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Background and Objective: Pancreatic Ductal Adenocarcinoma (PDAC) is a form of pancreatic cancer that is one of the primary causes of cancer-related deaths globally, with less than 10 % of the five years survival rate. The prognosis of pancreatic cancer has remained poor in the last four decades, mainly due to the lack of early diagnostic mechanisms. This study proposes a novel method for detecting PDAC using explainable and supervised machine learning from Raman spectroscopic signals., Methods: An insightful feature set consisting of statistical, peak, and extended empirical mode decomposition features is selected using the support vector machine recursive feature elimination method integrated with a correlation bias reduction. Explicable features successfully identified mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor suppressor protein53 (TP53) in the fingerprint region for the first time in the literature. PDAC and normal pancreas are classified using K-nearest neighbor, linear discriminant analysis, and support vector machine classifiers., Results: This study achieved a classification accuracy of 98.5% using a nonlinear support vector machine. Our proposed method reduced test time by 28.5 % and saved 85.6 % memory utilization, which reduces complexity significantly and is more accurate than the state-of-the-art method. The generalization of the proposed method is assessed by fifteen-fold cross-validation, and its performance is evaluated using accuracy, specificity, sensitivity, and receiver operating characteristic curves., Conclusions: In this study, we proposed a method to detect and define the fingerprint region for PDAC using explainable machine learning. This simple, accurate, and efficient method for PDAC detection in mice could be generalized to examine human pancreatic cancer and provide a basis for precise chemotherapy for early cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pancreatic cancer is the deadliest cancer type with a five-year survival rate of less than 9%. Detection of tumor margins plays an essential role in the success of surgical resection. However, histopathological assessment is time-consuming, expensive, and labor-intensive. We constructed a lab-designed, hand-held Raman spectroscopic system that could enable intraoperative tissue diagnosis using convolutional neural network (CNN) models to efficiently distinguish between cancerous and normal pancreatic tissue. To our best knowledge, this is the first reported effort to diagnose pancreatic cancer by CNN-aided spontaneous Raman scattering with a lab-developed system designed for intraoperative applications. Classification based on the original one-dimensional (1D) Raman, two-dimensional (2D) Raman images, and the first principal component (PC1) from the principal component analysis on the 2D image, could all achieve high performance: the testing sensitivity, specificity, and accuracy were over 95%, and the area under the curve approached 0.99. Although CNN models often show great success in classification, it has always been challenging to visualize the CNN features in these models, which has never been achieved in the Raman spectroscopy application in cancer diagnosis. By studying individual Raman regions and by extracting and visualizing CNN features from max-pooling layers, we identified critical Raman peaks that could aid in the classification of cancerous and noncancerous tissues. 2D Raman PC1 yielded more critical peaks for pancreatic cancer identification than that of 1D Raman, as the Raman intensity was amplified by 2D Raman PC1. To our best knowledge, the feature visualization was achieved for the first time in the field of CNN-aided spontaneous Raman spectroscopy for cancer diagnosis. Based on these CNN feature peaks and their frequency at specific wavenumbers, pancreatic cancerous tissue was found to contain more biochemical components related to the protein contents (particularly collagen), whereas normal pancreatic tissue was found to contain more lipids and nucleic acid (particularly deoxyribonucleic acid/ribonucleic acid). Overall, the CNN model in combination with Raman spectroscopy could serve as a useful tool for the extraction of key features that can help differentiate pancreatic cancer from a normal pancreas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Appendiceal neuroendocrine tumors (ANETs) are rare neoplasms usually discovered incidentally during appendectomy. ANETs < 2 cm were thought to have no metastatic potential, and this dogma has driven management. Our aim is to evaluate the metastatic potential of ANETs < 2 cm., Patients and Methods: A retrospective review was performed in a series of patients with ANETs who presented to our tertiary referral center from 1998 to 2019. Demographics, tumor characteristics, treatment, and clinical outcomes were evaluated., Results: In total, 114 patients were included. Median follow-up was 3.3 years (range, 21 days-15 years). At last follow-up, 34 (30%) patients had positive regional lymph nodes and 20 (18%) patients had metastatic disease. Of the 20 patients with metastatic disease, 11 (55%) had primary ANETs < 2 cm. Patient age > 40 years at diagnosis and ANETs with serosal invasion, lymphovascular invasion, intermediate tumor grade, or positive lymph nodes were features significantly more likely to present with metastatic disease. We found no difference in the rate of lymph node positivity, metastatic disease, or overall survival when patients were stratified by tumor size or type of resection (appendectomy vs. right hemicolectomy). On multivariate analysis, patients with metastatic disease at diagnosis had worse overall survival (HR = 24.4, p = 0.008)., Conclusions: In our cohort, tumor size was not a significant risk factor for metastatic disease or worse outcome as many patients with ANETs < 2 cm developed metastatic disease. Appendectomy alone was sufficient surgical management for most ANETs. Patients with risk factors for metastatic disease, regardless of primary ANET size, should be evaluated thoroughly and counseled for further management and surveillance.

Capecitabine and temozolomide (CAPTEM) have shown promising results in the treatment of neuroendocrine neoplasms (NEN). The aim of this study was to evaluate the outcome and role for CAPTEM in malignant neuroendocrine neoplasms. Data were obtained from NEN patients who received at least one cycle of CAPTEM between November 2010 and June 2018. The average number of cycles was 9.5. For analysis, 116 patients were included, of which 105 patients (91%) underwent prior treatment. Median progression free survival (PFS) and overall survival (OS) were 13 and 38 months, respectively. Overall response rate (ORR) was 21%. Disease control rate (DCR) was 73% in all patients. PFS, median OS, ORR, and DCR for pancreatic NENs (pNEN) vs. non-pNEN was 29 vs. 11 months, 35 vs. 38 months, 38% vs. 9%, and 77% vs. 71%, respectively. Patients with pNEN had a 50% lower hazard of disease progression compared to those with non-pNEN (adjusted Hazard Ratio: 0.498, p = 0.0100). A significant difference in PFS was found between Ki-67 < 3%, Ki-67 3-20%, Ki-67 > 20-54%, and Ki-67 ≥ 55% (29 vs. 12 vs. 7 vs. 5 months; p = 0.0287). Adverse events occurred in 74 patients (64%). Our results indicate that CAPTEM is associated with encouraging PFS, OS, and ORR data in patients with NENs., Competing Interests: The authors declare no conflicts of interest.

