James S. Tomlinson

Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients.

Background:Pancreatic neuroendocrine tumors (PNET) have a poorly defined natural history, and a staging system is not available. The objective of this study was to identify factors predicting survival after pancreatectomy for PNETs and to establish a postresection prognostic score. Patients and Methods:From the National Cancer Data Base (1985–2004), patients were identified who underwent PNET resection. Multivariable Cox proportional hazards modeling was used to assess the impact of patient, tumor, treatment, and hospital factors on survival. A prognostic score based on the predictive factors from the Cox model was developed. Results:Three thousand eight hundred fifty-one patients underwent resection for PNETs. Five-year overall survival was 59.3%, and the 10-year survival was 37.7%. On multivariable analysis, age, grade, distant metastases, tumor functionality, and type of resection were independent predictors of survival after resection of PNETs (P < 0.0001). Gender, race, socioeconomic status, tumor size, nodal status, margins, adjuvant chemotherapy, and hospital volume were not associated with survival. Age, grade, and distant metastases were the most significant predictors of survival and were incorporated into a PNET postresection prognostic score. The prognostic score correlated with outcomes and offered excellent survival discrimination by each of the 3 score subgroups: 76.7%, 50.9%, and 35.7% (P < 0.0001). The concordance index was 0.63 (95% CI 0.59–0.67), indicating reasonable agreement between actual outcomes and that predicted by the prognostic score. Conclusions:The prognostic score can be used to predict outcomes, guide adjuvant treatment, and stratify patients for clinical trials.

Multimodality therapy for pancreatic cancer in the U.S.: Utilization, outcomes, and the effect of hospital volume

Despite decreased perioperative morbidity and mortality and clinical trials suggesting improved outcomes with adjuvant therapy, national practice patterns in the management of pancreatic cancer remain poorly defined. The purpose of the current study was to evaluate multimodality therapy utilization and outcomes relative to hospital type and volume.

Evaluation of the Guidelines for Management of Pancreatic Branch-Duct Intraductal Papillary Mucinous Neoplasm

BACKGROUND & AIMS The 2006 Sendai Consensus Guidelines recommend surgical resection for all suspected branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) greater than 3 cm irrespective of symptoms, and those less than 3 cm with worrisome features. We aimed to evaluate the surgical characteristics of these guidelines retrospectively in pathologically confirmed cases of BD-IPMN. METHODS IPMNs resected at our institution (1995-2006) were classified as main-duct predominant or branch-duct (BD) predominant based on preoperative imaging and postoperative histology. Resected BD-IPMNs were classified histologically: low risk (adenoma, borderline) and high risk (carcinoma in situ or invasive cancer). Clinical data (presence of symptoms, mural nodule, dilated pancreatic duct, and cyst size) were correlated with pathology. RESULTS Between 1995 and 2006, there were 204 patients who underwent surgical resection of pancreatic cysts. Sixty-one patients had IPMN including 31 with BD-IPMN. A total of 74.2% (23 of 31) of BD-IPMNs would have been recommended for surgical resection including 69.2% (18 of 26) of low-risk lesions and 100% (5 of 5) of high-risk lesions. All 8 cases of BD-IPMN that would have been recommended for nonsurgical management were low-risk lesions. The positive predictive value of the guidelines is 21.7% (95% confidence interval, 9.7%-41.9%). The negative predictive value is 100% (95% confidence interval, 67.6%-100.0%). Between 2000 and 2007, 351 patients with likely BD-IPMN were evaluated but not resected. CONCLUSIONS Implementation of the Consensus Guidelines to our single-institution, referral-based, surgical BD-IPMN population would have recommended resection of all histologically high-risk lesions. All lesions recommended for nonsurgical management were histologically low-risk lesions. For presumed BD-IPMNs less than 3 cm, the application of the Consensus Guidelines may reduce the resection rate for low-risk lesions.

