Kevin K. Roggin

Papillary Phenotype Confers Improved Survival After Resection of Hilar Cholangiocarcinoma

Objective:The current study compares outcome after resection of papillary hilar cholangiocarcinoma to that of the more common nodular-sclerosing subtype. Methods:Clinical, radiologic, histopathologic, and survival data on all patients with hilar cholangiocarcinoma were analyzed. Resected tumors were reexamined and classified as nodular-sclerosing (no component of papillary carcinoma) or papillary (any component of papillary carcinoma); for papillary tumors, the proportion of invasive carcinoma present was determined. Differences in the clinical behavior and histopathologic features of nodular-sclerosing and papillary tumors were assessed. Results:From January 1991 to November 2003, 279 patients were evaluated, 154 men (55.2%) and 125 women (44.8%), with a mean age of 65.4 ± 0.7 years (median = 68, range 23–87 years). Of the 215 patients explored, 106 (49.5%) underwent a complete gross resection. An en bloc partial hepatectomy (n = 87) and an R0 resection (n = 82) were independent predictors of favorable outcome. Operative mortality was 7.5% but was 2.8% over the last 4 years of the study, and there were no operative deaths in the last 33 consecutive resections. Twenty-five resected tumors (23.6%) contained a papillary component: 12 were minimally or noninvasive (<10% invasive cancer) and 13 had an invasive component ranging from 10% to 95% (≥10%). Patients with papillary and nodular-sclerosing tumors had similar demographics, operative procedures, and proportion of R0 resections. By contrast, papillary tumors were significantly larger, more often well-differentiated, and earlier stage. Disease-specific survival after resection of papillary tumors (55.7 months) was greater than after resection of nodular-sclerosing lesions (33.5 months, P = 0.013). The papillary phenotype was an independent predictor of survival, although the benefit was more pronounced for less invasive tumors. Conclusions:The presence of a component of papillary carcinoma is more common than previous reports have suggested and is an important determinant of survival after resection of hilar cholangiocarcinoma.

Central pancreatectomy revisited.

Central pancreatectomy is a surgical procedure that removes the middle segment of the pancreas and preserves the distal pancreas and spleen. This limited resection has the advantage of conserving normal, uninvolved pancreatic parenchyma, thus reducing the possibility of postoperative exocrine and endocrine dysfunction. While the incidence of postoperative endocrine insufficiency may be as low as 4%, procedural morbidity, specifically pancreatic fistula, appears to exceed the published rates for standard resections (i.e., distal/subtotal pancreatectomy or pancreaticoduodenectomy). We have reviewed our prospective pancreatic cancer database to determine the utilization of central pancreatectomy in a major cancer center with expertise in pancreatic surgery. We identified only 10 cases of central pancreatectomy over the past 13 years. Six (60%) had postoperative complications including three cases (30%) of pancreatic fistula. No patients died as a result of the procedure. At a median follow-up of 13.6 months (mean, 25.2 months), only one patient had mild endocrine insufficiency and no patients had clinically significant exocrine dysfunction. The associated morbidity of central pancreatectomy may outweigh any potential benefit in long-term pancreatic secretory function. We suggest that such a procedure be used selectively, where preservation of the pancreas appears essential.

Differential Cell Cycle–Regulatory Protein Expression in Biliary Tract Adenocarcinoma: Correlation With Anatomic Site, Pathologic Variables, and Clinical Outcome