Background: Midgut neuroendocrine tumor (NET) patients are often diagnosed at advanced stages with extensive mesenteric nodal and hepatic metastasis. The only potentially curative treatment is surgical tumor eradication. Despite an aggressive resection, macro and microscopic residual disease still may remain in the resection bed. We hypothesize that the application of 5-fluorouracil (5-FU) within the tumor bed will help eliminate microscopic residual disease., Methods: Records of 189 patients who underwent extensive cytoreductive surgeries during 2003-2012 for advanced, midgut NETs with extensive mesenteric lymphadenopathy were reviewed. Eighty-six patients (46%) who had 5-FU saturated gel foam strips secured into their mesenteric resection sites served as the study group and a matching 103 patients (54%) who did not have such an intra-operative chemotherapy served as controls. Survival from the time of diagnosis and post-operative complications between the two groups were compared., Results: Mortality rates at 30, 60 and 90 days post-operatively were 4%, 0%, 0% versus 2%, 0%, 2% for study and control groups, respectively. Major complications (Grades III & IV) at the same intervals were 0, 0, 1 versus 2, 3, 2 for study and control groups, respectively. Median survival was 236 months versus 148 months for the study and control groups, respectively 24 (P=0.15)., Conclusions: Intraoperative tumor resection bed chemotherapy is a safe adjuvant without discernible toxicity. This procedure may provide survival benefits to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery. Further study in prospective trials must be conducted to determine definitive benefit to the NET patient., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Gastrointestinal Oncology. All rights reserved.)

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) are a rare neoplasm with a bleak prognosis. Currently there are little prospective data available for optimal treatment. This review discusses the current available regimens and the future direction for the treatment of GEPNECs. Treatment plans for GEPNECs are often adapted from those devised for small cell lung cancer; however, differences in these malignancies exist, and GEPNECs require their own treatment paradigms. As such, current first-line treatment for GEPNECs is platinum-based chemotherapy with etoposide. Studies show that response rate and overall survival remain comparable between cisplatin and carboplatin versus etoposide and irinotecan; however, prognosis remains poor, and more efficacious therapy is needed to treat this malignancy. Additional first-line and second-line treatment options beyond platinum-based chemotherapy have also been investigated and may offer further treatment options, but again with suboptimal outcomes. Recent U.S. Food and Drug Administration approval of peptide receptor radionuclide therapy in low- and intermediate-grade neuroendocrine tumors may open the door for further research in its usefulness in GEPNECs. Additionally, the availability of checkpoint inhibitors lends promise to the treatment of GEPNECs. This review highlights the lack of large, prospective studies that focus on the treatment of GEPNECs. There is a need for randomized control trials to elucidate optimal treatment regimens specific to this malignancy. IMPLICATIONS FOR PRACTICE: There are limited data available for the treatment of poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) because of the rarity of this malignancy. Much of the treatment regimens used in practice today come from research in small cell lung cancer. Given the poor prognosis of GEPNECs, it is necessary to have treatment paradigms specific to this malignancy. The aim of this literature review is to summarize the available first- and second-line GEPNEC therapy, outline future treatments, and highlight the vast gap in the literature., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Objectives: Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs., Methods: Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery., Results: PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively., Conclusions: Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.

Objectives: Elevated neurokinin A (NKA) levels are associated with poor prognosis in patients with small bowel neuroendocrine tumors. We hypothesized that patients with NKA levels that remain elevated despite treatment with surgical cytoreduction have a poor prognosis., Methods: Patients diagnosed with small bowel neuroendocrine tumors who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Patients were grouped by the trend of their NKA levels (group 1, continuously normal; group 2, transiently elevated but normalized after therapy; group 3, remained elevated despite therapy). Survival rates were calculated from the date of the patient's first NKA level., Results: Serial NKA values after surgical cytoreduction were monitored in 267 patients. Kaplan-Meier 2-year, 5-year, and 10-year survival rates were as follows: group 1 (n = 157), 97%, 89%, and 62%; group 2 (n = 78), 99%, 90%, and 78%; and group 3 (n = 32), 88%, 69%, and 0%. Survival rates were statistically significant between groups 1 and 3 and between groups 2 and 3 (P < 0.01)., Conclusions: Serial monitoring of plasma NKA levels is useful in identifying patients who have a poor prognosis. Elevated NKA levels can indicate the need for immediate therapeutic intervention.

Background: Typical and atypical carcinoids represent approximately 2% of all lung tumors. Survival of patients with typical bronchial carcinoids, unlike the survival of patients with most lung tumors, is generally long but dependent on stage. We report the findings of the Ochsner Medical Center/Louisiana State University (LSU) Health Sciences Center neuroendocrine tumor (NET) program., Methods: A database with all patients seen at the Ochsner Medical Center/LSU NET program was queried for patients with bronchopulmonary NET. We included patients who had confirmed pathologic bronchopulmonary carcinoid and who had at least 1 clinic visit. Patients with large or small cell NETs or diffuse idiopathic pulmonary neuroendocrine cell hyperplasia were excluded., Results: A total of 169 patients seen from January 1996 to March 2015 met the inclusion criteria. The mean age at diagnosis was 53 years. Of the tumors, 51% percent (86/169) were well-differentiated, 12% (21/169) were moderately differentiated, and 85% and 53% were positive on positron emission tomography and octreotide scanning, respectively. The 5- and 10-year survival rates were 88% and 81% for well-differentiated tumors and 80% and 42% for moderately differentiated tumors, respectively. The 10-year survival rates stratified by Ki-67 index ranges 0-2%, >2%-10%, and >10% were 90%, 72%, and 44%, respectively ( P <0.05)., Conclusion: Overall, patients with bronchial carcinoids have long 5- and 10-year survival rates. We found significant survival differences between nodal status, differentiation status, and carcinoid phenotype. Interestingly, the difference in survival stratified by Ki-67 indices was statistically significant despite its absence in the World Health Organization grading system. As with gastroenteropancreatic NETs, Ki-67 index could become a valuable prognostic indicator for bronchial carcinoids.