Pseudomyxoma Peritonei Is a Disease of MUC2-Expressing Goblet Cells

Pseudomyxoma peritonei, a syndrome first described by Karl F. Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although past interest in the syndrome has focused on the questions of the site of origin (appendix versus ovary), mechanisms of peritoneal spread (multicentricity, redistribution phenomenon, or metastasis), and the degree of malignant transformation present (adenoma, borderline tumor, or carcinoma), another important question is the mechanism behind the accumulation of extracellular mucin, the real cause of the diseases morbidity and mortality irrespective of the site of origin, mechanism of peritoneal spread, or transformed status of its epithelium. Taking advantage of the recently cloned human mucin genes, we decided to investigate this question. Our studies revealed that pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. These cells also express MUC5AC but the latter mucin is not specific for pseudomyxoma peritonei. MUC2 expression accounts for the voluminous deposits of extracellular mucin (mucin:cell ratios exceeding 10:1) and distinguishes pseudomyxoma peritonei secondarily involving the ovary from primary ovarian mucinous tumors with peritoneal implants. Because mucinous tumors of the appendix similarly express MUC2, the MUC2 expression profile also supports an appendiceal rather than ovarian origin for pseudomyxoma peritonei. Increased steady-state mRNA is observed in pooled cases of pseudomyxoma peritonei but does not occur on the basis of gene rearrangement or gene amplification. Primary epithelial cell cultures obtained from pseudomyxoma peritonei express MUC2 whose levels can be epigenetically regulated. These lines up-regulate MUC2 expression in response to both methylation inhibition by 5-azacytidine and exposure to Pseudomonas aeruginosa lipopolysaccharide, both of whose effects can be suppressed by genistein pretreatment. Both immunocytochemical as well as in situ hybridization studies with ancillary digital image analysis reveal that MUC2 expression in cases of pseudomyxoma peritonei is independent of the degrees of malignant transformation that are present and, in fact, reflects the constitutive levels of expression observed in normal goblet cells of the appendix. Extracellular mucin accumulates dramatically in pseudomyxoma peritonei because the number of MUC2-secreting cells dramatically increase and because this MUC2 has no place to drain. These studies suggest that pseudomyxoma peritonei should be regarded as a disease of MUC2-expressing goblet cells whose MUC2 expression might be susceptible to pharmacological targeting.

Postoperative complications reduce adjuvant chemotherapy use in resectable pancreatic cancer

Objective:To assess the impact of postoperative complications on the receipt of adjuvant chemotherapy. Background:Randomized trials have demonstrated that adjuvant chemotherapy is associated with improved long-term survival. However, pancreatic surgery is associated with significant morbidity and the degree to which complications limit subsequent treatment options is unknown. Methods:Patients from the American College of Surgeons National Surgical Quality Improvement Program and the National Cancer Data Base who underwent pancreatic resection for cancer were linked (2006–2009). The associations between complications and adjuvant chemotherapy use or treatment delay (≥70 days from surgery) were assessed using multivariable regression methods. Results:From 149 hospitals, 2047 patients underwent resection for stage I-III pancreatic adenocarcinoma of which 23.2% had at least 1 serious complication. Overall adjuvant chemotherapy receipt was 57.7%: 61.8% among patients not experiencing any complication and 43.6% among those who had a serious complication. Serious complications increased the likelihood of not receiving adjuvant therapy over twofold [odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.73–2.80]. Specific complications associated with adjuvant chemotherapy omission were reintubation (OR = 7.79, 95% CI: 3.59–16.87), prolonged ventilation (OR = 5.92, 95% CI: 3.23–10.86), pneumonia (OR = 2.83, 95% CI: 1.63–4.90), sepsis/shock (OR = 2.76, 95% CI: 2.02–3.76), organ space/deep surgical site infection (OR = 2.19, 95% CI: 1.53–3.13), venous thromboembolism (OR = 1.92, 95% CI: 1.08–3.43), and urinary tract infection (OR = 1.61, 95% CI: 1.02–2.54). Serious complications also doubled the likelihood of delaying adjuvant treatment administration (OR = 2.08, 95% CI: 1.42–3.05). Sensitivity analysis in a younger, healthier patient cohort demonstrated similar associations. Conclusions:Postoperative complications are common following pancreatic surgery and are associated with adjuvant chemotherapy omission and treatment delays.

Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma

Inflammatory breast carcinoma (IBC) is characterized by florid tumor emboli within lymphovascular spaces termed lymphovascular invasion (LVI). Using a human-scid model of IBC (MARY-X), we have demonstrated using retrovirally-mediated dominant-negative E-cadherin mutant approaches (H-2Kd-E-cad), that the tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin/α, β-catenin axis which mediates tumor cell–tumor cell adhesion analogous to the embryonic blastocyst and accounts for the compactness of the embolus. The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells both in vitro and in vivo because of markedly decreased sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This tumor cell-endothelial cell aversion further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. This passivity is manifested by a dramatic increase in metastatic pulmonary emboli following palpation of the primary tumor. In assessing this passivity of metastatic dissemination, we compared the effects of palpation on MARY-X with the effects of palpation on a derived dominant-negative E-cadherin mutant (H-2Kd-E-cad), as well as other well known human tumoral xenografts exhibiting no (MCF-7, T47D), low (MDA-MB-231, MDA-MB-468) or high (C8161, M24met) levels of spontaneous metastasis but no LVI. Palpation of each xenograft similarly increased intratumoral pressure by 200% (10→30 mmHg) but dramatically increased the numbers and sizes of pulmonary metastases 10–100-fold (P<0.001) only in MARY-X. The mechanism of this effect was through an immediate post-palpation release of circulating tumor emboli detected 2–3 min after palpation (P<0.01) by human cytokeratin 19 RT–PCR of extracted RNA from 300 μl of murine blood. Although circulating human tumor cell–derived growth factors (IGF-I, IGF-II, TGF-α and TGF-β) and angiogenic factors (VEGF and bFGF) were detected by ELISA in murine serum of MARY-X, palpation did not further increase the circulating levels of these factors (P>0.1). Our findings support the cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in IBC.

The human myoepithelial cell displays a multifaceted anti-angiogenic phenotype

Human myoepithelial cells which surround ducts and acini of certain organs such as the breast form a natural border separating epithelial cells from stromal angiogenesis. Myoepithelial cell lines (HMS-1-6), derived from diverse benign myoepithelial tumors, all constitutively express high levels of active angiogenic inhibitors which include TIMP-1, thrombospondin-1 and soluble bFGF receptors but very low levels of angiogenic factors. These myoepithelial cell lines inhibit endothelial cell chemotaxis and proliferation. These myoepithelial cell lines sense hypoxia, respond to low O2 tension by increased HIF-1α but with only a minimal increase in VEGF and iNOS steady state mRNA levels. Their corresponding xenografts (HMS-X-6X) grow very slowly compared to their non-myoepithelial carcinomatous counterparts and accumulate an abundant extracellular matrix devoid of angiogenesis but containing bound angiogenic inhibitors. These myoepithelial xenografts exhibit only minimal hypoxia but extensive necrosis in comparison to their non-myoepithelial xenograft counterparts. These former xenografts inhibit local and systemic tumor-induced angiogenesis and metastasis presumably from their matrix-bound and released circulating angiogenic inhibitors. These observations collectively support the hypothesis that the human myoepithelial cell (even when transformed) is a natural suppressor of angiogenesis.

Impact of Tumor Grade on Prognosis in Pancreatic Cancer: Should We Include Grade in AJCC Staging?

BackgroundAJCC staging of pancreatic cancer (PAC) is used to determine prognosis, yet survival within each stage shows wide variation and remains unpredictable. We hypothesized that tumor grade might be responsible for some of this variation and that the addition of grade to current AJCC staging would provide improved prognostication.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database (1991–2005) was used to identify 8082 patients with resected PAC. The impact of grade on overall and stage-specific survival was assessed using Cox regression analysis. Variables in the model were age, sex, tumor size, lymph node status, and tumor grade.ResultsFor each AJCC stage, survival was significantly worse for high-grade versus low-grade tumors. On multivariate analysis, high tumor grade was an independent predictor of survival for the entire cohort (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.31–1.48) as well as for stage I (HR 1.28, 95% CI 1.07–1.54), stage IIA (HR 1.43, 95% CI 1.26–1.61), stage IIB (HR 1.38, 95% CI 1.27–1.50), stage III (HR 1.28, 95% CI 1.02–1.59), and stage IV (HR 1.58, 95% CI 1.21–2.05) patients. The addition of grade to staging results in a statistically significant survival discrimination between all stages.ConclusionsTumor grade is an important prognostic variable of survival in PAC. We propose a novel staging system incorporating grade into current AJCC staging for pancreas cancer. The improved prognostication is more reflective of tumor biology and may impact therapy decisions and stratification of future clinical trials.