PURPOSE Biliary tract adenocarcinomas (BTAs), although anatomically related, arise through ill-defined and possibly different location-related pathogenetic pathways. This clinicopathologic study characterizes differences in cell cycle-regulatory protein expression across the spectrum of BTA. METHODS Tissue microarrays were prepared from paraffin-embedded surgical specimens with triplicate cores of BTA and benign tissue. Immunohistochemical expression of p53, cyclin D1, p21, Bcl2, p27, Mdm2, and Ki-67 was assessed, and the results were correlated with pathologic variables and survival. Hierarchical clustering was used to partition the data based on protein expression, and then the data were analyzed according to anatomic location. RESULTS Tissue from 128 surgical patients (1992 to 2002) was obtained. Tumor sites of origin were intrahepatic cholangiocarcinoma (IH; n = 23), hilar cholangiocarcinoma (Hilar; n = 54), gallbladder (GB; n = 32), and distal bile duct (Distal; n = 19). p27 expression decreased progressively from proximal to distal in the biliary tree and correlated with location-related differences in outcome; cyclin D1 and Bcl2 overexpression also varied according to anatomic site. Aberrant p53 staining and cyclin D1 overexpression were lower in papillary tumors compared with the more common sclerosing tumors. The expression profiles of GB and Hilar were more similar to each other than either was to IH or Distal (86% clustering in the first partition). After an R0 resection, overexpression of Mdm2 (P = .0062) and absent p27 expression (P = .0165) independently predicted poor outcome. CONCLUSION BTAs differentially express cell cycle-regulatory proteins based on tumor location and morphology. Prognostic roles were identified for Mdm2 and p27. Overlap in the pathogenesis of GB and Hilar tumors was suggested.

Limitations of Ampullectomy in the Treatment of Nonfamilial Ampullary Neoplasms

BackgroundPancreaticoduodenectomy (PD) is the standard surgical management of invasive ampullary neoplasms. A rational plan to use ampullectomy (AMP) for lesions at this location requires careful analysis of preoperative clinical information (comorbidity, lesion size, and histopathology) and intraoperative data (frozen section pathology and clinical impression) to properly select patients for this treatment.MethodsWe identified 140 consecutive cases of nonfamilial ampullary neoplasms from our prospective institutional database over a 7-year period (1996–2003). Preoperative and intraoperative factors were analyzed and related to outcomes.ResultsAMP was planned for 37 patients with small lesions (median, 1.86 cm [range, 0–3 cm] vs. 2.6 cm [range, 0–8 cm] in PD). AMP was converted to PD because of the extent of disease in three and an intraoperative diagnosis of invasive cancer in five patients. Preoperative biopsy had a diagnostic accuracy of 79% (97 of 123) but missed 23 cancers. Intraoperative frozen section had a diagnostic accuracy of 84%; two cases of high-grade dysplasia and invasive cancer were missed. Patients with invasive cancer treated by AMP had a decreased recurrence-free and disease-specific survival compared with those treated by PD. Lymphatic spread of disease was associated with diminished long-term survival. Although both vascular invasion and tumor stage independently predicted lymphatic metastases, both were limited by their sensitivity.ConclusionsThe reduced morbidity and mortality of AMP makes this the preferred treatment for benign lesions of the ampulla. Conversion to PD should be considered when intraoperative or final pathology identifies invasive adenocarcinoma. Refinement of clinicopathologic factors may reduce the occasional PD for benign disease and AMP for malignancy.

Geriatric assessment improves prediction of surgical outcomes in older adults undergoing pancreaticoduodenectomy: a prospective cohort study.

Objective:To prospectively evaluate the additional value of geriatric assessment (GA) for predicting surgical outcomes in a cohort of older patients undergoing a pancreaticoduodenectomy (PD) for pancreatic tumors. Background:Older patients are less often referred for possible PD. Standard preoperative assessments may underestimate the likelihood of significant adverse outcomes. The prospective utility of validated GA has not been studied in this group. Methods:PD-eligible patients were enrolled in a prospective outcome study. Standard preoperative assessments were recorded. Elements of validated GA were also measured, including components of Frieds model of frailty, the Vulnerable Elders Survey (VES-13), and the Short Physical Performance Battery (SPPB). All postoperative adverse events were recorded, systematically reviewed, and graded using the Clavien-Dindo system by a surgeon blinded to the GA results. Multivariate regression analyses were conducted. Results:Seventy-six older patients underwent a PD. Significant unrecognized vulnerability was identified at the baseline: Frieds “exhaustion” (37.3%), SPPB <10 (28.5%), and VES-13 >3 (15.4%). Within 30 days of PD, 46% experienced a severe complication (Clavien-Dindo grade ≥III). In regression analyses controlling for age, the body mass index, the American Society of Anesthesiologists score, and comorbidity burden, Frieds “exhaustion” predicted major complications [odds ratio (OR) = 4.06; P = 0.01], longer hospital stays (&bgr; = 0.27; P = 0.02), and surgical intensive care unit admissions (OR = 4.30; P = 0.01). Both SPPB (OR = 0.61; P = 0.04) and older age predicted discharge to a rehabilitation facility (OR = 1.1; P < 0.05) and age correlated with a lower likelihood of hospital readmission (OR = 0.94; P = 0.02). Conclusions:Controlling for standard preoperative assessments, worse scores on GA prospectively and independently predicted important adverse outcomes. Geriatric assessment may help identify older patients at high risk for complications from PD.

