-Meier method, Cox regression models, and the log-rank test. RESULTS: Median overall survival (OS) from diagnosis was 21.4 months (95% confidence interval [CI]: 16.6-28.4); median OS from radioembolization was 12.0 months (95% CI: 8.0-15.2). Seven episodes of severe toxicity occurred. At 3 months, 6.2% of patients had partial response, 64.2% had stable disease, and 29.6% had progressive disease. Median OS from radioembolization was significantly longer in patients with Eastern Cooperative Oncology Group (ECOG) scores of 0 and 1 than patients with an ECOG score of 2 (18.5 vs 5.5 months, P = .0012), and median OS from radioembolization was significantly longer in patients with well-differentiated histology than patients with poorly differentiated histology (18.6 vs 9.7 months, P = .012). Patients with solitary tumors had significantly longer median OS from radioembolization than patients with multifocal disease (25 vs. 6.1 months, P = .006). The absence of extrahepatic metastasis was associated with significantly increased median OS (15.2 vs. 6.8 months, P = .003). Increased time from diagnosis to radioembolization was a negative predictor of OS. The morphology of the tumor (mass-forming or infiltrative, hyper- or hypo-enhancing) had no effect on survival. Post-treatment increased cancer antigen 19-9 level, increased international normalized ratio, decreased albumin, increased bilirubin, increased aspartate aminotransferase, and increased Model for End-Stage Liver Disease score were significant predictors of decreased OS. CONCLUSIONS: These data support the therapeutic role of radioembolization for the treatment of unresectable ICC with good efficacy and an acceptable safety profile.

Predictors and survival for pathologic tumor response grade in borderline resectable and locally advanced pancreatic cancer treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy.

BACKGROUND: Neoadjuvant therapy response correlates with survival in multiple gastrointestinal malignancies. To potentially augment neoadjuvant response for pancreas adenocarcinoma, we intensified treatment with stereotactic body radiotherapy (SBRT) following multi-agent chemotherapy. Using this regimen, we analyzed whether the College of American Pathology (CAP) tumor regression grade (TRG) at pancreatectomy correlated with established response biomarkers and survival. MATERIALS AND METHODS: We identified borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer patients treated according to our institutional clinical pathway who underwent surgical resection with reported TRG (n = 81, median follow-up after surgery 24.2 months). Patients had baseline CA19-9, computed tomography (CT), endoscopic ultrasound, and FDG positron emission tomography (PET)/CT then underwent multi-agent chemotherapy (79% with three cycles of gemcitabine, docetaxel and capecitabine) followed by 5-fraction SBRT. They then underwent restaging CT, PET/CT and CA19-9. Overall (OS) and progression-free (PFS) survival were estimated and compared by Kaplan-Meier and log-rank methods. Univariate ordinal logistic regression correlated TRG with baseline, restaging and change in CA19-9 and the PET maximum standardized uptake value (SUVmax). RESULTS: Restaging level and decrease in CA19-9 correlated with improved TRG (p = .02 for both) as did restaging SUVmax (p < .01), yet there was no TRG correlation with decrease in SUVmax (p = .10) or CT response (p = .30). The TRG groups had similar OS and PFS except the TRG 0 (complete response) group. Compared to partial response levels (TRG 1-3, median OS 33.9 months, median PFS 13.0 months), the six (7%) patients with TRG 0 had no deaths (p = .05) and only one progression (p = .03). A group of 10 (12%) TRG 1 patients with only residual isolated tumor cells had similar outcomes to the other TRG 1-3 patients. CONCLUSION: Pre-operative PET-CT and CA19-9 response correlate with histopathologic tumor regression. Patients with complete pathologic response have superior outcomes, suggesting a rationale for intensification and personalization of neoadjuvant therapy in BRPC and LAPC.

Systematic Review and Case Series Report of Acinar Cell Carcinoma of the Pancreas.

