Mackenzie R. Cook

A rising ioPTH level immediately after parathyroid resection: are additional hyperfunctioning glands always present? An application of the Wisconsin Criteria.

Objective:This study was designed to determine if a rising intraoperative parathyroid hormone (ioPTH) level following parathyroid resection indicates multiple hyperfunctioning glands and to determine the appropriate intraoperative management. Summary Background Data:IoPTH monitoring is commonly used to guide parathyroid surgery. A significant rise in the ioPTH immediately after resection of a single parathyroid is often perceived to be indicative of the presence of additional hyperfunctioning glands. Methods:A total of 797 consecutive patients underwent parathyroidectomy for primary hyperparathyroidism with ioPTH monitoring. Patients with an elevated 5 minute ioPTH were extensively studied. Operative success was defined as normocalcemia 6 months after surgery. Results:Of the 797 patients, 108 (14%) had a rising ioPTH 5 minutes after resection of a single parathyroid. Of these 108 patients, 36 (33%) continued to have elevated ioPTH levels and further exploration revealed additional hyperfunctioning glands. Importantly, in the majority of patients (n = 72 or 67%), the ioPTH started to fall after an additional 5 minutes (10 minutes after resection). The ioPTH declined by more than 50% from the 5 minute elevated value in 30%, 89%, and 99% of patients at 10, 15, and 20 minutes after resection, respectively. Importantly, this fall correctly predicted operative success in 100% of patients after removal of a single abnormal gland. Conclusions:A rising ioPTH level immediately after parathyroidectomy is observed in 14% of patients. The majority of these patients do not have additional hyperfunctioning glands. Most of patients fell below 50% of the 5 minute elevated value within 20 minutes of gland resection and in all cases this fall correctly predicted operative success.

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.

Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3β

Medullary thyroid cancer (MTC) is a relatively uncommon neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Unfortunately, MTC frequently metastasizes, precluding curative surgical resection and causing significant morbidity. Thus, there is an urgent need for new treatment modalities. Tautomycin and tautomycetin are antifungal antibiotics isolated from Streptomyces spiroverticillatus and Streptomyces griseochromogens, respectively. Glycogen synthase kinase-3β is a serine/threonine protein kinase that regulates multiple cellular processes and is important in various cancers, including MTC. Treatment with tautomycin and tautomycetin decreased neuroendocrine markers, suppressed hormonal secretion, and inhibited growth through apoptosis in MTC cells. Importantly, we describe a novel action of these compounds: inhibition of glycogen synthase kinase-3β.[Mol Cancer Ther 2009;8(4):914–20]

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

Pericardiocentesis in trauma: A systematic review

BACKGROUND Pericardiocentesis (PCC) had been taught as a mandatory skill in the Advanced Trauma Life Support (ATLS®) course as a bridge to definitive surgical therapy for traumatic pericardial tamponade since its inception in 1978. Immediate thoracotomy for penetrating trauma to the heart and chest has resulted in the decreased use of PCC in trauma. PCC is now offered as an optional skill in the ninth edition of the ATLS®. A review of the literature regarding the use and effectiveness of PCC in traumatic pericardial tamponade in the modern era is necessary to better define its current role in trauma care. METHODS Scientific publications from 1970 to 2010 involving PCC after trauma were identified. The Preferred Reporting Items for Systematic reviews and Meta-Analyses was used. Human studies describing acute traumatic tamponade were included. Publications involving nontraumatic or chronic pericardial tamponade from effusions caused by inflammatory, infectious, or neoplastic etiology were excluded. Publications were categorized by level of evidence. RESULTS Of the 135 publications identified, 27 were included, composing of 2,094 trauma patients with suspected cardiac tamponade. The reported use of PCC decreased from 45.9% of patients in the period 1970 to 1979 down to 6.4% of patients in the period between 2000 and 2010 (p < 0.05). Reported rates describing the use of PCC as the sole intervention decreased from 13.7% in the period 1970 to 1979 to 2.1% in the period 2000 to 2010 (p < 0.05). Survival analysis after PCC was possible for 380 patients. Overall survival following PCC was 83.4% (n = 317) and 91.8% (n = 145) when used as the sole intervention. In patients who received PCC then thoracotomy, survival rate was 79.5% (n = 178). CONCLUSION Studies on the use of PCC for trauma are limited and biased toward survivors. The reported survival rate is high. There remains a limited role for PCC in nontrauma centers where definitive surgical management is not immediately available and transport time to a higher level of care facility supports the use of temporary decompression by PCC. LEVEL OF EVIDENCE Systematic review, level III.