Background: Neuroendocrine tumors (NETs) are rare neoplasms. Our group has treated more than 2,000 NET patients and has performed more than 1,000 surgical cytoreductive procedures., Study Design: Records of 834 NET patients who underwent surgical cytoreduction at our institution were reviewed. Demographic information, intraoperative findings, extent of disease, complications, and survival rates were calculated., Results: Eight hundred patients underwent 1,001 cytoreductive operations. Sixty-five percent had small bowel primaries. One hundred and thirty-eight patients presented with an unknown primary site, which was localized intraoperatively in 89% of these cases. The intraoperative complication rate was 9%. The incidence of intraoperative carcinoid crisis was 1%. Mean ± SD operative time was 368 ± 146 minutes. Mean ± SD hospital stay was 9 ± 10 days. Minor postoperative complications occurred after 43% of procedures and major postoperative complications were noted after 19% of procedures. The 30-day postoperative mortality rate was 2%. Median overall survival (OS) for patients with pancreatic NETs was 124 months. The 5-, 10-, and 20-year OS rates for patients with pancreatic NETs were 67%, 51%, and 36%, respectively. The life expectancy difference (between OS and actuarial survival) after surgical cytoreduction for patients with pancreatic NETs was 16.6 years. Median OS for patients with small bowel NETs was 161 months. The 5-, 10-, and 20-year OS rates for patients with small bowel NETs were 84%, 67% and 31%, respectively. The life expectancy difference after surgical cytoreduction for patients with small bowel NETs was 11.7 years., Conclusions: Surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival. We believe that surgical cytoreduction should play a major role in the care of patients with NETs., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Study Objective: The prophylactic use of a preoperative, intraoperative, and postoperative high-dose continuous octreotide acetate infusion was evaluated for its ability to minimize the incidence of carcinoid crises during neuroendocrine tumor (NET) cytoreductive surgeries., Design: A retrospective study was approved by the institutional review boards at Ochsner Medical Center-Kenner and Louisiana State University Health Sciences Center., Setting: Ochsner Medical Center-Kenner operating room and multispecialty NET clinic., Patients: One hundred fifty consecutive patients who underwent a total of 179 cytoreductive surgeries for stage IV, small bowel NETs., Interventions: All patients received a 500-μg/h infusion of octreotide acetate preoperatively, intraoperatively, and postoperatively., Measurements: Anesthesia and surgical records were reviewed. Carcinoid crisis was defined as a systolic blood pressure of less than 80mm Hg for greater than 10minutes. Patients who experienced intraoperative hypertension or hypotension, profound tachycardia, or a "crisis" according to the operative note were also reviewed., Main Results: One hundred sixty-nine (169/179; 94%) patients had normal anesthesia courses. The medical records of 10 patients were further investigated for a potential intraoperative crisis using the aforementioned criteria. Upon review, 6 patients were determined to have had a crisis. The final incidence of intraoperative crisis was 3.4% (6/179)., Conclusions: A continuous high-dose infusion of octreotide acetate intraoperatively minimizes the incidence of carcinoid crisis. We believe that the low cost and excellent safety profile of octreotide warrant the use of this therapy during extensive surgical procedures for midgut and foregut NETs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Neuroendocrine tumors (NETs) are commonly treated with multimodality therapy. The combination of capecitabine and temozolomide (CAPTEM) has been suggested as a treatment option for patients with metastatic NETs. We present our experience with CAPTEM., Methods: Data on NET patients who were placed on CAPTEM and received at least one cycle were obtained from a Velos eResearch database. Response rate was calculated by RECIST 1.1. Overall survival and progression-free survival (PFS) were calculated by the Kaplan-Meier survival method., Results: A total of 29 patients (17 male and 12 female) were included. Median age at CAPTEM initiation was 58 years (range: 26-77). Primary tumors included 9 small bowel (31%), 15 pancreas (52%), 3 lung (10%), and 2 rectum (7%). Median number of CAPTEM cycles was 8 (range: 1-55). Partial response occurred in 5 patients (5 of 29, 17%); 14 patients (14 of 29, 48%) had stable disease, and 10 patients (10 of 29, 34%) had progressive disease. A total of 3 (20%) and 5 (33%) pancreatic NETs experienced partial response and stable disease, respectively. A total of 2 (14%) and 9 (64%) nonpancreatic NETs experienced partial response and stable disease, respectively. Partial response was noted in 1 patient (13%) and stable disease in 5 patients (63%) with Ki-67 values of less than 2%. In patients with Ki-67 values of 2%-20%, partial response was noted in 3 (19%) and stable disease in 8 (50%). Partial response and stable disease were noted in 1 patient each (20%) with Ki-67 values greater than 20%. Median PFS was 12 months. Adverse reactions caused dose reductions in 24% of patients., Conclusion: Although adverse reactions were experienced, most patients tolerated this regimen. CAPTEM should be considered as a reasonable treatment option for metastatic NET patients., Implications for Practice: The role of chemotherapy in neuroendocrine tumors has evolved in recent years. The results of this study suggest that the combination of capecitabine and temozolomide provides an adequate treatment option and may prolong survival in patients with a wide variety of metastatic neuroendocrine tumors. Although prospective data are needed, this research adds to the abundance of retrospective experience with this combination that appears to show that capecitabine and temozolomide could potentially be an option for patients with advanced neuroendocrine tumors who have progressed on standard treatment., (©AlphaMed Press.)

