Theodore P. McDade

26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS‐341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21Cip1‐Waf‐1, a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS‐341 significantly inhibited tumor growth. Both cellular apoptosis and p21Cip1‐Waf‐1 protein levels were increased in PS‐341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS‐341 was combined with the tumoricidal agent CPT‐11. Combined CPT‐11/PS‐341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF‐κB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy. J. Cell. Biochem. 82: 110–122, 2001.

Pancreatic neuroendocrine tumors: the impact of surgical resection on survival

Although surgical resection is generally recommended for patients with localized pancreatic neuroendocrine tumors (PNETs), the impact of resection on overall survival is unknown. The authors investigated the survival advantage of pancreatic resection using a national database.

Sodium salicylate inhibits proliferation and induces G1 cell cycle arrest in human pancreatic cancer cell lines.

The mutations most common in pancreatic cancer decrease the ability to control Gl to S cell cycle progression and cellular proliferation. In colorectal cancer cells, nonsteroidal anti-inflammatory drugs inhibit proliferation and induce cell cycle arrest. We examined whether sodium salicylate, an aspirin metabolite, could inhibit proliferation in human pancreatic cancer cell lines (BxPC3 and Panc-1). Quiescent cells were treated with medium containing 10% fetal calf serum, with or without salicylate. Cellular proliferation was measured by MTT assay and bromodeoxyuridine incorporation. The fractions of cells in G0/G1, S, and G2/M phases of the cell cycle were quantitated by fluorescence-activated cell sorting. Results were compared between groups by two-tailed t test. Cydin Dl expression was determined by Western blot analysis and prostaglandin E2 expression by enzyme-linked immunosorbent assay. Serum-starved cells failed to proliferate, with most arrested in the Gl phase. Salicylate significantly inhibited serum-induced progression from Gl to S phase, cellular proliferation, and the expression of cyclin Dl. The concentrations at which 50% of serum-induced proliferation was inhibited were 1.2 mmol/L (Panc-1) and 1.7 mmol/L (BxPC3). The annproliferative effect of sodium salicylate was not explained by inhibition of prostaglandin E2 production. This study provides further evidence in a noncolorectal cancer model for the antineoplastic effects of nonsteroidal anti-inflammatory drugs.

Progress for resectable pancreatic [corrected] cancer?: a population-based assessment of US practices.

Pancreatic adenocarcinoma is a deadly disease; however, recent studies have suggested improved outcomes in patients with locoregional cancer. Progress was evaluated at a national level in resected patients, as measured by the proportion who received guideline‐directed treatment and trends in survival.BACKGROUND : Pancreatic adenocarcinoma is a deadly disease; however, recent studies have suggested improved outcomes in patients with locoregional cancer. Progress was evaluated at a national level in resected patients, as measured by the proportion who received guideline-directed treatment and trends in survival. METHODS : The linked Surveillance, Epidemiology, and End Results and Medicare databases were queried to identify resections for pancreatic adenocarcinoma performed between 1991 and 2002. Receipt and timing of chemotherapy and radiation with respect to time-trend were assessed. Using logistic regression, factors associated with adjuvant combination chemoradiotherapy were identified. Kaplan-Meier curves stratified by year and treatment were used to assess survival. RESULTS : Of the 1910 patients, 47.9% (n = 915) received some form of adjuvant therapy within the first 6 months postoperatively; 34.4% (n = 658) received combination chemoradiotherapy (chemoRT). ChemoRT demonstrated a significant increase, from 29.2% to 37.5% (P < .0001). Neoadjuvant therapy was used in 5.7% (n = 108) of patients; no trend was observed during the study (P = .1275). The in-hospital mortality rate was 8.0% (n = 153 patients); no significant trend was noted (P = .3116). Kaplan-Meier survival, stratified by year group of diagnosis, did not change significantly over time (log-rank test, P = .4381), even with comparisons of the first 3 years with the last 3 years of the study (log-rank test, P = .3579). CONCLUSIONS : Adherence to guideline-directed care isimproving in the United States; however, the pace is slow, and overall survival has yet to be impacted significantly. Both increased use of adjuvant therapy and the development of more promising systemic treatments are necessary to improve survival for patients with resectable pancreatic cancer. Cancer 2010. (c) 2010 American Cancer Society.

