Nakul P. Valsangkar

Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes

Objective Invasive cancers arising from intraductal papillary mucinous neoplasm (IPMN) are recognised as a morphologically and biologically heterogeneous group of neoplasms. Less is known about the epithelial subtypes of the precursor IPMN from which these lesions arise. The authors investigate the clinicopathological characteristics and the impact on survival of both the invasive component and its background IPMN. Design and patients The study cohort comprised 61 patients with invasive IPMN (study group) and 570 patients with pancreatic ductal adenocarcinoma (PDAC, control group) resected at a single institution. Multivariate analyses were performed using a stage-matched Cox proportional hazard model. Results The histology of invasive components of the IPMN cohort was tubular in 38 (62%), colloid in 16 (26%), and oncocytic in seven (12%). Compared with PDAC, invasive IPMNs were associated with a lower incidence of adverse pathological features and improved mortality by multivariate analysis (HR 0.58; 95% CI 0.39 to 0.86). In subtype analysis, this favourable outcome remained only for colloid and oncocytic carcinomas, while tubular adenocarcinoma was associated with worse overall survival, not significantly different from that of PDAC (HR 0.85; 95% CI 0.53 to 1.36). Colloid and oncocytic carcinomas arose only from intestinal- and oncocytic-type IPMNs, respectively, and were mostly of the main-duct type, whereas tubular adenocarcinomas primarily originated in the gastric background, which was often associated with branch-duct IPMN. Overall survival of patients with invasive adenocarcinomas arising from gastric-type IPMN was significantly worse than that of patients with non-gastric-type IPMN (p=0.016). Conclusions Tubular, colloid and oncocytic invasive IPMNs have varying prognosis, and arise from different epithelial subtypes. Colloid and oncocytic types have markedly improved biology, whereas the tubular type has a course that resembles PDAC. Analysis of these subtypes indicates that the background epithelium plays an equally, if not more, important role in defining the biology and prognosis of invasive IPMNs.

851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital.

BACKGROUND The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at an academic referral center during a 33-year period. METHODS Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011. RESULTS A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%. CONCLUSION Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms.

N0/N1, PNL, or LNR? The Effect of Lymph Node Number on Accurate Survival Prediction in Pancreatic Ductal Adenocarcinoma

IntroductionWe evaluated the prognostic accuracy of LN variables (N0/N1), numbers of positive lymph nodes (PLN), and lymph node ratio (LNR) in the context of the total number of examined lymph nodes (ELN).MethodsPatients from SEER and a single institution (MGH) were reviewed and survival analyses performed in subgroups based on numbers of ELN to calculate excess risk of death (hazard ratio, HR).ResultsIn SEER and MGH, higher numbers of ELN improved the overall survival for N0 patients. The prognostic significance (N0/N1) and PLN were too variable as the importance of a single PLN depended on the total number of LN dissected. LNR consistently correlated with survival once a certain number of lymph nodes were dissected (≥13 in SEER and ≥17 in the MGH dataset).ConclusionsBetter survival for N0 patients with increasing ELN likely represents improved staging. PLN have some predictive value but the ELN strongly influence their impact on survival, suggesting the need for a ratio-based classification. LNR strongly correlates with outcome provided that a certain number of lymph nodes is evaluated, suggesting that the prognostic accuracy of any LN variable depends on the total number of ELN.

Circulating tumor cells found in patients with localized and advanced pancreatic cancer

Objectives Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis. Results Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (⩽American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (≥ American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors. Conclusions Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC.

Determining the Drivers of Academic Success in Surgery: An Analysis of 3,850 Faculty