Early National Experience with Laparoscopic Pancreaticoduodenectomy for Ductal Adenocarcinoma: A Comparison of Laparoscopic Pancreaticoduodenectomy and Open Pancreaticoduodenectomy from the National Cancer Data Base

BACKGROUND There is considerable debate about the safety and clinical equivalence of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDCA). STUDY DESIGN We queried the National Cancer Data Base to identify patients undergoing LPD and OPD for PDCA between 2010 and 2011. Chi-square and Students t-tests were used to evaluate differences between the 2 approaches. Multivariable logistic regression modeling was performed to identify patient, tumor, or facility factors associated with perioperative mortality. RESULTS Four thousand and thirty-seven (91%) patients underwent OPD. Three hundred and eighty-four (9%) patients underwent LPD. There were no statistical differences between the 2 surgical cohorts with regard to age, race, Charlson score, tumor size, grade, stage, or treatment with neoadjuvant chemoradiotherapy. Laparoscopic pancreaticoduodenectomy demonstrated a shorter length of stay (10 ± 8 days vs 12 ± 9.7 days; p < 0.0001) and lower rates of unplanned readmission (5% vs 9%; p = 0.027) than OPD. In an unadjusted comparison, there was no difference in 30-day mortality between the LPD and OPD cohorts (5.2% vs 3.7%; p = 0.163). Multivariable logistic regression modeling predicting perioperative mortality controlling for age, Charlson score, tumor size, nodal positivity, stage, facility type, and pancreaticoduodenectomy volume identified age (odds ratio [OR] = 1.05; p < 0.0001), positive margins (OR = 1.45; p = 0.030), and LPD (OR = 1.89; p = 0.009) as associated with an increased probability of 30-day mortality; higher hospital volume was associated with a lower risk of 30-day mortality (OR = 0.98; p < 0.0001). In institutions that performed ≥10 LPDs, the 30-day mortality rate of the laparoscopic approach was equal to that for the open approach (0.0% vs 0.7%; p = 1.00). CONCLUSIONS Laparoscopic pancreaticoduodenectomy is equivalent to OPD in length of stay, margin-positive resection, lymph node count, and readmission rate. There is a higher 30-day mortality rate with LPD, but this appears driven by a surmountable learning curve for the procedure.

Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors

PURPOSE The biologic potential of nonfunctioning pancreatic neuroendocrine tumors (PNETs) is highly variable and difficult to predict before resection. This study was conducted to identify clinical and pathologic factors associated with malignant behavior and death in patients diagnosed with PNETs. METHODS We used International Classification of Diseases 9th edition codes to identify patients who underwent pancreatectomy for PNETs from 1998 to 2011 in the databases of 4 institutions. Functioning PNETs were excluded. Multivariate regression Cox proportional models were constructed to identify clinical and pathologic factors associated with distant metastasis and survival. RESULTS The study included 128 patients-57 females and 71 males. The age (mean ± standard deviation) was 55 ± 14 years. The body mass index was 28 ± 5 kg/m(2). Eighty-nine (70%) patients presented with symptoms, and 39 (30%) had tumors discovered incidentally. The tumor size was 3.3 ± 2 cm with 56 (44%) of the tumors measuring ≤2 cm. Seventy-three (57%) patients had grade 1 histology tumors, 37 (29%) had grade 2, and 18 (14%) had grade 3. Peripancreatic lymph node involvement was present in 31 patients (24%), absent in 75 (59%), and unknown in 22 (17%). Distant metastasis occurred in 18 patients (14%). There were 12 deaths, including 1 perioperative, 8 disease related, and 3 of unknown cause. With a median follow-up of 33 months, the overall 5-year survival was 75%. Multivariate Cox regression analysis identified age >55 (hazard ratio [HR], 5.89; 95% confidence interval [CI], 1.64-20.58), grade 3 histology (HR, 6.08; 95% CI, 1.32-30.2), and distant metastasis (HR, 8.79; 95% CI, 2.67-28.9) as risk factors associated with death (P < .05). Gender, race, body mass index, clinical symptoms, lymphovascular and perineural invasion, and tumor size were not related to metastasis or survival (P > .05). Three patients with tumors ≤2 cm developed distant metastasis resulting in 2 disease-related deaths. CONCLUSION Age >55 years, grade 3 histology, and distant metastasis predict a greater risk of death from nonfunctioning PNETs. Resection or short-term surveillance should be considered regardless of tumor size.