Xanthohumol Inhibits the Neuroendocrine Transcription Factor Achaete-Scute Complex-Like 1, Suppresses Proliferation and Induces Phosphorylated ERK1/2 in Medullary Thyroid Cancer

BACKGROUND Achaete-scute complex-like 1 (ASCL1) is a transcription factor important in the malignant development of medullary thyroid cancer (MTC). Activation of Raf-1 signaling is associated with ASCL1 suppression and growth inhibition. Xanthohumol, a natural compound, has recently been shown to have anticancer properties. We thus hypothesized that xanthohumol would suppress growth by activating Raf-1 signaling, thus altering the malignant phenotype of MTC. METHODS Human MTC cells were treated with xanthohumol (0-30 micromol/L) for up to 6 days. Proliferation was measured by a methylthiazolyldiphenyl-tetrazolium bromide (MTT) colorimetric assay. Western blot analysis was performed for ASCL1 and markers of Raf-1 pathway activation. RESULTS Treatment of MTC cells with xanthohumol resulted in a dose dependent inhibition of growth. Additionally, induction of phosphorylated ERK1/2 and a reduction of ASCL1 protein was noted. CONCLUSIONS Xanthohumol is a potent Raf-1 activator in MTC cells. This compound suppresses MTC growth, alters the malignant phenotype, and warrants further preclinical study.

Damage-control resuscitation and emergency laparotomy: Findings from the PROPPR study.

BACKGROUND The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial has demonstrated that damage-control resuscitation, a massive transfusion strategy targeting a balanced delivery of plasma–platelet–red blood cell in a ratio of 1:1:1, results in improved survival at 3 hours and a reduction in deaths caused by exsanguination in the first 24 hours compared with a 1:1:2 ratio. In light of these findings, we hypothesized that patients receiving 1:1:1 ratio would have improved survival after emergency laparotomy. METHODS Severely injured patients predicted to receive a massive transfusion admitted to 12 Level I North American trauma centers were randomized to 1:1:1 versus 1:1:2 as described in the PROPPR trial. From these patients, the subset that underwent an emergency laparotomy, defined previously in the literature as laparotomy within 90 minutes of arrival, were identified. We compared rates and timing of emergency laparotomy as well as postsurgical survival at 24 hours and 30 days. RESULTS Of the 680 enrolled patients, 613 underwent a surgical procedure, 397 underwent a laparotomy, and 346 underwent an emergency laparotomy. The percentages of patients undergoing emergency laparotomy were 51.5% (174 of 338) and 50.3% (172 of 342) for 1:1:1 and 1:1:2, respectively (p = 0.20). Median time to laparotomy was 28 minutes in both treatment groups. Among patients undergoing an emergency laparotomy, the proportions of patients surviving to 24 hours and 30 days were similar between treatment arms; 24-hour survival was 86.8% (151 of 174) for 1:1:1 and 83.1% (143 of 172) for 1:1:2 (p = 0.29), and 30-day survival was 79.3% (138 of 174) for 1:1:1 and 75.0% (129 of 172) for 1:1:2 (p = 0.30). CONCLUSION We found no evidence that resuscitation strategy affects whether a patient requires an emergency laparotomy, time to laparotomy, or subsequent survival. LEVEL OF EVIDENCE Therapeutic study, level IV.

A nonmetropolitan surgery clerkship increases interest in a surgical career

BACKGROUND The optimal way to recruit the best and brightest medical students to fill the impending shortfall of general surgeons is uncertain. METHODS Forty-three students were placed into nonmetropolitan sites for their basic surgical clerkship over 3 years. We surveyed students and compared match trends. RESULTS When students selected to participate in the nonmetropolitan clerkship were examined, only 22% of students reported interest in a surgical career before their clerkship. This interest in surgery increased to 63% after the nonmetropolitan clerkship, P < .05. When match numbers were examined, students who completed the nonmetropolitan clerkship were significantly more likely to match to a general surgical residency than students who completed the standard clerkship (17% vs 6%, P < .02). CONCLUSIONS These data challenge the perception that students should remain at a teaching university for their introductory clerkships. It may be that pairing students with individual faculty, or chief residents, could increase interest in a surgical career.

Cirrhosis increases mortality and splenectomy rates following splenic injury

BACKGROUND Cirrhosis may be a risk factor for mortality following blunt splenic injury (BSI) and it predicts the need for an operative intervention. METHODS We performed a case-control study at 3 level 1 trauma centers. Comparisons were made with chi-square test, Wilcoxon rank-sum test, and binary logistic regression, and stratified by propensity for splenectomy. Data are presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS Mortality was 27% (21/77) and cirrhosis was a strong risk factor for death (OR 8.8, 95% CI 3.7 to 21.1). Compared with controls, cirrhosis was an independent risk factor for splenectomy (OR 5.4, 95% CI 2.5 to 11.5), and only splenic injury grade was associated with splenectomy (OR 2.2, 95% CI 1.3 to 3.6). Only admission model for end-stage liver disease was independently associated with mortality after an operation (OR 1.7, 95% CI 1.1 to 2.8). After propensity score matching, we found no association between splenectomy and mortality in cirrhotic patients. CONCLUSION Cirrhosis dramatically increases mortality and the odds of an operative intervention in BSI patients with pre-existing cirrhosis, and BSI requires vigilant attention and early intervention should be considered.