Objective Determine drivers of academic productivity within U.S. departments of surgery. Methods Eighty academic metrics for 3,850 faculty at the top 50 NIH-funded university- and 5 outstanding hospital-based surgical departments were collected using websites, Scopus, and NIH RePORTER. Results Mean faculty size was 76. Overall, there were 35.3% assistant, 27.8% associate, and 36.9% full professors. Women comprised 21.8%; 4.9% were MD-PhDs and 6.1% PhDs. By faculty-rank, median publications/citations were: assistant, 14/175, associate, 39/649 and full-professor, 97/2250. General surgery divisions contributed the most publications and citations. Highest performing sub-specialties per faculty member were: research (58/1683), transplantation (51/1067), oncology (41/777), and cardiothoracic surgery (48/860). Overall, 23.5% of faculty were principal investigators for a current or former NIH grant, 9.5% for a current or former R01/U01/P01. The 10 most cited faculty (MCF) within each department contributed to 42% of all publications and 55% of all citations. MCF were most commonly general (25%), oncology (19%), or transplant surgeons (15%). Fifty-one-percent of MCF had current/former NIH funding, compared with 20% of the rest (p<0.05); funding rates for R01/U01/P01 grants was 25.1% vs. 6.8% (p<0.05). Rate of current-NIH MCF funding correlated with higher total departmental NIH rank (p < 0.05). Conclusions Departmental academic productivity as defined by citations and NIH funding is highly driven by sections or divisions of research, general and transplantation surgery. MCF, regardless of subspecialty, contribute disproportionally to major grants and publications. Approaches that attract, develop, and retain funded MCF may be associated with dramatic increases in total departmental citations and NIH-funding.

Current management of gastrointestinal stromal tumors: Surgery, current biomarkers, mutations, and therapy

In the past decade, the addition of molecular diagnosis of mutations and use of tyrosine kinase inhibitors (TKIs), either as neoadjuvant/adjuvant therapy with surgery or as primary therapy in nonresectable gastrointestinal stromal tumors (GIST), has improved patient outcomes markedly. Additional therapeutics also are on the horizon. The goal of this review is to identify the current incidence, diagnostic modalities, and trends in personalizing the medical and operative management for patients with GIST. Medline, PubMed, and Google scholar were queried for recently published literature regarding new molecular mechanisms, targeted therapies, and clinical trials investigating the treatment of GIST. The objective of this review is to highlight the biomarkers under development, newly discovered mutations, and newer therapies targeting specific mutational phenotypes which are continually improving the outlook for patients with this disease.

Sonic Hedgehog in pancreatic cancer: From bench to bedside, then back to the bench

Developmental genes are known to regulate cell proliferation, migration, and differentiation; thus, it comes as no surprise that the misregulation of developmental genes plays an important role in the biology of human cancers. One such pathway that has received an increasing amount of attention for its function in carcinogenesis is the Hedgehog (Hh) pathway. Initially the domain of developmental biologists, the Hh pathway and one of its ligands, Sonic Hedgehog (Shh), have been shown to play an important role in body planning and organ development, particularly in the foregut endoderm. Their importance in human disease became known to cancer biologists when germline mutations that resulted in the unregulated activity of the Hh pathway were found to cause basal cell carcinoma and medulloblastoma. Since then, misexpression of the Hh pathway has been shown to play an important role in many other cancers, including those of the pancreas. In many institutions, investigators are targeting misexpression of the Hh pathway in clinical trials, but there is still much fundamental knowledge to be gained about this pathway that can shape its clinical utility. This review will outline the evolution of our understanding of this pathway as it relates to the pancreas, as well as how the Hh pathway came to be a high-priority target for treatment.

The Role of PhD Faculty in Advancing Research in Departments of Surgery.

Objective: To determine the academic contribution as measured by number of publications, citations, and National Institutes of Health (NIH) funding from PhD scientists in US departments of surgery. Summary Background Data: The number of PhD faculty working in US medical school clinical departments now exceeds the number working in basic science departments. The academic impact of PhDs in surgery has not been previously evaluated. Methods: Academic metrics for 3850 faculties at the top 55 NIH-funded university and hospital-based departments of surgery were collected using NIH RePORTER, Scopus, and departmental websites. Results: MD/PhDs and PhDs had significantly higher numbers of publications and citations than MDs, regardless of academic or institutional rank. PhDs had the greatest proportion of NIH funding compared to both MDs and MD/PhDs. Across all academic ranks, 50.2% of PhDs had received NIH funding compared with 15.2% of MDs and 33.9% of MD/PhDs (P < 0.001). The proportion of PhDs with NIH funding in the top 10 departments did not differ from those working in departments ranked 11 to 50 (P = 0.456). A greater percentage of departmental PhD faculty was associated with increased rates of MD funding. Conclusions: The presence of dedicated research faculty with PhDs supports the academic mission of surgery departments by increasing both NIH funding and scholarly productivity. In contrast to MDs and MD/PhDs, PhDs seem to have similar levels of academic output and funding independent of the overall NIH funding environment of their department. This suggests that research programs in departments with limited resources may be enhanced by the recruitment of PhD faculty.