Background: Neuroendocrine tumors (NETs) of the duodenum are rare, heterogeneous, and often indolent neoplasms. We hypothesized that elevated pancreastatin levels are an indicator of a poor prognosis in well-differentiated duodenal NETs., Study Design: Data from patients diagnosed with a primary duodenal NET were analyzed. Patients that underwent esophogogastroduodenoscopy, endoscopic ultrasound, or exploratory surgery to localize their neoplasm and whose tumors were confirmed histologically were included., Results: Eighty-four patients were diagnosed with duodenal NETs from January 1991 to January 2014. Seventy-five percent and 21% of patients had their tumor localized by esophogogastroduodenoscopy and endoscopic ultrasound, respectively. The remaining 4% were localized during exploratory surgery. The 5-year Kaplan-Meier survival rate for the entire cohort (N = 84) was 80%. Survival sorted by normal vs abnormal pancreastatin level was statistically significant (p < 0.0001). Five-year survival rates were 94% and 37% for normal and abnormal pancreastatin, respectively. In contrast, survival sorted by normal vs abnormal plasma chromogranin A level was not statistically significant (p = 0.24)., Conclusions: Patients with primary duodenal NETs have high 5-year survival rates. Serial monitoring of plasma pancreastatin levels can identify patients who have a poor prognosis., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Neuroendocrine tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and the true incidence remains unclear. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Therefore, traditionally the treatments for patients with unknown primaries have been passive and directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that NET of unknown primary are predominantly low-grade and easily located surgically and therefore are amendable to surgical debulking and cytoreduction, which will likely increase survival in these patients., Methods: The charts for all 342 surgical patients, seen in our clinic at Ochsner-Kenner between 1/2009 and 9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a "NET with unknown primary". Twenty-two patients (6.4%) were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified was recorded. Survival for these "unknown primary" patients were compared to a large similar group of NET patients from a recent study collected from this same Ochsner clinic group., Results: Twenty-two (22/342, 6.4%) NET patients with a pre-operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 22 patients (100%). The primary sites identified for these patients were 19 small intestines (86.4%) and 3 pancreatic (13.6%). All 22 patients had low-grade tumors and all were still alive as of 9/2012, not allowing for a survival curve to be generated., Conclusions: Unknown primary NETs are not associated with a poor prognosis as previously reported. Timely surgical exploration and debulking always results in the identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients, as for the known counterpart.

Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well-differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post-operative adjuvant therapy., Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between May/2012 and October/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their ribonucleic acids (RNA) were then extracted to analyze the expressivity, a total of 88 different biomarkers. Based on our patients' specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically beneficial or non-beneficial., Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: fluorouracil, cisplatin and carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively., Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.

Recent increases in the use of over-the-counter (OTC) medicines and the underreporting of the use of these medications to physicians have sparked interest in the number and types of "supportive" therapies used by patients with neuroendocrine tumors (NETS). Patients with NETS are of special interest as a result of the potential interactions/interferences between tumor-associated peptide and amine production and OTC supplements. A prospective analysis of patients with primary small bowel NETS between 1998 and 2012 was conducted to define and catalog each patient's prescription and OTC medication use at each clinic visit. The most recently recorded patient medications were used for this analysis. Three hundred sixty-two patients with small bowel primary NETS were studied. One hundred eighty-seven patients (51.6%) were taking nutritional supplements. Of these taking supplements, the per cent of patients taking one, two, three, or more than three supplements was 28.3, 24.1, 22.5, and 25.1 per cent, respectively. Females (n = 109) were more likely to take supplements in comparison to males (n = 78; P = 0.037). Fifty one patients (14.1%) took proton pump inhibitors and 31 patients (8.6%) took loperamide. OTC supplements were used by 50 per cent of patients with primary small bowel NETS in this study. Over one-third of our patients reported using three or more OTC medicines daily. These medicines have the potential to interact with the metabolism of prescribed medicines, modify ability to clot during surgery, exacerbate NET symptoms, and alter NET markers. Given the prevalence of OTC medications and their potential actions, it is important to carefully catalog their use.

Background: Well-differentiated neuroendocrine tumors (NETs) of the gastrointestinal tract are rare, slow-growing neoplasms. Clinical outcomes in a group of stage IV, well-differentiated patients with NETs with small bowel primaries undergoing cytoreductive surgery and multidisciplinary management at a single center were evaluated., Study Design: The charts of 189 consecutive patients who underwent surgical cytoreduction for their small bowel NETs were reviewed. Information on the extent of disease, complications, and Kaplan-Meier survival were collected from the patient records., Results: A total of 189 patients underwent 229 cytoreductive operations. Ten percent of patients required an intraoperative blood transfusion and 3% (6 of 229) had other intraoperative complications. For all 229 procedures performed, mean (± SD) stay in the ICU was 4 ± 3 days and in the hospital was 9 ± 10 days. Before discharge, 51% of patients had no postoperative complications and 39% of patients had only minor complications. In a 30-day follow-up period from discharge, 85% of patients had no additional complications and 13% had only minor complications. The 30-day postoperative death rate was 3% (5 of 189). Mean survival from histologic diagnosis of NET was 236 months. The 5-, 10-, and 20-year Kaplan-Meier survival rates from diagnosis were 87%, 77%, and 41%, respectively., Conclusions: Cytoreductive surgery in patients with well-differentiated midgut NETs has low mortality and complication rates and is associated with prolonged survival. We believe that cytoreductive surgery is a key component in the care of patients with NETs., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