BACKGROUND: Acinar cell carcinoma of the pancreas is a rare malignancy representing less than 1% of all pancreatic malignancies. METHODS: We report on a case series of 21 patients with acinar cell carcinoma of the pancreas treated at a high-volume quaternary center. A systematic review of the medical literature was performed that described typical therapeutic management approaches for acinar cell carcinoma of the pancreas and reported on disease control and survival rates. Data for the case series were obtained from a prospective database. RESULTS: In our systematic review of 6 articles, study patients had a median age of 61 years, 66% were male, 52% had stage I/II disease, and 55% of lesions were located in the pancreatic head. The rates of median survival were approximately 47 months after resection with adjuvant therapy, 38 months for nonmetastatic, locally unresectable disease, and 17 months for metastatic disease treated with chemotherapy. Combination fluoropyrimidine-based chemotherapy regimens had better rates of disease control than other therapies. Our case series included 21 study patients, 14 of whom required resection and 7 who had metastatic disease. The rates of median survival were 40.2 ± 31.9 months in those who underwent surgery and were treated with adjuvant therapy and 13.8 ± 11.3 months for patients with metastatic disease. CONCLUSIONS: Multidisciplinary treatment for acinar cell carcinoma of the pancreas should be considered due to the rarity of the disease and its lack of high-level therapeutic data. Progress in the molecular analysis of this tumor may improve outcomes through the use of personalized therapy based on underlying tumor mutations.

Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma.

PURPOSE: Limited data are available to guide neoadjuvant treatment of borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer. MATERIAL AND METHODS: We updated our institutional outcomes with a neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) approach. An IRB-approved analysis was performed of all BRPC and LAPC patients treated with our departmental treatment protocol. After staging, medically fit patients underwent chemotherapy for 2-3 months, with regimen at the discretion of the treating medical oncologist. Patients then received SBRT delivered in five consecutive daily fractions with median total radiation doses of 30 Gy to tumor and 40 Gy dose painted to tumor-vessel interfaces. This was followed by restaging imaging for possible resection. Overall survival (OS), event free survival (EFS), and locoregional control (LRC) rates were estimated and compared by Kaplan-Meier and log-rank methods. RESULTS: We identified 159 patients, 110 BRPC and 49 LAPC, with 14.0 months median overall follow-up. The resection and margin negative (R0) rate for BRPC patients who completed neoadjuvant therapy was 51% and 96%, respectively. Estimated median OS was 19.2 months for BRPC patients and 15.0 months for LAPC patients (p = 0.402). Median OS was 34.2 months for surgically resected patients versus 14.0 months for unresected patients (p < 0.001). Five of 21 (24%) LAPC patients receiving FOLFIRINOX chemotherapy underwent R0 resection. In LAPC, FOLFIRINOX recipients underwent R0 resection more often than other chemotherapy recipients (5 of 21 vs. 0 of 28, p = 0.011). There was a trend for improved survival in those resected LAPC patients (p = 0.09). For those not undergoing resection, one year LRC was 78%. Any grade ≥ 3 potentially radiation-related toxicity rate was 7%. CONCLUSIONS: These data underscore the feasibility, safety, and effectiveness of neoadjuvant SBRT and chemotherapy for BRPC and LAPC.

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors.

AIMS: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. MATERIALS & METHODS: Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. RESULTS: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. CONCLUSION: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Comparative long-term outcomes of upfront resected pancreatic cancer after preoperative biliary drainage.

BACKGROUND: We evaluated whether preoperative biliary drainage was predictive of recurrence and survival among patients with resectable pancreatic cancer. METHODS: Patients with pancreatic cancer who were treated with upfront surgery between 2000 and 2012 were identified and stratified by preoperative percutaneous transhepatic cholangiogram-guided drainage (PTBD), placement of endoscopic stents (ERCP), or no biliary drainage (NBD). The primary endpoint was overall survival. RESULTS: We identified 193 patients with resectable pancreatic head cancer (33 PTBD; 96 ERCP; and 64 NBD). Key differences between the three groups were more patients who underwent >1 preoperative biliary procedures (p = 0.004) in the PTBD cohort. PTBD patients had a significant increase in hepatic recurrence rate compared with patients who did not undergo PTBD (44.8 vs. 23.3 %, p = 0.02). PTBD patients also had worse overall survival. Median and 5-year survival for PTBD, ERCP, and NBD patients were 17.5 months and 3 %, 22.4 months and 24 %, and 28.9 months and 32 %, respectively (p = 0.002). MVA revealed that percutaneous drainage was an independent predictor of worse overall survival [HR 1.76, 95 % CI (1.05-2.99), p = 0.03]. CONCLUSIONS: Patients with resectable pancreatic cancer who receive PTBD have more advanced disease, higher hepatic recurrence, and worse survival.

Adjuvant radiotherapy and lymph node dissection in pancreatic cancer treated with surgery and chemotherapy.