Do Plastic Surgery Programs with Integrated Residencies or Subspecialty Fellowships Have Increased Academic Productivity

Background: The aim of this study was to evaluate the effect of different surgical training pathways on the academic performance of plastic surgical divisions. Methods: Eighty-two academic parameters for 338 plastic surgeons (PS), 1737 general surgeons (GS), and 1689 specialist surgeons (SS) from the top 55 National Institutes of Health (NIH)-funded academic departments of surgery were examined using data gathered from websites, SCOPUS, and NIH Research Portfolio Online Reporting Tools. Results: The median size of a PS division was 7 faculty members. PS faculty had lower median publications (P)/citations (C) (ie, P/C) than GS and SS (PS: 25/328, GS: 35/607, and SS: 40/713, P < 0.05). Publication and citation differences were observed at all ranks: assistant professor (PS: 11/101, GS: 13/169, and SS: 19/249), associate professor (PS: 33/342, GS: 40/691, and SS: 44/780), and professor (PS: 57/968, GS: 97/2451, and SS: 101/2376). PS had a lower percentage of faculty with current/former NIH funding (PS: 13.5%, GS: 22.8%, and SS: 25.1%, P < 0.05). Academic productivity for PS faculty was improved in integrated programs. P/C for PS faculty from divisions with traditional 3-year fellowships was 19/153, integrated 6-year residency was 25/329, and both traditional and 6-year programs were 27/344, P < 0.05. Craniofacial and hand fellowships increased productivity within the integrated residency programs. P/C for programs with a craniofacial fellowship were 32/364 and for those that additionally had a hand fellowship were 45/536. PS faculty at divisions with integrated training programs also had a higher frequency of NIH funding. Conclusions: PS divisions vary in degree of academic productivity. Dramatically improved scholarly output is observed with integrated residency training programs and advanced specialty fellowships.

Is there an impending loss of academically productive trauma surgical faculty? An analysis of 4,015 faculty.

OBJECTIVE The aim of this work was to compare the academic impact of trauma surgery faculty relative to faculty in general surgery and other surgery subspecialties. METHODS Scholarly metrics were determined for 4,015 faculty at the top 50 National Institutes of Health (NIH)-funded university-based departments and five hospital-based surgery departments. RESULTS Overall, 317 trauma surgical faculty (8.2%) were identified. This compared to 703 other general surgical faculty (18.2%) and 2,830 other subspecialty surgical faculty (73.5%). The average size of the trauma surgical division was six faculty. Overall, 43% were assistant professors, 29% were associate professors, and 28% were full professors, while 3.1% had PhD, 2.5% had MD and PhD, and, 16.3% were division chiefs/directors. Compared with general surgery, there were no differences regarding faculty academic levels or leadership positions. Other surgical specialties had more full professors (39% vs. 28%; p < 0.05) and faculty with research degrees (PhD, 7.7%; and MD and PhD, 5.7%). Median publications/citations were lower, especially for junior trauma surgical faculty (T) compared with general surgery (G) and other (O) surgical specialties: assistant professors (T, 9 publications/76 citations vs. G, 13/138, and O, 18/241; p < 0.05), associate professors (T, 22/351 vs. G, 36/700, and O, 47/846; p < 0.05), and professors (T, 88/2,234 vs. G, 93/2193; p = NS [not significant for either publications/citations] and O, 99/2425; p = NS). Publications/Citations for division chiefs/directors were comparable with other specialties: T, 77/1,595 vs. G, 103/2,081 and O, 74/1,738; p = NS, but were lower for all nonchief faculty; T, 23/368 vs. G, 30/528 and O, 37/658; p < 0.05. Trauma surgical faculty were less likely to have current or former NIH funding than other surgical specialties (17 % vs. 27%; p < 0.05), and this included a lower rate of R01/U01/P01 funding (5.5% vs. 10.8%; p < 0.05). CONCLUSIONS Senior trauma surgical faculty are as academically productive as other general surgical faculty and other surgical specialists. Junior trauma faculty, however, publish at a lower rate than other general surgery or subspecialty faculty. Causes of decreased academic productivity and lower NIH funding must be identified, understood, and addressed.