Scott N. Pinchot

A Multicenter Analysis of Distal Pancreatectomy for Adenocarcinoma: Is Laparoscopic Resection Appropriate?

BACKGROUND As compared with open distal pancreatectomy (ODP), laparoscopic distal pancreatectomy (LDP) affords improved perioperative outcomes. The role of LDP for patients with pancreatic ductal adenocarcinoma (PDAC) is not defined. STUDY DESIGN Records from patients undergoing distal pancreatectomy (DP) for PDAC from 2000 to 2008 from 9 academic medical centers were reviewed. Short-term (node harvest and margin status) and long-term (survival) cancer outcomes were assessed. A 3:1 matched analysis was performed for ODP and LDP cases using age, American Society of Anesthesiologists (ASA) class, and tumor size. RESULTS There were 212 patients who underwent DP for PDAC; 23 (11%) of these were approached laparoscopically. For all 212 patients, 56 (26%) had positive margins. The mean number of nodes (+/- SD) examined was 12.6 +/-8.4 and 114 patients (54%) had at least 1 positive node. Median overall survival was 16 months. In the matched analysis there were no significant differences in positive margin rates, number of nodes examined, number of patients with at least 1 positive node, or overall survival. Logistic regression for all 212 patients demonstrated that advanced age, larger tumors, positive margins, and node positive disease were independently associated with worse survival; however, method of resection (ODP vs. LDP) was not. Hospital stay was 2 days shorter in the matched comparison, which approached significance (LDP, 7.4 days vs. ODP, 9.4 days, p = 0.06). CONCLUSIONS LDP provides similar short- and long-term oncologic outcomes as compared with OD, with potentially shorter hospital stay. These results suggest that LDP is an acceptable approach for resection of PDAC of the left pancreas in selected patients.

Accuracy of Fine-Needle Aspiration Biopsy for Predicting Neoplasm or Carcinoma in Thyroid Nodules 4 cm or Larger

HYPOTHESIS All thyroid nodules 4 cm or larger should be surgically removed regardless of fine-needle aspiration biopsy (FNAB) results because of an unacceptably high rate of false-negative preoperative biopsy results in these large nodules. DESIGN Retrospective cohort study. SETTING Single-institution, tertiary academic referral center. PATIENTS A retrospective analysis was performed on all patients who underwent surgery for a thyroid nodule 4 cm or larger from May 1, 1994, through January 31, 2007. MAIN OUTCOME MEASURES Preoperative FNAB results were correlated with final surgical pathologic results. The FNAB results were reported as nondiagnostic, benign, inconclusive (follicular neoplasm), or malignant, whereas the final surgical pathologic data were reported as benign or malignant. RESULTS Of 155 patients who underwent a thyroidectomy for a nodule 4 cm or larger, 21 patients (13.5%) had a clinically significant thyroid carcinoma within the nodule on final pathologic analysis. Preoperative cytologic testing of the mass was performed on 97 patients, and the results read as benign for 52, inconclusive for 23, nondiagnostic for 11, and malignant for 11. In lesions 4 cm or larger, 26 of 52 FNAB results reported as benign (50.0%) turned out to be either neoplastic (22) or malignant (4) on final pathologic analysis. Among patients with nondiagnostic FNAB results, the risk of malignant neoplasms was 27.3%. CONCLUSIONS In patients with thyroid nodules 4 cm or larger, the FNAB results are highly inaccurate, misclassifying half of all patients with reportedly benign lesions. Furthermore, those patients with a nondiagnostic FNAB result display a high risk of differentiated thyroid carcinoma. Therefore, we recommend that diagnostic lobectomy be strongly considered in patients with thyroid nodules 4 cm or larger regardless of FNAB cytologic test results.

Identification and validation of Notch pathway activating compounds through a novel high-throughput screening method

Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells.

Resveratrol Induces Notch2-mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer

BackgroundCurrently, complete surgical resection is the only curative option for medullary thyroid cancer (MTC). Previous work has shown the Notch pathway is a potent tumor suppressor in MTC and that resveratrol activates the Notch pathway in carcinoid cancer, a related neuroedocrine malignancy. In this study, we hypothesized that the effects observed on carcinoid cells could be extended to MTC.MethodsMTC cells treated with varying doses of resveratrol were assayed for viability by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Western blot analysis for achaete-scute complex-like 1 (ASCL1), chromogranin A (CgA), full-length and cleaved caspase 3, and poly-ADP ribose polymerase (PARP) was performed. Quantitative real-time polymerase chain reaction (qPCR) was used to measure relative mRNA expression.ResultsTreatment with resveratrol resulted in growth suppression and an increase in the cleavage of caspase-3 and PARP. A dose-dependent inhibition of ASCL1, a neuroedocrine transcription factor, was observed at the protein and mRNA levels. Protein levels of CgA, a marker of hormone secretion, were also reduced after treatment with resveratrol. A dose-dependent induction of Notch2 mRNA was observed by qPCR.ConclusionsResveratrol suppresses in vitro growth, likely through apoptosis, as demonstrated by cleavage of caspase-3 and PARP. Furthermore, resveratrol decreased neuroedocrine markers ASCL1 and chromogranin A. Induction of Notch2 mRNA suggests that this pathway may be central in the anti-MTC effects observed.

Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid cell growth.

Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration–approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G2-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal–regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation. Mol Cancer Ther; 9(2); 429–37

Are surgical progeny more likely to pursue a surgical career

BACKGROUND For nearly two decades, interest in general surgery has been declining among U.S. medical school graduates. Many factors appear to be important in a medical students choice of a surgical residency and career. We hypothesized that previous exposure to family members who are surgeons would significantly influence a students decision to pursue a career in surgery. METHODS Since 2001, nearly 600 third-year medical students completing the general surgery clerkship were issued a pre- and post-clerkship survey. Responses were collected, retrospectively analyzed, and correlated to the 2001-2007 National Residency Matching Program match results. RESULTS The response rate of students completing both surveys was 87% (n = 510). Based on a numeric scale, surgical progeny (SP) indicated a significantly higher likelihood than nonsurgical progeny (NSP) of pursing a surgical career/residency in the pre-clerkship period (SP mean, 5.1 +/- 0.42; NSP mean, 3.7 +/- 0.11; P = 0.0005). Post-clerkship, SPs noted no more enjoyment from the surgical clerkship than NSPs (SP mean, 7.2 +/- 0.25; NSP mean, 6.9 +/- 0.96; P = 0.91); furthermore, there was no difference in the percentage of students pursuing a surgical residency (categorical or surgical subspecialty) in the National Residency Matching Program match (SP, 12.5%; NSP, 12.7%; P = 1.00). CONCLUSION These data suggest that previous exposure to a surgeon within the family positively influences a medical students pre-clerkship interest in pursuing a surgical career. However, this interest is not sustained; SPs and NSPs match into surgical residencies at equivalent rates. Clearly, further studies are needed to identify the factors responsible for this phenomenon.

Multi-targeted approach in the treatment of thyroid cancer

While accounting for only 1% of solid organ malignancies (9% in women), thyroid carcinoma is the most common malignancy of the endocrine system. Although most patients have a favorable prognosis, over 1,500 people will die from thyroid carcinoma each year. The spectrum of disease types range from papillary thyroid cancer, which is a well-differentiated indolent tumor, to anaplastic carcinoma, a poorly differentiated fulminant cancer. With advances in diagnostic methods, surgical techniques, and clinical care of patients with thyroid carcinoma, the current management of thyroid cancer demands a multidisciplinary approach. The majority of patients with well-differentiated thyroid carcinoma of follicular cell origin are cured with adequate surgical management; however, some thyroid malignancies such as medullary thyroid carcinoma (MTC) or poorly differentiated thyroid carcinomas frequently metastasize, precluding patients from a curative resection. As such, novel palliative and therapeutic strategies are needed for this patient population. Here, we explore the current management of thyroid carcinoma, including surgical management of the primary tumor, lymph node disease, and locoregional recurrence. Likewise, we explore the application of current molecular techniques, reviewing nearly two decades of data that have begun to elucidate critical genetic pathways and therapeutic drug targets which may be important in specific thyroid tumor types.

Medullary Thyroid Carcinoma: Targeted Therapies and Future Directions

Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm that accounts for approximately 5% of all thyroid malignancies. The natural history of MTC is characterized by early lymph node and distant metastases, making complete surgical cure often impossible. Conventional chemotherapy and external beam radiation have been largely ineffective in altering the natural history of MTC. Therefore, there is a great need to develop novel therapeutic strategies to affect symptom control and reduce tumor burden in patients with widely disseminated disease. Here, we review several pathways which have been shown to be vital in MTC tumorigenesis and focus on the pathways of interest for which targeted drug therapies are currently being developed.

Tautomycin suppresses growth and neuroendocrine hormone markers in carcinoid cells through activation of the Raf-1 pathway

BACKGROUND Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Raf-1 pathway activation has been shown to suppress hormone production in carcinoid cells. We investigated a novel treatment for carcinoid cell growth based on pharmacologic Raf-1 activation using the compound tautomycin (TTY). METHODS Human carcinoid cells were treated with TTY for 48 hours. Western blot analysis was used to demonstrate Raf-1 pathway activation by phosphorylation of ERK1/2 and to determine the effect on NE tumor markers. Cellular growth was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. RESULTS Treatment with TTY resulted in dose-dependent activation of the Raf-1 pathway. Furthermore, a significant decrease in NE tumor markers was seen. Importantly, TTY inhibited carcinoid cellular growth and induced the cell-cycle inhibitors p21 and p27. CONCLUSION TTY activates the Raf-1 pathway, limits carcinoid cell growth, and suppresses NE marker production in vitro. This new compound warrants further investigation in animal models of carcinoid cancer.

ACTH-producing carcinoma of the pituitary with refractory Cushing's Disease and hepatic metastases: a case report and review of the literature

BackgroundPituitary carcinomas are rare neuroendocrine tumors affecting the adenohypophysis. The hallmark of these lesions is the demonstration of distant metastatic spread. To date, few well-documented cases have been reported in the literature.Case presentationHere, we report the case of a fatal pituitary carcinoma evolving within two years from an adrenocorticotrophic hormone (ACTH)-secreting macroadenoma and review the global literature regarding this rare neuroendocrine tumor.ConclusionPituitary carcinomas are extremely rare neoplasms, representing only 0.1% to 0.2% of all pituitary tumors. To date, little is understood about the molecular basis of malignant transformation. The latency period between initial presentation of a pituitary adenoma and the development of distal metastases marking carcinoma is extremely variable, and some patients may live well over 10 years with pituitary carcinoma.