This epidemiological review analyzed cases of Naegleria fowleri primary amebic meningoencephalitis (PAM) and Balamuthia mandrillaris granulomatous amebic encephalitis (GAE) for behavioral and demographic risk factors for pathogen exposures and potential transmission by organ transplantation. The Centers for Disease Control and Prevention (CDC) Naegleria Workgroup Registry provided 121 cases of laboratory-confirmed PAM over the period, 1937-2007. The CDC and the California Encephalitis Project provided 28 cases of GAE over the period, 1994-2010. There was a statistically significant increase in clusters of PAM cases between the periods, 1937-1996 and 1997-2007. Risk factors for PAM included male gender, freshwater exposures, summer exposures, and exposures in southern-tier US (United States) states. Risk factors for GAE included male gender, exposures in southern-tier US states, Hispanic ethnicity in California, occupational or recreational contacts with soil, and recent organ transplantation. Fatal free-living amebic infections of the brain are increasing today due to more frequent environmental, recreational, and occupational exposures; organ transplantation; and unanticipated clusters of PAM due to N. fowleri inoculations following nasal sinus irrigation using neti pots filled with municipal tap water. Potential organ donors dying from meningoencephalitis of unexplained causes should be screened for free-living amebic infections of the brain capable of hematogenous dissemination in organ recipients.

Background: Recent European investigations have shown that persistently elevated (>50 pg/mL) plasma neurokinin A levels are associated with poor short-term survival in patients with midgut neuroendocrine neoplasms. We hypothesized that American patients with persistently elevated plasma neurokinin A levels (>50 pg/mL) will also have a poor short-term survival., Methods: Serial plasma neurokinin A levels were collected from the charts of 180 patients with metastatic midgut neuroendocrine neoplasms. Patients were grouped according to their plasma neurokinin A values, and survival rates were calculated. Group 1 had plasma neurokinin A levels <50 pg/mL. Group 2 at one point had plasma neurokinin A levels >50 pg/mL, but are currently <50 pg/mL. Group 3 had plasma neurokinin A values consistently >50 pg/mL., Results: Group 1 patients (n = 143) have not reached their median survival and have a 24-month survival of 93%. Thirteen of 14 (93%) group 2 patients are currently alive. Group 3 patients (n = 23) had a median survival of 20 months and a 24-month survival of 48%., Conclusion: Patients with midgut neuroendocrine neoplasms who have serial plasma neurokinin A levels <50 pg/mL have an excellent short-term prognosis, while patients with plasma neurokinin A levels >50 pg/mL have a poor short-term prognosis., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Purpose: Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human angiogenesis model., Methods: A total of 74 neuroendocrine tumors were tested with five therapeutic agents for anti-angiogenic activity. Angiogenic responses were assessed visually and the percent of tumor explants that developed an angiogenic response was determined. The extent of neovessel growth was rated using a validated semi-quantitative visual scale. Analysis of variance was used to compare treatment outcome results to control values for these angiogenic parameters., Results: Vatalanib (2 × 10(-5) M) and patupilone (1 × 10(-8) M) were highly effective inhibitors of human tumor angiogenesis (mean overall angiogenic response for drug versus control 1.3 vs. 5.9 and 0.2 vs. 5.2, respectively) and were statistically significant at p <0.0001. Imatinib (2.5 × 10(-6) M) and everolimus (1 × 10(-8) M) were also effective (mean overall angiogenic response for drug versus control 2.2 vs. 5.9 and 4.5 vs. 5.9, respectively), and these were also statistically significant at p <0.0001. Pasireotide (1 × 10(-8) M) had no effect on angiogenesis (mean overall angiogenic response for drug vs. control 5.5 vs. 5.2)., Conclusions: Significant differences in angiogenic response to test drugs were noted in this neuroendocrine patient population. In vitro screening of a large series of fresh human tumors may be a cost-effective way to select drugs for continued clinical development.

Background: The incidence, clinical importance, and optimal management of cervical and upper mediastinal lymph node metastasis from gastrointestinal and pancreatic neuroendocrine tumors (NETS) are largely unknown. Historically, cervical nodes have been regarded as asymptomatic and ignored. We hypothesized that these lesions have clinical implications and should be removed surgically., Study Design: Consecutive (111)In pentetreotide scans (OctreoScan) performed at our institution from May 2008 to October 2010 were reviewed to determine the incidence of cervical and upper mediastinal lymph node metastases among patients with gastrointestinal and pancreatic NETs. The charts of surgically treated patients were reviewed to evaluate the clinical importance of these metastases and the subsequent outcomes of their surgical treatment., Results: A total of 161 NET patients presented with positive OctreoScans. Fourteen patients (8.7%) scanned positive for cervical and upper mediastinal lymph node metastasis. Nine patients underwent surgical exploration; 8 had successful removal of their metastatic nodes. Seven had clinical symptoms that resolved after surgery., Conclusions: Cervical and upper mediastinal lymph node metastases from gastrointestinal and pancreatic NETs were seen in up to 8.7% of patients. In the past, these metastases were assumed to be insignificant and ignored. Our study clearly demonstrates that most, if not all, such metastases are symptomatic and their clinical implications should not be overlooked. Notably, these metastases can be easily and safely resected using radioguided surgery., (Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Only one tumor site is usually biopsied to determine the histologic features of that patient's entire tumor burden. We hypothesized that there are significant histologic and functional differences in primary neuroendocrine tumors (NETS) and their nodal or organ metastases. We also hypothesized that limited tumor sampling could lead to erroneous assumptions about the tumor's histologic characteristics and clinical behavior., Materials and Methods: Thirteen patients with metastatic well differentiated midgut NETS underwent simultaneous removal of their primary tumor, nodal metastasis, and organ metastasis. Each tumor site was stained quantitatively for Ki-67, chromogranin A (CGA), synaptophysin, CD31, and Factor VIII. Samples were also evaluated with in vitro tumor angiogenesis and drug chemoresistance assays., Results: Ki-67 staining was nearly identical at all sites tested. Quantitative stains for CGA, synaptophysin, cluster of differentiation 31 (CD31), and Factor VIII varied considerably among the patient's three tissue site samples. Only 6% of the tissue samples tested against a battery of chemotherapeutic agents exhibited susceptibility to a single drug at all three tumor sites. In contrast, several antiangiogenic agents exhibited uniform effectiveness across all three tissue sites in multiple patients., Conclusions: Sampling only one NET tumor site may lead to erroneous assumptions about the tumor's histologic features and functional behavior. Evaluation of primary tumors and their nodal and organ metastasis may be necessary to optimize clinical decision making., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Radioguided exploration (RGS) can be an important tool to direct the cytoreduction of neuroendocrine tumors (NETs). The selection of the proper radiolabeled isotope, the dose, and the time interval between isotope injection and exploration are the major factors that lead to the successful use of this technique., Methods: Data on 43 patients who underwent RGS of their NET at our facility (Ochsner Medical Center-Kenner) was collected. These cases were reviewed to determine the optimal radiopharmaceutical, dose, and interval between injection and exploration., Results: The isotopes used were (99)technetium sulfur colloid in three patients, (123)I metaiodobenzylguanidine ((123)I-MIBG) in six patients, and (111)In-pentreotide in 30 abdominal NET patients and in four patients undergoing neck and mediastinum explorations. In 29 of 30 (111)In-pentreotide-guided abdominal explorations (five of which were re-explorations, all successful), the gamma detector was determined to be "helpful". In the four neck and mediastinum explorations, the gamma probe was deemed "essential" for completing a quick, safe, and minimally invasive procedure. (123)I-MIBG injection, in contrast, was useful in only one patient. The optimal dose and interval between injection and exploration of (111)In-pentreotide were discovered to be 6 mCi injected 7 days prior to the planned exploration., Conclusion: Radioguided exploration is a useful tool to guide the cytoreduction of NETs. The correct choice of radiopharmaceutical, its dose, and the interval between injection and exploration are critical for obtaining optimal results.

Carcinoid tumors are uncommon, slow-growing neoplasms. These tumors are capable of secreting numerous bioactive substances, which results in significant potential challenges in the management of patients afflicted with carcinoid syndrome. Over the past two decades, both surgical and medical therapeutic options have broadened, resulting in improved outcomes. The pathophysiology, clinical signs and symptoms, diagnosis, treatment options, and perioperative management, including anesthetic considerations, of carcinoid syndrome are presented., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Neuroendocrine tumors (NETs) are rare neoplasms found in diverse locations within the body. These tumors are commonly classified by the primary tumor's location, further subclassified by their differentiation, and finally segregated by their ability to hypersecrete peptides or amines. A number of groups have summarized their recommendations for diagnosis and therapy; however, the rarity of these lesions makes prospective randomized multiinstitutional trials difficult. Thus, these "consensus statements" often remain opinion-based. The authors have collaboratively developed a consensus on the current diagnostic work-up necessary for patients with NETs to help clinicians with this confusing field and followed this with some of the more advanced surgical techniques and considerations that are currently only available in specialty centers to show the evolving management of NETs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The only therapy with the potential for complete cure of patients with gastroenteropancreatic neuroendocrine tumors is complete surgical excision. Surgical options per se are often dictated by the tumor's site of origin, degree of tumor burden, and overall health or debility of the individual patient. This article considers different options based on the type of tumor and site of origin., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Well-differentiated neuroendocrine tumors (NETs) of the jejunum, ileum, and appendix are also collectively known as midgut carcinoids. Similar to NETs in general, the diagnosed incidence of the midgut NETs is on the rise. Their presenting symptoms vary depending on stage and primary site. Local-regional NETs often present with vague and nonspecific symptoms. Classic carcinoid syndrome is more likely to appear in patients with advanced disease. Local-regional NETs of the small bowel should be resected whenever possible. With the exception of small well-differentiated NETs of the appendix, NETs of the midgut have substantial risk of relapse after resection and need to be followed for at least 7 years.Metastatic/advanced NETs of the midgut are incurable. Optimal management requires a multidisciplinary approach. Somatostatin analogs are effective in the management of carcinoid syndrome. Octreotide long-acting release has also recently been shown to delay disease progression. Liver-directed therapy and surgical debulking can improve quality of life in selected patients. Pivotal phase 3 studies with bevacizumab targeting vascular endothelial growth factor and everolimus targeting mTOR (mammalian target of rapamycin) are ongoing and may lead to improved outcome. Further studies of novel approaches such as peptide receptor radiotherapy are also warranted.

Objective: Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies that cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume., Methods: We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino acids 286-301 of the human CgA., Results: Our assay measures more than 95% of circulating pancreastatin levels; has little or no cross-reactivity with CgA, even at plasma concentrations of 1000 ng/mL; and can detect pancreastatin levels of 17 pg/mL. Interassay reproducibility for the pancreastatin radioimmunoassay was determined from results of 3 quality control pools in 15 consecutive assays. Coefficients of variation for low, medium, and high pancreastatin levels were less than 20%. The sensitivity of serial pancreastatin assays to detect early liver tumor activity was demonstrated in 2 patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction., Conclusions: This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the United States.

External compression of extracranial/mediastinal vessels has not been reported as an etiology of pulsatile tinnitus. We present a case in which compression of extracranial vasculature led to long term pulsatile tinnitus which resolved completely with surgical resection of metastatic lymph nodes. This should be included in the list of differential diagnoses when dealing with any patient with a complaint of pulsatile tinnitus. Patients with advanced carcinoid cancer often present with distant metastases to their left superior mediastinum and supraclavicular lymph node chain. We believe a careful search for nodal metastases compressing vascular structures in such patients is warranted as debilitating pulsatile tinnitus may be cured by a simple surgical procedure.

Background: In preclinical models, VEGF is a potent stimulant of both physiologic and pathologic angiogenesis. Conversely, anti-VEGF regimens have successfully inhibited angiogenesis both in vitro and in vivo. We hypothesized that VEGF would stimulate both physiologic and pathologic angiogenesis in a human-based fibrin-thrombin clot angiogenesis assay. We further speculated that anti-VEGF regimens would inhibit angiogenesis in this assay., Methods: To test these hypotheses, discs of human placental veins (physiologic model) and fragments of human tumors (pathologic model) were embedded in fibrin-thrombin clots and treated with either VEGF-A165 (VEGF) or anti-VEGF pathway reagents including bevacizumab, IMC-18F1, IMC-1121, and PTK787 (n=30 wells per treatment group, multiple concentrations tested in each specimen). Angiogenic responses were assessed visually using a previously validated grading scheme. The percent of tissue explants that developed angiogenic invasion into the clot (% I) as well as the extent of angiogenic growth (AI) via a semi-quantitative scale were assessed at set intervals., Results: VEGF failed to stimulate angiogenesis in both the physiologic and the pathologic model. While anti-VEGF reagents that targeted only one element of the VEGF pathway failed to consistently inhibit angiogenesis, PTK787, a receptor tyrosine kinase inhibitor that targets multiple VEGF and non-VEGF receptors, profoundly inhibited both physiologic and pathologic angiogenesis., Conclusion: These results suggest that VEGF-related pathways may not be solely responsible for stimulating angiogenesis in humans. Targeting the VEGF pathway in combination with elements of other growth factor pathways may provide a more effective means of inhibiting angiogenesis than targeting VEGF alone., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The widespread use of computed tomography (CT) scans for evaluating patients has resulted in the detection of many small solitary pulmonary nodules of uncertain significance. Workup of these nodules can be expensive and emotionally draining, especially in patients who have an established diagnosis of malignancy. Since the early 1990s, video-assisted thoracoscopic surgery (VATS) has become a procedure of choice in the workup and therapy of small lung lesions. Many different techniques have been described that would assist surgeons in localising small non-descript lesions in the lung during VATS. Most commonly, a single agent or mechanical device has been used for tumour localisation. We have modified the existing pre-VATS localisation techniques, evolving from one single agent with single spot injection to a dual-agent approach. In this approach, each agent is injected at two different locations. This technique provides us with a more precise 'linear projection' to the lesion of interest rather than the vague 'field localisation' provided by a single agent with a single spot injection. This modified dual agent's preoperative localisation is logical, practical and easy to be adopted into the clinical setting for surgeons who choose to use the VATS technique in addressing these lung nodules., (Copyright 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: The extensive mesenteric lymphadenopathy associated with midgut carcinoids often causes lymphatic obstruction and leads to the development of alternative lymphatic drainage pathways. We hypothesized that altered lymphatic drainage makes traditional determination of resection margins inadequate., Methods: One hundred and seventy patients underwent cytoreductive surgery for neuroendocrine tumors from November 2006 to August 2008. Forty-nine patients underwent intra-operative lymphatic mapping with lymphazurin dye as a single agent. Twenty-seven patients had midgut primaries. We reviewed operative findings and pathology to evaluate the safety and efficacy of lymphatic mapping for midgut carcinoids. Lymphatic mapping defined resection margins were compared to traditional surgical margins., Results: There were no adverse events associated with the 49 lymphatic mapping procedures. Twenty-five (92%) patients had ileal and 2 had jejunal primaries. Lymphatic mapping changed traditional resection margins in 88% of patients. We preserved the ileocecal valve in 6 of 15 (40%) of patients with terminal ileal primaries., Conclusion: Lymphatic mapping seems to be a safe, time efficient, and effective way to determine adequate resection margins for midgut carcinoids. We advocate using lymphatic mapping for patients with midgut carcinoids to identify adequate resection margins and assist in preservation of the ileocecal valve in patients with terminal ileal primary carcinoids.

Background: Well-differentiated, "typical" carcinoid tumors traditionally have a very poor response to chemotherapy. We hypothesized that tumor specimens from well-differentiated carcinoid tumors would be highly resistant to the effects of chemotherapy when tested against a variety of antineoplastic agents in vitro., Methods: Ninety-eight typical carcinoid specimens were surgically harvested, cultured, and tested against antineoplastics in vitro. (3)H-Thymidine incorporation was used to assess the percentage of cell-growth inhibition (PCI) of tested specimens. PCI was used to determine if specimens had extreme drug resistance (EDR), intermediate drug resistance (IDR), or low drug resistance (LDR) to each reagent against which they were tested., Results: Seventy specimens generated results. Each was tested with an average of six drugs. The mean proportions of drugs classified as LDR, IDR, and EDR were 0.48 (range 0-1), 0.34 (range 0-1), and 0.18 (range 0-0.80), respectively. The mean numbers of drugs per specimen exhibiting LDR, IDR, and EDR chemoresistance were 2.7, 2.1, and 1.2, respectively. 57 of 70 specimens (81%) had LDR to at least two drugs. 5-FU had the highest frequency of low chemoresistance at 69%, followed by doxorubicin at 67%. Low in vitro resistance to chemotherapeutics was prevalent among typical carcinoids, while EDR was comparatively infrequent., Conclusions: This implies that there may be less clinical chemoresistance and more chemosensitivity among typical carcinoid tumors than clinical trials have previously revealed. These findings warrant additional investigations assessing the response of carcinoid tumors to assay-guided chemotherapy regimens.

We studied tracking of BP and its impact on GFR in 44 PRTP followed for 56 months. Three months PT 77% had elevated SBP percentile. First year SBP and DBP correlated positively with final values (p < 0.0001, 0.0002, respectively). Pretransplant and three month PT SBP correlated positively (p = 0.02). At one yr, SBP and DBP were inversely associated with GFR (p = 0.002, p < 0.0001, respectively). SBP and BMI were positively associated at all time points. DBP was significantly higher in deceased recipients throughout the study period. Final DBP was higher (p = 0.03) and GFR lower (p = 0.04) in African-American patients. Patients with end-stage renal disease caused by glomerular disease had higher SBP (p = 0.03) and DBP (p = 0.04) than those with congenital malformations. GFR at one-yr PT (p = 0.02) and end of study (p = 0.003) was significantly lower in patients with high BP. Moreover, patients who maintained a normal systolic BP throughout the study had a significantly higher final GFR than those who were hypertensive at both time points [84 (normal BP throughout) vs. 52 mL/min/1.73 m(2) (high BP throughout), p = 0.02]. We conclude that PT hypertension is common in PRTP and predicts lower GFR.

Pediatric renal TP recipients are at risk for CVD. We performed a cross-sectional study of the prevalence of RF for CVD in 45 long-term pediatric renal TP patients. The time since TP was 42 months. The GFR was 87.8 +/- 3.4 mL/min/1.73 m(2); 25/45 (56%) had Stage 2-4 CKD. A total of 33% had elevated SBP and 24% had high DBP; 57% had elevated SBP or DBP. A total of 20% had elevated serum CHOL levels, while 45% had high serum TG levels. A total of 42% had high HCY levels and 50% had low HCT levels. The vast majority (66.7%) had at least two RF for CVD. A total of 18.2% had abnormal post-TP echocardiography results. There was a negative correlation between GFR and SBP, DBP, serum CHOL, HCY, and BMI. There was a positive correlation between GFR and HCT. Serum CHOL was significantly lower and SBP and DBP trended lower in patients on a SF immunosuppression regimen. Similarly, SBP and DBP trended higher and CHOL was significantly higher in patients receiving SRL vs. mycophenolate mofetil. We conclude that the majority of pediatric renal TP patients exhibit multiple CVD RF.

Objective: To evaluate clinical outcomes in a large group of advanced-stage carcinoid patients (stage IV) following multimodal surgical therapy., Summary Background Data: Patients with advanced-stage carcinoid have traditionally experienced poor 5-year survival (18%-30%). Few recent series have evaluated a large number of patients treated with aggressive surgical rescue therapy., Methods: This single-center retrospective review analyzes the records of 82 consecutive carcinoid patients treated by the same 2 surgeons, from August 1998 through August 2004 with a 3- to 72-month follow-up., Results: Surprisingly, one third of 26 (32%) patients were found to have intestinal obstructions; 10 being moribund at presentation. Mesenteric encasement with intestinal ischemia was successfully relieved in 10 of 12 cases. Five of eighty-two "terminal" patients were rendered free of macroscopic disease. Karnofsky performance scores improved from 65 to 85 (P < 0.0001). Two- and four-year survival for patients with no or unilateral liver metastases (n = 23) was 89%, while 2- and 4-year survival for patients with bilateral liver disease (n = 59) was 68% and 52% (P = 0.072), respectively., Conclusion: We think that all patients with advanced-stage carcinoid should be evaluated for possible multimodal surgical therapy. Primary tumors should be resected, even in the presence of distant metastases to prevent future intestinal obstruction. The "wait and see" method of management of this slow-growing cancer no longer has merit. We offer an algorithm for the surgical evaluation and management of these patients.

Hypertension (HTN) contributes to the high incidence of cardiovascular disease mortality as well as chronic allograft nephropathy (CAN) and late graft failure in renal transplant recipients. The mechanisms are complex and may involve pathogenic factors attributable to the host, allograft, and immunosuppressive drugs. Calcium channel blockers should be used to ameliorate the nephrotoxicity of calcineurin inhibitors in the early years after transplantation. Angiotensin-converting enzyme inhibitors and angiotensin-2 type-1 receptor blockers are safe and effective, have antiproteinuric effects, slow the progression of CAN, and may provide survival benefits. Diuretics and/or beta-adrenergic receptor blockers are frequently added in combination regimen. Appropriate adjustment of the immunosuppressive drugs should also be considered for the long-term care of kidney recipients with HTN.

The role of aggressive surgical resections as well as criteria for resectability in patients with advanced carcinoid tumors is not clearly defined. Thirty patients (17 male and 13 female) who were previously diagnosed to have "unresectable carcinoid disease" were treated using a multimodality approach over a period of 2 years. Extensive liver involvement was present in 28 of 30 (93%) of the cases. Small bowel involvement was noted in 22 of 30 (73%), and peritoneal/retroperitoneal/mesenteric invasion was observed in 15 of 30 (50%) of the cases. Three patients had remote metastases (brain, bone, and eye). Twenty of 30 (66%) patients had carcinoid syndrome with severely disabling symptoms. Eight patients (26%) had small bowel obstruction. All patients underwent at least one surgical exploration/intervention. Radiofrequency ablation (RFA) of one or more liver lesions was performed as an adjunct in 22 of 30 (73%) patients. Six patients (20%) had a second surgical procedure. There were 11 complications in eight patients (27%) after the initial operation. Median hospital stay for patients who underwent RFA only, RFA/liver resection, and liver resection with abdominal tumor debulking were 2, 4, 8, and 16 days respectively. Twenty-five of 30 patients (83%) showed symptomatic improvement. Mean pre- and postoperative Karnofsky physical performance scores were 55 and 85 respectively (P < 0.02). Small bowel obstruction was due to adhesions in five patients. All patients with intestinal obstruction had complete relief of their symptoms postoperatively. 5-Hydroxyindolacetic acid levels decreased by 50 per cent in all patients with follow-up determinations available. Aggressive surgical exploration and tumor debulking could be performed with significantly improved symptomatic outcome and relatively minor complications. Longer follow-up is needed for assessment of effect on survival.