The laparoscopic approach to distal pancreatectomy for ductal adenocarcinoma results in shorter lengths of stay without compromising oncologic outcomes

BACKGROUND The oncologic equivalence of laparoscopic distal pancreatectomy (LDP) to open pancreatectomy (ODP) for ductal adenocarcinoma (DAC) is not established. METHODS The National Cancer Data Base was used to compare perioperative outcomes following LDP and ODP for DAC between 2010 and 2011. RESULTS One hundred forty-five patients underwent LDP; 625 underwent ODP. Compared with ODP, patients undergoing LDP were older (68 ± 10.1 vs 66 ± 10.5 years, P = .027), more likely treated in academic centers (70% vs 59%, P = .01), and had shorter hospital stays (6.8 ± 4.6 vs 8.9 ± 7.5 days, P < .001). Demographic data, lymph node count, 30-day unplanned readmission, and 30-day mortality were identical between groups. Multivariable regression identified a lower probability of prolonged length of stay with LDP (odds ratio .51, 95% confidence interval .327 to .785, P = .0023). There was no association between surgical approach and node count, readmission, or mortality. CONCLUSION LDP for DAC provides shorter postoperative lengths of stay and rates of readmission and 30-day mortality similar to OPD without compromising perioperative oncologic outcomes.

Modern treatment of gastric gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.

Characteristics of Highly Ranked Applicants to General Surgery Residency Programs

IMPORTANCE With duty hour debates, specialization, and sex distribution changes in the applicant pool, the relative competitiveness for general surgery residency (GSR) is undefined. OBJECTIVE To determine the modern attributes of top-ranked applicants to GSR. DESIGN Validation cohort, survey. SETTING National sample of university and community-based GSR programs. PARTICIPANTS Data were abstracted from Electronic Residency Application Service files of the top 20-ranked applicants to 22 GSR programs. We ranked program competitiveness and blinded review of personal statements. MAIN OUTCOMES AND MEASURES Characteristics associated with applicant ranking by the GSR program (top 5 vs 6-20) and ranking by highly competitive programs were identified using t and χ2 tests and modified Poisson regression. RESULTS There were 333 unique applicants among the 440 Electronic Residency Application Service files. Most applicants had research experience (93.0%) and publications (76.8%), and 28.4% had Alpha Omega Alpha membership. Nearly half were women (45.2%), with wide variation by program (20.0%-75.0%) and a trend toward fewer women at programs in the South and West (38.0% and 37.5%, respectively). Men had higher United States Medical Licensing Examination Step 1 scores (238.0 vs 230.1; P < .001) but similar Step 2 scores (245.3 vs 244.5; P = .54). Using bivariate analysis, highly competitive programs were more likely to rank applicants with publications, research experience, Alpha Omega Alpha membership, higher Step 1 scores, and excellent personal statements and those who were male or Asian. However, the only significant predictors were Step 1 scores (relative risk [RR], 1.36 for every 10-U increase), publications (RR, 2.20), personal statements (RR, 1.62), and Asian race (RR, 1.70 vs white). Alpha Omega Alpha membership (RR, 1.62) and Step 1 scores (RR, 1.01) were the only variables predictive of ranking in the top 5. CONCLUSIONS AND RELEVANCE This national sample shows GSR is a highly competitive, sex-neutral discipline in which academic performance is the most important factor for ranking, especially in the most competitive programs. This study will inform applicants and program directors about applicants to the GSR program.