Quality of care in advanced ovarian cancer: The importance of provider specialty

BACKGROUND One of the cornerstones of ovarian cancer therapy is cytoreductive surgery, which can be performed by surgeons with different specialty training. We examined whether surgeon specialty impacts quality of life (as proxied by presence of ostomy) and overall survival for women with advanced ovarian cancer. METHODS Stage IIIC/IV ovarian cancer patients were identified using 4 state cancer registries: California, Washington, New York, and Florida and linked records to the corresponding inpatient-hospital discharge file, AMA Masterfile, and 2000 U.S. Census SF4 File. Predictors of receipt of care by a general surgeon and creation of fecal ostomy were analyzed. Multivariate modeling was performed to assess the association of hospital volume (low volume (LV) [0-4 cases], middle volume (MV) [5-9], high volume (HV) [10-19], and very high volume (VHV) [20+]) and surgeon specialty training (gynecologic oncologists/gynecologists, general surgeons, and other specialty) on survival. RESULTS We identified 31,897 Stage IIIC/IV patients; mean age was 64 years. Treatment of patients by a general surgeon was predicted by LV, rural patient residence, poverty, and high level of comorbidity. Patients had lower hazard of death when treated in higher volume hospitals as compared to LV [VHV hazard ratio (HR)=0.79, P<.0001; HV HR=0.89, P<0.001]. Patients treated by a general surgeon had higher likelihood of an ostomy (OR=4.46, P<.0001) and hazard of death (HR=1.63, P<.0001) compared to gynecologic oncologist/gynecologist. CONCLUSIONS Advanced stage ovarian cancer patients have better survival when treated by gynecologic oncology/gynecology trained surgeons. Data suggest that referral to these specialists may optimize surgical debulking and minimize the creation of a fecal ostomy.

Effect of Hospital Type and Volume on Lymph Node Evaluation for Gastric and Pancreatic Cancer

HYPOTHESIS For gastric and pancreatic cancer, regional lymph node evaluation is important to accurately stage disease in a patient and may be associated with improved survival. We hypothesized that National Comprehensive Cancer Network (NCCN), National Cancer Institute (NCI)-designated institutions, and high-volume hospitals examine more lymph nodes for gastric and pancreatic malignant neoplasms than do low-volume centers and community hospitals. DESIGN Volume-outcome study. SETTING Academic research. PATIENTS Using the National Cancer Data Base (January 1, 2003, to December 31, 2004), patients were identified who underwent resection for gastric (n = 3088) and pancreatic (n = 1130 [pancreaticoduodenectomy only]) cancer. MAIN OUTCOME MEASURES Multivariable logistic regression analysis was used to assess the effect of hospital type and volume on nodal evaluation (>or=15 nodes). RESULTS Only 23.2% of patients with gastric cancer and 16.4% of patients with pancreatic cancer in the United States underwent evaluation of at least 15 lymph nodes. Patients undergoing surgery had more lymph nodes examined at NCCN-NCI hospitals than at community hospitals (median, 12 vs 6 for gastric cancer and 9 vs 6 for pancreatic cancer; P < .001). Patients at highest-volume hospitals had more lymph nodes examined than patients at low-volume hospitals (median, 10 vs 6 for gastric cancer and 8 vs 6 for pancreatic cancer; P < .001). On multivariable analysis, patients undergoing surgery at NCCN-NCI and high-volume hospitals were more likely to have at least 15 lymph nodes evaluated compared with patients undergoing surgery at community hospitals and low-volume centers (P < .001 and P =.02, respectively). CONCLUSIONS Nodal examination is important for staging, adjuvant therapy decision making, and clinical trial stratification. Moreover, differences in nodal evaluation may contribute to improved long-term outcomes at NCCN-NCI centers and high-volume hospitals for patients with gastric and pancreatic cancer.