Pancreatic resection: a key component to reducing racial disparities in pancreatic adenocarcinoma

Blacks are affected disproportionately by pancreatic adenocarcinoma and have been linked with poor survival. Surgical resection remains the only potential curative option. If surgical disparities exist, then they may provide insight into outcome discrepancies.

Ubiquitin-proteasome inhibition enhances apoptosis of human pancreatic cancer cells.

BACKGROUND Tumor necrosis factor (TNF-a)-induced apoptosis is limited by coactivation of nuclear factor kappa B (NF-kb)-dependent antiapoptotic genes. Nuclear translocation of NF-kB requires degradation of ubiquitinated phospho-IkB-a by the 26S proteasome. We examined whether inhibition of the ubiquitin-proteasome pathway enhances TNF-a-induced apoptosis in BxPC-3 human pancreatic cancer cells. METHODS Serum-starved BxPC-3 cells (12 hours) were pretreated or not for 50 minutes with PSI (30 m mol/L), a peptide aldehyde known to inhibit specifically the chymotrypsin-like activity of the 26S proteasome. Cells were subsequently stimulated with recombinant human TNF-a (400 units/mL). Western blots were performed using antibodies to IkB-a and phospho-IkB-a. Level of apoptosis was determined by two methods: enzyme-linked immunosorbent assay detection of interhistone DNA fragments and flow cytometry with propidium iodide staining. RESULTS TNF-a-induced degradation of IkB-a was inhibited by PSI. Phospho-IkB-a accumulation was observed 20 minutes after TNF-a stimulation. Apoptosis relative to constitutive levels was significantly increased after PSI pretreatment, as measured by DNA fragmentation (P < or = .05 by Student t test). Percent apoptosis by flow cytometry confirmed marked increases in apoptotic cell fractions from 5.9% (untreated) to 6.8% (TNF-a alone), 16.4% (PSI alone), and 18.9% (PSI and TNF-a). CONCLUSIONS PSI enhances both constitutive and TNF-a-induced apoptosis through inhibition of IkB-a degradation in BxPC-3 human pancreatic cancer cells.

Complications After Pancreatectomy for Neuroendocrine Tumors: A National Study

BACKGROUND Although resection of pancreatic neuroendocrine tumors (PNETs) has a demonstrated survival advantage, further evaluation of the overall morbidity of these procedures is needed. Our objective was to examine a composite outcome of major postoperative complications, including in-hospital mortality. MATERIALS AND METHODS The Nationwide Inpatient Sample (NIS), 1998-2006, was used to identify all patients with a diagnosis of PNET who had undergone pancreatectomy. Candidate predictors consisted of patient and hospital characteristics. Univariate analyses included chi(2) tests. Multivariate analyses were performed with logistic regression to determine which predictors were independently associated with the composite outcome. RESULTS A total of 463 (2274 nationally weighted) patients were identified. Overall composite postoperative complication rate was 29.6%. The majority of complications involved infections (11.1%), digestive complications (8.8%), or pulmonary compromise (7.3%). In-hospital mortality rate was 1.7%. High Charlson comorbidity score, procedure type of Whipple or total pancreatectomy, and urban hospital location were all associated with significantly increased complication rate. Logistic regression analysis demonstrated: Charlson score of > or =3 versus score of 0 (adjusted odds ratio (OR) 4.1, 95% confidence interval (CI) 2.1-8.3), surgery type of Whipple or total pancreatectomy versus partial pancreatectomy (adjusted OR 2.7, 95% CI 1.8-4.1), and hospital location of urban versus rural (adjusted OR 4.5, 95% CI 3.0-6.9). CONCLUSIONS While in-hospital mortality rates are low for surgical resection of PNETs, there is a considerable overall postoperative complication rate associated with these procedures. Careful patient and surgery selection may be the key to a surgical treatment approach for PNETs that may optimize outcomes.

