[Show abstract][Hide abstract] ABSTRACT: Pancreatic adenocarcinoma is amongst the most lethal malignancies with dismal five-year survival rates. Surgical excision is the mainstay of therapy and unresectable disease is considered incurable. Herein, we describe a patient with unresectable, advanced stage pancreatic adenocarcinoma with a remarkable clinical course following definitive chemoradiotherapy.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to examine predictors of cancer-related financial difficulties and work modifications in a national sample of cancer survivors.
Using the 2011 Medical Expenditure Panel Survey and Experiences with Cancer Survivorship Supplement, the prevalence of financial difficulties and work modifications was examined. Logistic regression and survey weights were used to model these outcomes as functions of sociodemographic and health covariates separately among survivors in active treatment and survivors under age 65 years.
Among all survivors, 33.2 % reported any financial concern, with 17.9 % reporting financial difficulties such as debt or bankruptcy. Among working survivors, 44.0 % made any work modification and 15.3 % made long-term work modifications (e.g., delayed or early retirement). Among those in active treatment, predictors of financial difficulty included: race/ethnicity other than white, non-Hispanic [OR = 8.0; 95 % CI 2.2-28.4]; income <200 % of federal poverty level (FPL) [OR = 15.7; 95 % CI 2.6-95.2] or between 200 and 400 % of FPL [OR = 8.2; 95 % CI 1.3-51.4]; residence in a non-metropolitan service area [OR = 6.4; 95 % CI 1.6-25.0]; and good/fair/poor self-rated health [OR = 3.8; 95 % CI 1.0-14.2]. Among survivors under age 65 years, predictors of long-term work modifications included good/fair/poor self-rated health [OR = 4.1; 95 % CI 1.6-10.2], being married [OR = 2.2; 95 % CI 1.0-4.7], uninsured [OR = 3.5; 95 % CI 1.3-9.3], or publicly insured [OR = 9.0; 95 % CI 3.3-24.4].
A substantial proportion of cancer survivors experience cancer-related financial difficulties and work modifications, particularly those who report race/ethnicity other than white, non-Hispanic, residence in non-metropolitan areas, worse health status, lower income, and public or no health insurance.
Attention to the economic impact of cancer treatment is warranted across the survivorship trajectory, with particular attention to subgroups at higher risk.
No preview · Article · Jul 2015 · Journal of Cancer Survivorship
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Despite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease.
This review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results.
Promising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation.
No preview · Article · Mar 2015 · Expert Opinion on Investigational Drugs
[Show abstract][Hide abstract] ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) are tumors that arise from hormone-secreting cells of the islets of Langerhans; however, not all tumors will be associated with a clinical syndrome of hormonal hypersecretion. Surgical intervention is guided by overarching principles of functioning/nonfunctioning tumors, extent of disease, and location of the tumor. Even in the setting of advanced disease including hepatic metastasis, surgical intervention may be appropriate and can provide durable periods of disease-free survival. In addition, recent molecular characterization of PNETs has allowed the identification of newer systemic therapies with improving efficacy.
[Show abstract][Hide abstract] ABSTRACT: Background
Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena.Methods
We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined.ResultsCombination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2.Conclusion
The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.
Preview · Article · Dec 2014 · Journal of Experimental & Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Objectives: To evaluate readmission rates and associated factors to identify potentially preventable readmissions. Background: The decision to penalize hospitals for readmissions is compelling health care systems to develop processes to minimize readmissions. Research to identify preventable readmissions is critical to achieve these goals. Methods: We performed a retrospective review of University HealthSystem Consortium database for cancer patients hospitalized from January 2010 to September 2013. Outcome measures were 7-, 14-, and 30-day readmission rates and readmission diagnoses. Hospital and disease characteristics were evaluated to evaluate relationships with readmission. Results: A total of 2,517,886 patients were hospitalized for cancer treatment. Readmission rates at 7, 14, and 30 days were 2.2%, 3.7%, and 5.6%, respectively. Despite concern that premature hospital discharge may be associated with increased readmissions, a shorter initial length of stay predicted lower readmission rates. Furthermore, high-volume centers and designated cancer centers had higher readmission rates. Evaluating institutional data (N = 2517 patients) demonstrated that factors associated with higher readmission rates include discharge from a medical service, site of malignancy, and emergency primary admission. When examining readmission within 7 days for surgical services, the most common readmission diagnoses were infectious causes (46.3%), nausea/vomiting/dehydration (26.8%), and pain (6.1%). Conclusions: A minority of patients after hospitalization for cancer-related therapy are readmitted with potentially preventable conditions such as nausea, vomiting, dehydration, and pain. However, most factors associated with readmission cannot be modified. In addition, high-volume centers and designated cancer centers have higher readmission rates, which may indicate that readmission rates may not be an appropriate marker for quality improvement.
No preview · Article · Oct 2014 · Annals of Surgery
[Show abstract][Hide abstract] ABSTRACT: Purpose
Practice patterns vary with the planning and delivery of post mastectomy radiation therapy (PMRT). Our investigation examines practice patterns in the use of chest wall bolus and a boost among the Athena Breast Health Network (“Athena”).
Athena is a collaboration among the five University of California Medical Centers that aims to integrate clinical care and research . From February 2011 to June 2011, all physicians specializing in the multidisciplinary treatment of breast cancer were invited to take a web-based practice patterns survey. Sixty-two of the 239 questions focused on radiation therapy practice environment, decision making processes, and treatment management, including the use of a bolus or boost in PMRT.
Ninety-two percent of the radiation oncologists specializing in breast cancer completed the survey. All of the responders use a material to increase the surface dose to the chest wall during PMRT. Materials used included brass mesh, commercial bolus, and custom designed wax bolus. Fifty percent used tissue equivalent superflab bolus. Fifty-five percent of the respondents routinely use a boost to the chest wall in PMRT. Eighteen percent give a boost depending on the margin status, and 3/11 (27%) do not use a boost.
Our investigation documents practice pattern variation for the use of a PMRT boost and the use of chest wall bolus among the University of California breast cancer radiation oncologists. Further understanding of the practice pattern variation will help guide clinicians in our cancer centers to a more uniform approach in the delivery of PMRT.
No preview · Article · Aug 2014 · Clinical Breast Cancer
[Show abstract][Hide abstract] ABSTRACT: Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.
Preview · Article · Aug 2014 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Background:
The relationship between procedural relative value units (RVUs) for surgical procedures and other measures of surgeon effort are poorly characterized. We hypothesized that RVUs would poorly correlate with quantifiable metrics of surgeon effort.
Using the 2010 American College of Surgeons - National Surgical Quality Improvement Program (NSQIP) database, we selected 11 primary current procedural terminology codes associated with high volume surgical procedures. We then identified all patients with a single reported procedural RVU who underwent nonemergent, inpatient general surgical operations. We used linear regression to correlate length of stay (LOS), operative time, overall morbidity, frequency of serious adverse events (SAEs), and mortality with RVUs. We used multivariable logistic regression using all preoperative NSQIP variables to determine other significant predictors of our outcome measures.
Among 14,481 patients, RVUs poorly correlated with individual LOS (R(2) = 0.05), operative time (R(2) = 0.10), and mortality (R(2) = 0.35). There was a moderate correlation between RVUs and SAEs (R(2) = 0.79) and RVUs and overall morbidity (R(2) = 0.75). However, among low- to mid-level RVU procedures (11-35) there was a poor correlation between SAEs (R(2) = 0.15), overall morbidity (R(2) = 0.05), and RVUs. On multivariable analysis, RVUs were significant predictors of operative time, LOS, and SAEs (odds ratio 1.06, 95% confidence interval: 1.05-1.07), but RVUs were not a significant predictor of mortality (odds ratio 1.02, 95% confidence interval: 0.99-1.05).
For common, index general surgery procedures, the current RVU assignments poorly correlate with certain metrics of surgeon work, while moderately correlating with others. Given the increasing emphasis on measuring and tracking surgeon productivity, more objective measures of surgeon work and productivity should be developed.
No preview · Article · May 2014 · Journal of Surgical Research
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Changes in health care reimbursement policy have led to an era in which hospitals are motivated to improve quality of care while simultaneously reducing costs. Research demonstrating the most efficient means to target costs may have a positive effect on patient quality of life and the overburdened health care system. OBJECTIVE To evaluate the effect of hospital length of stay (LOS) and the occurrence of postoperative complications on total charges in patients undergoing elective pancreaticoduodenectomy. DESIGN, SETTING, AND PATIENTS We performed a retrospective review of 89 cases identified in an institutional database of patients who underwent elective pancreaticoduodenectomy at an academic tertiary care center from December 1, 2007, through May 31, 2012. MAIN OUTCOMES AND MEASURES Occurrence of postoperative and inpatient complications, LOS, incidence of readmission within 60 days of discharge, and hospital charges from initial postoperative hospitalization. Linear regression analysis was performed comparing LOS with hospital charges. RESULTS Thirty-four of 89 patients (38%) developed postoperative complications. Mean and median LOSs were 12 and 8 days, respectively. The LOS was significantly related to postoperative complications. Of the 34 patients who developed complications, the mean LOS was 19 days compared with 7 days for those patients not developing complications (P < .001). Only 2 of 55 patients (4%) without complications were readmitted to the hospital, whereas 13 of 34 patients (38%) with complications required readmission. Perioperative hospital charges were significantly related to LOS (R2 = 0.840, R = 0.917). For those patients without complications, linear regression demonstrated a daily hospital charge of $11 612 (R2 = 0.923, R = 0.961). However, for those patients with complications, the optimal relationship between LOS and hospital charges was exponential (R2 = 0.832). CONCLUSIONS AND RELEVANCE Prolonged LOS is associated with increased total charges, but given the exponential increase in charges, the complication itself has an effect on increased charges above and beyond that of a prolonged hospitalization. The drive to reduce LOS after pancreaticoduodenectomy has minimal effect on overall charges to the patient. Efforts should be directed instead at reducing complications because this has a much more significant effect on financial outcomes.
[Show abstract][Hide abstract] ABSTRACT: Cancer is the second leading cause of death in the United States. Cancer care is a complex and complicated process involving diverse practitioners, multiple specialists, and a range of inpatient, outpatient, and home care services with numerous transitions for the patients. Cancer patients undergoing chemotherapy are at risk of unplanned emergency visits and hospitalizations and can benefit from care coordination. There are few examples of systems that fully engage patients, family and caregivers along with clinicians and other care resources to collaboratively coordinate chemotherapy. This paper reports on the development of a prototype “personal health network” (PHN) using social networking technology to support patient-centered chemotherapy care coordination in a comprehensive cancer center. Requirements for the prototype were generated by analyzing two frameworks, the cancer continuum framework and the framework for information technology in care coordination, and reviewing the literature on self-management and care coordination. The resulting requirements were implemented and reviewed with a trans-disciplinary team of clinicians and researchers. The PHN was found to fulfill the key requirements identified through the analysis of frameworks. A prototype was built rapidly and reviewed by an internal trans-disciplinary team. The refined prototype will be field tested with patients and nurse care coordinators to assess usefulness and usability in preparation for a larger scale clinical trial.
[Show abstract][Hide abstract] ABSTRACT: Background/Aim: The Akt signaling pathway mediates a potent anti-apoptotic signal in pancreatic cancer and inhibition of this pathway has become an attractive mechanism to increase the efficacy of traditional chemotherapies. Autophagy is a lysosomal catabolic pathway by which eukaryotic cells recycle macromolecules and organelles. Although autophagy may function as a survival mechanism under metabolic stress conditions, it also serves as an alternate route to programmed cell death distinct from apoptosis. In the present study, we examined the role of autophagy in Akt-mediated regulation of cell death in pancreatic cancer.
Mia-PaCa-2 and PANC-1 human pancreatic cancer cell lines were used in our experiments. The small-molecule inhibitor A-443654 was used to inhibit Akt, and rapamycin was used to inhibit mTOR. Autophagy was inhibited with Chloroquine and 3-methyladenine. Autophagy was assessed by immunoblotting for light chain-3 (LC-3) processing as well as fluorescence microscopy for autophagosome formation following transfection with a LC-3/GFP construct. Cell death was determined by fluorescence-activated cell sorting (FACS) with quantitation of the sub-G0 content.
Inhibition of either Akt or mTOR induced autophagy; inhibition of Akt but not of mTOR led to traditional caspase-mediated apoptosis. When autophagy was inhibited, cell death was abrogated following Akt, but not mTOR, inhibition.
The Akt signaling pathway regulates both autophagy and apoptosis through divergent pathways; mTOR mediates autophagy signaling but appears to be un-involved in cell death. Autophagy appears to play a role in the regulation of cell survival by Akt, but only when proximal signaling pathways not involving mTOR are simultaneously activated.
No preview · Article · Feb 2014 · Anticancer research