BACKGROUND: The objective of this study was to determine the effects of postoperative radiation therapy (PORT) and lymph node dissection (LND) on survival in patients with pancreatic cancer. METHODS: The 2004 to 2008 Surveillance, Epidemiology, and End Results (SEER) database was analyzed to identify patients with pancreatic cancer who underwent surgery and received chemotherapy and to evaluate the correlation between overall survival (OS), PORT, and LND. RESULTS: In total, 2966 patients were identified who underwent pancreatic resection (1842 PORT, 1124 no PORT). Median survival, 1-year OS, and 3-year OS were 21 months, 77%, and 28%, respectively, with PORT versus 20 months, 70%, and 25%, respectively, without PORT (P = .02). Subset analysis revealed that the benefit of PORT was limited to lymph node-positive (N1) patients. Median survival, 1-year OS, and 3-year OS for patients with N1 disease were 19 months, 73%, and 25%, respectively, for those who received PORT versus 18 months, 67%, and 20%, respectively, for those who did not receive PORT (P < .01). An increasing lymph node count was associated with increased survival on multivariate analysis in all patients and in patients with N1 disease (both P < .001). Significant cutoff points for OS based on LND in patients with N1 disease were identified for those who had ≥8, ≥10, ≥12, ≥15, and ≥20 lymph nodes resected. Multivariate analysis for OS revealed that increasing age, T3 and T4 tumors, N1 stage, and moderately and poorly differentiated grade were prognostic for increased mortality, while female gender, PORT, and LND were prognostic for decreased mortality. In patients with N1 disease, other than patient age, all of these factors remained significant. In patients with N0 disease, only T1 and T2 tumor classification and having a tumor that was less than high grade were associated with survival benefit. CONCLUSIONS: This SEER analysis demonstrated an associated survival benefit of PORT and LND in patients with N1, surgically resected pancreatic cancer who received chemotherapy.

Novel pancreatic cancer vaccines could unleash the army within.

BACKGROUND: Despite recent progress with novel chemotherapy regimens, pancreatic ductal adenocarcinoma remains the fourth leading cause of cancer death in the United States. Innovative approaches to treatment of this disease are needed to accelerate progress. METHODS: A review was conducted of the results of 2 pancreatic cancer vaccine programs with results that have shown promise in early-phase clinical trials. RESULTS: In a phase 2 trial, a cell-based allogeneic pancreatic cancer vaccine exploiting the hyperacute rejection response targeted against alpha-1,3 galactosyl epitopes (algenpantucel-L) has shown improvement in disease-free and overall survival rates in the adjuvant setting compared with a historical control. This vaccine has advanced to ongoing phase 3 trials. Compared with GVAX alone, a second whole-cell vaccine employing GM-CSF-expressing pancreatic cancer cells (GVAX) to enhance the antigen presentation in a priming phase followed by a Listeria-based vaccine targeting mesothelin in a boost phase improved survival rates. This vaccine platform is undergoing additional phase 2 testing. CONCLUSIONS: Allogenic whole-cell pancreatic adenocarcinoma vaccines show promise in early-phase trials and have the potential to improve survival rates by unleashing antitumor immunity.

Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family.

Leukocyte adhesion deficiencies are rare clinical syndromes of impaired host defense that provide novel insights into regulation of immune and inflammatory responses. Leukocyte adhesion deficiency (LAD)-I variant (LAD-Iv), also called LAD-III, is a unique disorder in which inside-out signaling of ß1, ß2, and ß3 integrins on leukocytes and platelets is disrupted, leading to impaired cellular adhesion, recurrent infections, and bleeding. We originally reported the second patient with this disorder to be identified and characterized the adhesive deficiencies and functional phenotype of this subject's leukocytes. Here, we show that the molecular defect in this index subject is a new mutation in FERMT3 (KINDLIN-3) which encodes KINDLIN-3, a cytoskeletal protein that interacts with the cytoplasmic tails of ß1, ß2, and ß3 integrins and is required for inside-out and outside-in signaling of these heterodimers. We also report clinical features and previously unrecognized defects in cells from a new patient, a sibling of the original subject that we described who carries the same FERMT3 mutation. Mutations in FERMT3 have now been shown to be the basis for LAD-Iv/LAD-III in each of the four original patients or families that established this syndrome, including the family that we describe.

Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study.

BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer.

Borderline resectable pancreatic cancer: on the edge of survival.

BACKGROUND: Patients with borderline resectable pancreatic cancer are at high risk of having positive surgical margins due to involvement of the tumor with adjacent vasculature. This article reviews the management of this subset of pancreatic cancer patients. METHODS: The authors review the current definitions of borderline resectable pancreatic cancer and how it is diagnosed and staged. The history, current approaches, and future directions in neoadjuvant therapy for borderline resectable pancreatic cancer are also reviewed with emphasis on various chemotherapy regimens that have been used. The application of intensity-modulated radiation therapy and image-guided radiation therapy that accounts for respiratory motion to targeting the gross tumor volume in the pancreas are discussed, and the promise of integrating targeted therapies in neoadjuvant treatment programs is highlighted. RESULTS: The use of neoadjuvant treatment programs that employ gemcitabine-based chemotherapy regimens followed by chemoradiation increases the likelihood of subsequent margin-negative resection in borderline resectable pancreatic cancer. CONCLUSIONS: There has been progress in the imaging, staging, surgical technique, and the use of chemotherapy and chemoradiotherapy in the management of borderline resectable pancreatic cancer. Patients can benefit from multidisciplinary management at high-volume pancreatic cancer treatment centers.

A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing.

PURPOSE: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies. EXPERIMENTAL DESIGN: Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity. RESULTS: Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses>or=100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P=0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect. CONCLUSION: This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.

Clinical Outcomes of Patients With Gastrointestinal Malignancies Participating in Phase I Clinical Trials.

OBJECTIVES: Early-phase clinical trials play a pivotal role in drug development. However, limited data are available on outcomes of gastrointestinal (GI) cancer patients enrolled in phase I clinical trials. Here, we evaluated the characteristics associated with survival in GI cancer patients participating in phase I clinical trials and attempted to validate previously established prognostic models. MATERIALS AND METHODS: All consecutive patients with advanced GI tumors who participated in phase I clinical trials at our institution from January 2007 to December 2013 and received at least 1 dose of the study drug were included. Cox regression models were used to estimate multivariable-adjusted hazard ratio (HR) and 95% confidence interval. RESULTS: In 243 study patients (median age, 62 y [range, 26 to 82 y]; 55% male), treatment included chemotherapy only (14%), targeted therapy (41%), chemotherapy+targeted therapy (42%), and others (2%) for the following disease types: pancreatic (42%), colorectal (34%), gastroesophageal (10%), hepatobiliary (13%), and others (2%). Response rate was 4%, with 38% achieving stable disease and 42% having progressive disease. Median survival was 5.8 months (range, 0.2 to 52.4 mo). Our multivariable Cox regression analyses included the following as predictors of survival: Eastern Cooperative Oncology Group performance score ≥1 (HR=1.76), prior systemic therapies ≥2 (HR=1.63), lactate dehydrogenase >618 IU/L (HR=1.85), sodium >135 mmol/L (HR=0.46), and white blood count >6×10/L (HR=1.5). Our data set was consistent with previous prognostic scores. CONCLUSIONS: This is the largest study to assess clinical outcomes in this patient population. Phase I trials provide clinical benefit to patients with advanced GI malignancies and should be recommended as a treatment option in appropriate patients.

Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail.

BACKGROUND: The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. METHODS: Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. RESULTS: Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20-25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. CONCLUSIONS: Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS.

Genetic structure of the dopamine receptor D4 gene (DRD4) and lack of association with schizophrenia in Japanese patients.

In order to investigate the contribution of genetic variation in the human dopamine receptor D4 gene (DRD4) to the risk of developing schizophrenia, we carried out a genetic analysis of 27 polymorphisms in 216 schizophrenic patients and 243 healthy controls from the Kyushu region of Japan. Twenty-two single nucleotide polymorphisms (SNPs) and five insertion/deletion polymorphisms were analyzed in this study, including four novel SNPs and a novel mononucleotide repeat. Linkage disequilibrium (LD) and haplotype analyses reveal weak LD across the DRD4 gene. In univariate analysis female individuals with allele -521C had a higher risk for schizophrenia. However, this finding was not significant after correction for multiple hypothesis testing. No other polymorphisms or haplotypes differed between schizophrenic patients and controls. Likewise, multivariate analyses did not reveal any statistically significant associations.

Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies.

Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase beta (LPAAT-beta), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-beta converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-beta was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-beta using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-beta also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-beta was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-alpha. These findings identify LPAAT-beta as a potential prognostic and therapeutic target in ovarian and endometrial cancer.

Outcomes of adjuvant radiotherapy and lymph node resection in elderly patients with pancreatic cancer treated with surgery and chemotherapy.

BACKGROUND: We sought to determine the effects of post-operative radiation therapy (PORT) and lymph node resection (LNR) on survival in patients ≥70 years with pancreatic cancer treated with surgery and chemotherapy. METHODS: An analysis of patients ≥70 years with surgically resected pancreatic cancer who received chemotherapy from the SEER database between 2004-2008 was performed to determine association of PORT and LNR on survival. RESULTS: We identified 961 patients who met inclusion criteria. There was a trend towards increased survival associated with PORT in all patients (P=0.052) and N1 patients (P=0.060) but no benefit in N0 patients (P=0.161). There was no difference in OS based on number of lymph nodes removed in all (P=0.741), N0 (P=0.588), and N1 (P=0.070) patients. MVA for all patients revealed that higher T stage, N1, and high grade tumors were prognostic for increased mortality, while there was decreased mortality with PORT and mild benefit with increased lymph nodes resected (P=0.084). CONCLUSIONS: PORT demonstrated no benefit in survival of pancreatic cancer patients ≥70 who are resected and treated with adjuvant chemotherapy. Future investigation will need to address age as a stratification factor for pancreatic cancer in the adjuvant setting.

Longitudinal cohort study to determine effectiveness of a novel simulated case and feedback system to improve clinical pathway adherence in breast, lung and GI cancers.

OBJECTIVES: This study examined whether a measurement and feedback system led to improvements in adherence to clinical pathways. DESIGN: The M-QURE (Moffitt-Quality, Understanding, Research and Evidence) Initiative was introduced in 2012 to enhance and improve adherence to pathways at Moffitt Cancer Center (MCC) in three broad clinical areas: breast, lung and gastrointestinal (GI) cancers. M-QURE used simulated patient vignettes based on MCC's Clinical Pathways to benchmark clinician adherence and monitor change over three rounds of implementation. SETTING: MCC, located in Tampa, Florida, a National Cancer Institute Comprehensive Cancer Center. PARTICIPANTS: Three non-overlapping cohorts at MCC (one each in breast, lung and GI) totalling 48 providers participated in this study, with each member of the multidisciplinary team (composed of medical oncologists, radiation oncologists, surgeons and advanced practice providers) invited to participate. INTERVENTIONS: Each participant was asked to complete a set of simulated patient vignettes over three rounds within their own cancer specialty. Participants were required to complete all assigned vignettes over each of the three rounds, or they would be excluded from this study. PRIMARY OUTCOME MEASURE: Increased domain and overall provider care adherence to clinical pathways, as scored by blinded physician abstractors. RESULTS: We found significant improvements in pathway adherence between the third and first rounds of data collection particularly for workup and treatment of cancer cases. By clinical grouping, breast improved by 13.6% (p<0.001), and lung improved by 12.1% (p<0.001) over baseline, whereas GI showed a decrease of 1.4% (p=0.68). CONCLUSIONS: Clinical pathway adherence improved in a short timeframe for breast and lung cancers using group-level measurement and individual feedback. This suggests that a measurement and feedback programme may be a useful tool to improve clinical pathway adherence.

Favorable perioperative outcomes after resection of borderline resectable pancreatic cancer treated with neoadjuvant stereotactic radiation and chemotherapy compared with upfront pancreatectomy for resectable cancer.

BACKGROUND: Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) are utilized to increase margin negative (R0) resection rates in borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) patients. Concerns persist that these neoadjuvant therapies may worsen perioperative morbidities and mortality. METHODS: Upfront resection patients (n=241) underwent resection without neoadjuvant treatment for resectable disease. They were compared to BRPC or LAPC patients (n=61) who underwent resection after chemotherapy and 5 fraction SBRT. Group comparisons were performed by Mann-Whitney U or Fisher's exact test. Overall Survival (OS) was estimated by Kaplan-Meier and compared by log-rank methods. RESULTS: In the neoadjuvant therapy group, there was significantly higher T classification, N classification, and vascular resection/repair rate. Surgical positive margin rate was lower after neoadjuvant therapy (3.3% vs. 16.2%, P=0.006). Post-operative morbidities (39.3% vs. 31.1%, P=0.226) and 90-day mortality (2% vs. 4%, P=0.693) were similar between the groups. Median OS was 33.5 months in the neoadjuvant therapy group compared to 23.1 months in upfront resection patients who received adjuvant treatment (P=0.057). CONCLUSIONS: Patients with BRPC or LAPC and sufficient response to neoadjuvant multi-agent chemotherapy and SBRT have similar or improved peri-operative and long-term survival outcomes compared to upfront resection patients.