Surgery and Radiotherapy for Retroperitoneal and Abdominal Sarcoma: Both Necessary and Sufficient

OBJECTIVE To evaluate the effect of surgical resection and radiotherapy (RT) in retroperitoneal or abdominal sarcoma. DESIGN Retrospective cohort. SETTING Surveillance, Epidemiology, and End Results, 1988-2005. PATIENTS Patients 18 years or older with initial diagnosis of primary retroperitoneal and nonvisceral abdominal sarcoma. MAIN OUTCOME MEASURES Survival for 2 years after diagnosis. Kaplan-Meier survival was stratified based on surgery and RT status. Cox proportional hazards model was used to assess adjusted effects of surgery and RT on survival in patients with locoregional disease. RESULTS Of 1901 patients with locoregional disease, 1547 (81.8%) underwent resection; 447 (23.5%) received RT. Overall, patients who received both surgery and RT demonstrated improved survival compared with patients who underwent either therapy alone; patients undergoing monotherapy in turn had more favorable survival compared with patients who received neither therapy (P < .001, log rank). Cox analysis demonstrated that surgical resection (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.21-0.29; P < .001) and RT (0.78; 0.63-0.95; P = .01) independently predicted improved survival in locoregional disease only. In adjusted analyses stratified for American Joint Commission on Cancer (AJCC) stage, for stage I disease (n = 694), RT provided an additional benefit (HR, 0.49; 95% CI, 0.25-0.96; P = .04) independent of that from resection (0.35; 0.21-0.58; P < .001). For stage II/III (n = 552), resection remained protective (HR, 0.24; 95% CI, 0.18-0.32; P < .001); however, RT was no longer associated with a significant benefit (0.78; 0.58-1.06; P = .11). CONCLUSIONS In a national cohort of retroperitoneal and abdominal sarcomas, surgical resection was associated with significant survival benefits for AJCC disease stages I to III. Radiotherapy provided additional benefit for patients with stage I disease. Resection should be offered to reasonable surgical candidates with nonmetastatic retroperitoneal/abdominal sarcomas; radiotherapy may most benefit patients with early-stage disease.

A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database

BACKGROUND Recent studies have shown adjuvant therapy improves outcomes from pancreatic cancer (PC). This study investigates receipt and timing of PC treatments, and association with outcomes. METHODS The analysis cohort consisted of patients with newly-diagnosed PC at a single institution over 5 years. Primary Endpoints were (i) receipt of recommended therapy, and (ii) overall survival (OS). RESULTS Among 102 patients, 52 underwent resection. Out of 36 localized resected and 16 locally advanced resected (LAR) patients, 26 and 13, respectively, received adjuvant therapy. Six of the latter group received neoadjuvant therapy. Median OS for resected patients was 15.7 months (range 0.6-51.4), compared with 7.7 for unresected patients (range 0.4-32.0) (P < 0.001), and 14.0 months for patients with resection alone (range 0.6-24.4) vs. 16.1 for patients who also received adjuvant therapy (range 3.2-51.4) (P= 0.027). Out of 46 patients undergoing up-front resection, 33 had R0 surgical margins. For the six LAR patients undergoing neoadjuvant therapy, all margins were R0. CONCLUSION After resection, a substantial proportion of patients do not receive adjuvant therapy, and have worse survival. In this study, neoadjuvant treatment increased both the proportion of patients receiving all components of recommended therapy and the R0 resection rate.

A national propensity-adjusted analysis of adjuvant radiotherapy in the treatment of resected pancreatic adenocarcinoma

The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national‐level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences.