Pancreatectomy predicts improved survival for pancreatic adenocarcinoma: results of an instrumental variable analysis.

BACKGROUND AND OBJECTIVE: Pancreatic resection is the standard treatment option for patients with stage I/II pancreatic ductal adenocarcinoma (PDA), yet many studies demonstrate low rates of resection. The objective of this study was to evaluate whether increasing resection rates would result in an increase in average survival in patients with stage I/II PDA. METHODS: SEER (Surveillance, Epidemiology, and End Results) data were analyzed for patients with stage I/II pancreatic head cancers treated from 2004 to 2009. Pancreatectomy rates were examined within Health Service Areas (HSAs) across 18 SEER regions. An instrumental variable analysis was performed, using HSA rates as an instrument, to determine the impact of increasing resection rates on survival. RESULTS: Pancreatectomy was performed in 4322 of 8323 patients evaluated with stage I/II PDA (overall resection rate = 51.9%). The resection rate across HSAs ranged from an average of 38.6% (lowest quintile) to 67.3% (highest quintile). Median survival was improved in HSAs with higher resection rates. Instrumental variable analysis revealed that, for patients whose treatment choices were influenced by rates of resection in their geographic region, pancreatectomy was associated with a statistically significant increase in overall survival. CONCLUSIONS: When controlling for confounders using instrumental variable analysis, pancreatectomy is associated with a statistically significant increase in survival for patients with resectable PDA. On the basis of these results, if resection rates were to increase in select patients, then average survival would also be expected to increase. It is important that this information be provided to physicians and patients so that they can properly weigh the risks and advantages of pancreatectomy as treatment of PDA.

Sarcopenia is an independent predictor of complications following pancreatectomy for adenocarcinoma.

BACKGROUND AND OBJECTIVES: Sarcopenia, which is subclinical loss of skeletal muscle mass, is commonly observed in patients with malignancy. The objective of this study is to determine the correlation between sarcopenia and operative complications following pancreatectomy for cancer. METHODS: A retrospective review of a pancreatectomy database was performed. The Hounsfield Unit Average Calculation (HUAC) of the psoas muscle, a marker of muscle density and fatty infiltration, was measured from preoperative CT scans. Complications were graded and multivariate logistic regression analysis was performed. RESULTS: One hundred eighteen patients met criteria for analysis; the overall morbidity rate was 78.8% (n = 93). There were 31 (26.3%) patients who met criteria for sarcopenia using the HUAC. When analyzed as a continuous variable, sarcopenia was an independent predictor of major grade III complications, length of stay, intensive care unit admission, delayed gastric emptying, and infectious, gastrointestinal, pulmonary, and cardiac complications. CONCLUSIONS: These data suggest that sarcopenia as measured with the HUAC, a value that can be obtained from a preoperative CT scan, is a significant independent predictor of surgical outcome and can be used to improve patient selection and informed consent prior to pancreatectomy in patients with cancer.

A matched case-control study of IBD-associated colorectal cancer: IBD portends worse outcome.

BACKGROUND AND OBJECTIVES: The effect of inflammatory bowel disease (IBD) on outcome in patients with colorectal cancer (CRC) remains unclear. Our objective is to evaluate oncologic outcomes of patients with IBD-associated CRC. METHODS: We retrospectively reviewed a prospectively maintained database to identify patients with IBD-associated CRC. Clinicopathologic variables and overall survival were compared to patients with sporadic CRC using a 2:1 matched-controlled analysis. RESULTS: Fifty-five patients with IBD and CRC were identified. On univariate analysis, CRC patients with IBD had a significantly shorter median overall survival (68.2 months vs. 204.3 months, P = 0.01) compared to patients with sporadic CRC. On multivariate analysis, after adjusting for N and M stage, IBD was associated with an increased risk of death compared to sporadic CRC (HR = 2.011, 95% CI 1.24-3.23, P = 0.004). Stage 3 CRC patients with IBD in particular showed significantly decreased survival (23.0 vs. 133.9 months, P = 0.008). CONCLUSIONS: In this study, patients with node-positive IBD-associated CRC had a significant increased risk of death and a shorter overall survival than those with sporadic disease and may require tailored adjuvant therapy and surveillance protocols. Continued investigation to elucidate the mechanisms that contribute to these observations is justified.

Population-based exploration of academic achievement outcomes in pediatric acute lymphoblastic leukemia survivors.

OBJECTIVE: Examine academic achievement among pediatric acute lymphoblastic leukemia survivors diagnosed during the years 1993-2008. METHOD: A deterministic linkage of the Iowa Cancer Registry and Iowa Testing Programs databases was performed and yielded 147 survivors. Achievement data, in the form of Iowa Percentile Rank scores, were obtained and analyzed by grade and content domain. RESULTS: Children diagnosed before age 5 evidenced more underachievement than those diagnosed later (p = .05). Underachievement was noted in mathematics in grades 8 and 11 (p's < .05), in addition to a longitudinal decrease in scores from grades 4 through 11 (p = .01). No differences were found in academic achievement between males and females. CONCLUSIONS: Utilization of a population-based approach with a nationally recognized, standardized instrument indicates that academic underachievement is subtle yet exists, most notably in mathematics.

Insurance Status Is Related to Receipt of Therapy and Survival in Patients with Early-Stage Pancreatic Exocrine Carcinoma.

Objectives. The study objective was to determine how insurance status relates to treatment receipt and overall survival for patients with early-stage pancreatic exocrine carcinoma. Methods. SEER data were evaluated for 17,234 patients diagnosed with Stage I/II pancreatic exocrine carcinoma. Multivariate regression models controlled for personal characteristics to determine whether insurance status was independently associated with overall survival and receipt of radiation/surgery. Results. Odds of receiving radiation were 1.50 and 1.75 times higher for insured patients compared to Medicaid and uninsured patients, respectively (p < 0.01). Insured patients had 1.68 and 1.57 times increased odds of receiving surgery compared to Medicaid and uninsured patients (p < 0.01). Risk of death was 1.33 times greater (p < 0.01) in Medicaid patients compared to insured patients; when further adjusted for treatment, the risk of death was attenuated but remained significant (HR = 1.16, p < 0.01). Risk of death was 1.16 times higher for uninsured patients compared to insured patients (p = 0.02); when further adjusted for treatment, the risk of death was no longer significant (HR = 1.01, p = 0.83). Conclusions. Uninsured and Medicaid-insured patients experience lower treatment rates compared to patients who have other insurances. The increased likelihood of treatment appears to explain the insured group's survival advantage.

Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor ß-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells.

Transforming growth factor ß-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH) and glutathione disulfide (GSSG). Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1-induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors.

TP53 oncomorphic mutations predict resistance to platinum­ and taxane­based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma.

Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non-functional protein, whereas others confer oncogenic activity, which we term 'oncomorphic'. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high-grade serous ovarian cancer patients uniformly treated with standard platinum- and taxane-based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas (TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function (LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression-free survival (PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence (HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance (χ(2) test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.

Relationships between chemotherapy, chemotherapy dose intensity and outcomes of follicular lymphoma in the immunochemotherapy era: a report from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource.

The optimal treatment of follicular lymphoma (FL) is not established. Rituximab's value potentially dilutes the impact of chemotherapy on FL. We reviewed 337 cases of FL treated initially with rituximab as monotherapy or with chemotherapy at the University of Iowa/Mayo Clinic from 2002 to 2009, investigating the association between chemotherapy delivery of cyclophosphamide or doxorubicin and survival. With median follow-up duration of 52.7 months, event-free survival (EFS) and overall survival (OS) were similar between the two groups, with a trend toward better EFS in the R-chemotherapy cohort (hazard ratio [HR]=1.24, p=0.28). In the R-chemotherapy group, increased total dose delivery and delivered dose intensity of doxorubicin were associated with improved EFS only in patients who did not receive R-maintenance (HR=0.81; p=0.02 and HR=0.94; p=0.04). Cyclophosphamide delivery was not associated with EFS. Thus, in the immunochemotherapy era, chemotherapy delivery strategy requires re-evaluation.

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. EXPERIMENTAL DESIGN: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. RESULTS: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. CONCLUSIONS: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.

Morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions: analysis of the American College of Surgeons National Surgical Quality Improvement Program data.

IMPORTANCE: Splenectomy is a commonly performed operation; however, data from large series regarding operative outcomes to help guide decision making and informed consent are lacking. OBJECTIVE: To evaluate clinical and pathologic variables associated with morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions in the United States. DESIGN, SETTING, AND PARTICIPANTS: A review of the American College of Surgeons National Surgical Quality Improvement Program data for elective splenectomy between January 1, 2005, and December 31, 2011, was performed, and 1715 eligible individuals were identified. INTERVENTION: Elective splenectomy for hematologic conditions. MAIN OUTCOMES AND MEASURES: Complications and operative mortality were evaluated for the entire cohort and compared between patients with benign vs malignant diseases. Multivariable logistic regression was used to evaluate factors predictive of operative complications and death. RESULTS: Splenectomy was performed in 1344 patients (78.4%) for benign disease and in 371 patients (21.6%) for malignant disease. Two hundred ninety-one patients (17.0%) had a complication, and operative mortality occurred in 27 patients (mortality rate, 1.6%). Patients treated for malignant disease had a higher rate of overall complications (27.2%) compared with patients treated for benign disease (14.1%) (P < .001). Several variables were independent predictors of complications, including malignant disease (vs benign) (Odds Ratio [OR], 1.86; 95% CI, 1.23-2.80; P = .003), independent performance status (vs dependent) (OR, 0.33; 95% CI, 0.07-1.52; P = .02), and increasing albumin level (OR, 0.75; 95% CI, 0.66-0.86; P < .001). Increasing age (OR, 1.03; 95% CI, 1.00-1.06; P = .05) was an independent predictor of mortality while increasing albumin level (OR, 0.63; 95% CI, 0.46-0.86; P = .003) predicted lower risk of operative death. From these data, a patient older than 60 years with a low preoperative albumin level has a predicted probability for operative death as high as 10.0%. CONCLUSIONS AND RELEVANCE: Preoperative performance and nutritional status are significant risk factors for complications and mortality following elective splenectomy. Although operative mortality continues to decrease over time, specific preoperative variables may help with patient selection before elective splenectomy for certain patients.

Randomized trial of pentoxifylline and vitamin E vs standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter.

PURPOSE: To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). METHODS AND MATERIALS: Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. RESULTS: The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. CONCLUSIONS: This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.

A comprehensive assessment of transfusion in elective pancreatectomy: risk factors and complications.

BACKGROUND: Specific data are needed regarding the impact of transfusion on operative complications in pancreatectomy. The objectives of this study were to determine risk factors for transfusion and to evaluate the potential association between transfusion and operative complications in elective pancreatectomy procedures. STUDY DESIGN: We reviewed our institution's pancreatectomy and ACS-NSQIP databases. Multivariate analysis was used to determine clinicopathologic risk factors predictive of transfusion, and then a transfusion propensity score was developed to evaluate the impact of transfusion on post-pancreatectomy complications. RESULTS: Of the 173 patients who were treated from September 2007 to September 2011, 78 patients (45 %) were transfused ≥ 1 unit of blood (median, 3.0 units; range, 1-55). Risk factors for transfusion included increasing Body Mass Index (BMI), smoking, increasing mortality risk score, preoperative anemia, intraoperative blood loss, and benign pathology. After controlling for these risk factors using a transfusion propensity score, transfusion was an independent predictor of increased complications, infectious complications, and hospital costs. CONCLUSIONS: Multiple factors are predictive of transfusion in pancreatectomy, including increasing BMI and smoking. When controlling for transfusion propensity based on these risk factors, RBC transfusion is associated with worse operative outcomes including infectious complications. Development of protocols and strategies to minimize unnecessary transfusion in pancreatectomy are justified.

Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts.

PURPOSE: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. EXPERIMENTAL DESIGN: Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively. RESULTS: The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. CONCLUSIONS: These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress.