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Gastric cancer is a global health issue. Most cases are diagnosed at an advanced stage with poor prognosis. Current therapies have a modest impact on survival. Surgery remains the only potentially curative treatment, but is associated with a high rate of locoregional recurrence and distant metastases. Total gastrectomy for proximal cancers is complicated by postoperative morbidity and quality-of-life impairment. Combined-modality therapy may improve outcomes in this disease. Adjuvant therapy for gastric cancer has now become the standard in the Western world. However, adjuvant therapy improves survival by only a few months and is associated with high morbidity. Neoadjuvant therapy is commonly used for esophageal and gastroesophageal junction cancers, but is still regarded as investigational in gastric cancer. Several small phase II studies indicate the feasibility of neoadjuvant strategies. The incorporation of novel, targeted agents into neoadjuvant programs and an assessment of biologic changes within the tumor may refine therapy. This article provides a concise review of the literature on neoadjuvant therapy for gastric cancer and suggests avenues for further investigation. [ABSTRACT FROM AUTHOR]

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Background: Current guidelines recommend adjuvant chemotherapy for resected pancreatic adenocarcinoma (PDAC). However, no studies have addressed its survival benefit for stage I patients as they comprise <10% of PDAC., Methods: Using the NCDB 2006-2012, resected PDAC patients with stage I disease who received adjuvant therapy (chemotherapy or chemoradiation) were analyzed. Factors associated with overall survival (OS) were identified., Results: 3909 patients with resected stage IA or IB PDAC were identified. Median OS was 60.3 months (mo) for stage IA and 36.9 mo for IB. 45.5% received adjuvant chemotherapy; 19.9% received adjuvant chemoradiation. There was OS benefit for both stage IA/IB patients with adjuvant chemotherapy (HR = 0.73 and 0.76 for IA and IB, respectively, p = 0.002 and <0.001). For patients with Stage IA disease (n = 1,477, 37.8%), age ≥70 (p < 0.001), higher grade (p < 0.001), ≤10 lymph nodes examined (p = 0.008), positive margins (p < 0.001), and receipt of adjuvant chemoradiation (p = 0.002) were associated with worse OS. For stage IB patients (n = 2,432, 62.2%), similar associations were observed with the exception of adjuvant chemoradiation whereby there was no significant association (p = 0.35)., Conclusion: Adjuvant chemotherapy was associated with an OS benefit for patients with stage I PDAC; adjuvant chemoradiation was either of no benefit or associated with worse OS., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Purpose: To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen., Methods and Materials: A retrospective review of 164 patients with gastrointestinal malignancies treated between 2002 and 2007 was conducted to evaluate change in renal function after concurrent chemotherapy and three-dimensional conformal abdominal radiotherapy (RT). Laboratory and biochemical endpoints were determined before RT and after RT at 6-month intervals. Factors assessed included smoking, diabetes, hypertension, blood urea nitrogen, creatinine, creatinine clearance (CrCl), chemotherapy, and dose-volume parameters. Renal toxicity was assessed by decrease in CrCl and scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema., Results: Of 164 patients, 63 had clinical and dosimetric data available. Median follow-up was 17.5 months. Creatinine clearance declined from 98.46 mL/min before RT to 74.20 mL/min one year after chemoradiation (p < 0.0001). Mean decrease in CrCl was 21.37%. Pre-RT CrCl, percentage of bilateral renal volume receiving at least 10 Gy (V(10)), and mean kidney dose were significantly associated with development of Grade > or =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively)., Conclusions: We observed correlation between pre-RT CrCl, V(10), and mean kidney dose and decline in CrCl 1 year after chemoradiation. These observations can assist in treatment planning and renal dose constraints in patients receiving chemotherapy and abdominal RT and may help identify patients at increased risk for renal complications., (Published by Elsevier Inc.)

CD24 has been described as an adverse prognostic marker in several malignancies. This study evaluates CD24 expression in cholangiocarcinoma and correlates the findings with clinicopathologic data and patient survival. Between 1996 and 2002, 22 consecutive patients with cholangiocarcinoma were treated at our institution. Demographic data, SEER stage, pathologic data, treatment, expression of CD24, mitogen-activated protein kinase (MAPK), phosphorylated MAPK, and survival were analyzed. The majority of the tumors demonstrated CD24 (81.8%) and p-MAPK (87%) expression. A negative association was noted between the expression of CD24 and p-MAPK. Median survival for patients with low expression of CD24 was 36 months and high expression was 8 months. Median survival for patients who received chemotherapy with low CD24 expression was 163 months, and for seven patients with high CD24 expression, it was 17 months (p=0.04). With the addition of radiation therapy, median survival for patients with low expression of CD24 was 52 months and high expression was 17 months (p=0.08). On multivariate analysis, the use of chemotherapy (p=0.0014, hazard ratio 0.069) and the CD24 overexpression (p=0.02, hazard ratio 7.528) were predictive of survival. CD24 is commonly expressed in cholangiocarcinoma, and overexpression is predictive of poor survival and possibly of lack of response to chemotherapy and radiation therapy. These findings may improve selection of patients for the appropriate treatment modality and the development of CD24-targeted therapy.

Background: This study objectively surveyed and compared the ability of participants to perform laparoscopic and robotic tasks, and attempted to determine the key advantages of each modality., Study Design: A task-based training course was developed that included laparoscopic and robotic task modules. Twenty-two participants (6 faculty members, 6 fellows, and 10 residents) completed a pretask and posttask questionnaire concerning 3 tasks, using both laparoscopy trainer and the daVinci robotic system (Intuitive Surgical, Inc). All tasks were timed and values were recorded. The surveys were completed by each participant to assess both pre- and posttask experiences., Results: In the pretask survey, 55% of subjects reported participating in more than 20 laparoscopic cases, and only 27% had ever worked at a robotic console. The median number of beads threaded in 5 minutes was similar for the 2 methods, but the median time to complete 5 beads was 98 seconds for the laparoscope compared with 160 seconds using the robot (p = 0.001). The median number of loops completed in 5 minutes was greater (p < 0.001) using the robot (7.5 versus 2). Only 9% of subjects completed 9 loops in 5 minutes using the laparoscope; 50% did so using the robot (p < 0.05). The percentage of subjects completing 3 knots in 5 minutes was similar when using the laparoscope (45%) and robot (68%). Familiarity and tactile feedback were the primary advantages with laparoscopy, and EndoWrist (Intuitive Surgical, Inc) and stereoscopic visualization were perceived as advantages of the robot., Conclusions: As with any new technology, skills must be mastered to use robotic technology for the most benefit. The EndoWrist action and stereoscopic visualization were the most valued advantages of the robot. Most fellows and residents would seek additional training in robotics if given the opportunity.

Background: Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins has not been reported. Co-expression may reflect cross-talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome., Methods: Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 to 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists independently scored the protein expression., Results: Cyclooxygenase-2, Akt, and p-MAPK were commonly expressed in biliary cancers (100%, 96% and 87% of malignant cells, respectively). EGFR (60%) and p-EGFR (22%) overexpression was also detected. There was a significant association between EGFR and p-EGFR (P = 0.027) and between Akt and p-Akt (P = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK and p-Akt (P = 0.054). Multivariate analysis using the Cox proportional hazard model identified the use of chemotherapy (hazard ratio [HR] = 0.039, P = 0.0002), radiation (HR = 0.176, P = 0.0441) and Akt expression (HR = 0.139, P = 0.006) as the best predictors of overall prognosis., Conclusion: Epidermal growth factor receptor signaling intermediates are commonly expressed in cholangiocarcinoma. Expression of Akt and use of systemic chemotherapy or radiation may correlate with improved survival.

Background: Long-term survival of surgically resectable pancreatic cancer patients is uncommon. The epidermal growth factor receptor (EGFR) and the phosphoinositol-3-kinase pathways are often activated in pancreatic cancer, and an understanding of their role in resected cases may help refine adjuvant therapy., Methods: We investigated the expression of EGFR, Erk, Akt, and their phosphoforms (p-) in pancreatectomy specimens and correlated these with survival. Thirty-nine consecutive surgically resected pancreatic adenocarcinoma cases were included. Immunohistochemical staining of paraffin-embedded blocks was performed by using monoclonal antibodies against EGFR, Erk, p-Erk, Akt, and p-Akt. A standard immunoperoxidase technique was used to detect the avidin-biotin peroxidase complex. Immunostaining was visually scored with the histoscore method by two surgical pathologists., Results: Patient characteristics were as follows: 17 men and 22 women; median age, 66 years; and American Joint Committee on Cancer stage I, 5 patients; stage II, 4 patients; stage III, 27 patients; and stage IV, 3 patients. The tumor was World Health Organization grade 1 in 4, grade 2 in 17, and grade 3 in 18 cases. Adjuvant therapies were chemotherapy (n = 6), radiotherapy (n = 1), and chemoradiotherapy (n = 17). Immunohistochemistry revealed positive expression of EGFR in 30.8%, Erk in 92.3%, p-Erk in 45.9%, Akt in 71.8%, and p-Akt in 20.5% of cases. On univariate analyses, tumor grade (P = .0098), p-Akt (P = .0003), and p-Erk (P = .0052) expression correlated with survival. On multivariate analyses, age (P = .0002; hazard ratio [HR], 1.8), grade (P = .00318; HR, 3.0), Akt (P = .0433; HR, .4), p-Akt (P = .0002; HR, .2), and p-Erk (P = .0003; HR, 3.5) expression correlated significantly with survival., Conclusions: p-Erk and p-Akt expression may have prognostic and therapeutic implications in pancreatic cancer.

Distinguishing benign tumors and pseudotumors of the liver from malignant tumors is a common clinical problem. Regenerative nodular hyperplasia (RNH) represents one of the more challenging pseudotumors to diagnose, because they can appear clinically indistinguishable from either a primary or a secondary liver malignancy. Even after comprehensive radiologic evaluation and image-guided percutaneous biopsy, the diagnosis of RNH can remain elusive. We reviewed the pathophysiology of RNH and present five cases illustrating the limitations of percutaneous biopsy and the utility of laparoscopic wedge biopsy in establishing the diagnosis. All patients underwent a complete workup that included percutaneous biopsy. Patients with a nondiagnostic percutaneous biopsy underwent a laparoscopic wedge biopsy or anatomical resection. H&E, vimentin, trichrome, and reticulin staining as well as CD34 immunostaining were performed. Five patients were diagnosed with RNH between May 2002 and April 2004. Three had focal nodular disease, whereas the other two had a diffuse multinodular presentation. Percutaneous biopsy definitively made the diagnosis in only one out of the five cases. Laparoscopic wedge biopsy was necessary to accurately make the diagnosis in three cases, whereas the fifth diagnosis was established after an anatomical resection. RNH is a unique pseudotumor of the liver that can present either as a solitary nodule or as a multinodular process. Percutaneous biopsy is associated with limitations in diagnosing RNH, and a more definitive surgical biopsy may be required. When RNH is considered, laparoscopic wedge biopsy is a safe and efficient way to obtain enough tissue to preserve the hepatic architecture required for diagnosis, while avoiding the morbidity of an unnecessary open resection.

The use of computed tomography scan (CT) of the abdomen and pelvis for surveillance of colorectal cancer (CRC) after primary curative therapy (PCT) remains controversial. Surveillance guidelines at Roswell Park Cancer Institute have included annual CT for the first 2 years after PCT. Isolated metastases from CRC may be amenable to surgical resection, potentially leading to a survival advantage. To assess this, a retrospective chart review of all 203 patients diagnosed with stage II or III CRC between January 1, 1990, and December 31, 1995, was conducted. First-year surveillance CT (CT-1) was performed for 146 of 203 patients and 81 of 146 patients had second-year surveillance CT (CT-2). CT was considered "directed" when at least 1 of the following prompted evaluation: suspicious symptoms or signs, rising carcinoembryonic antigen, findings from colonoscopies, chest x-rays, or laboratory tests. Otherwise, CT was considered "nondirected." Of 121 of 146 CT-1 and 63 of 81 CT-2 with nondirected CT, 7 of 121(5.8%) and 4 of 63 (6.4%) had proven recurrence, respectively. During 2 years of follow up, the estimated lower bound for detection of recurrence by nondirected CT was 11 of 121(9.1%). There were no apparent differences between the 2 groups in demographics, clinical presentation, surgical margins, treatment, tumor site, grade, or TNM stage. Surgical resectability of the metastases for directed and nondirected groups was 10 of 28 (36%) and 6 of 11 (54%), respectively. The median survival for the patients with recurrence in the directed and nondirected groups was 35 and 50 months, respectively. In conclusion, this retrospective study generates the hypothesis that CT surveillance may be of value. A prospective study, properly sized for power, is needed to answer this question.

Background: An estimated 5-10% of all pancreatic adenocarcinomas have a hereditary association. The objective of the current study was to characterize the clinical and pathologic features of familial pancreatic carcinoma and to determine potential differences in demographics, risk factors, and outcomes between familial and sporadic pancreatic carcinoma populations., Methods: A retrospective review was performed to identify patients diagnosed with pancreatic carcinoma who had an associated familial disposition. Demographic analyses and assessment of clinical features and treatment outcomes were performed for the familial subgroup, and the results were compared with observations made in the nonfamilial, or 'sporadic', population., Results: Thirty of 826 patients (3.6%) had familial pancreatic carcinoma. Baseline demographics, resectability, and metastases were similar in both the familial cohort and the sporadic cohort. The mean age of onset was slightly lower in the familial cohort (57.6 years, compared with 61 years in the sporadic cohort). However, the familial population had a significantly greater proportion of patients who were diagnosed at age <50 years compared with the sporadic population (36.7% vs. 18.3%; P=0.017). A positive smoking history was more commonly associated with familial pancreatic carcinoma (87% vs. 66%; P=0.06). The overall median survival durations were 7 months and 6 months for the familial group and the sporadic group, respectively., Conclusions: Patients with familial pancreatic carcinoma present at an earlier age compared with their counterparts who have nonfamilial disease. Smoking may play a significant role in the risk or promotion of pancreatic carcinoma in patients with an inherited predisposition.

Background/aims: Survivin is an anti-apoptotic protein expressed in cancer and may have prognostic value. Our study examined the prognostic role of survivin in biliary cancer., Methodology: Twenty-four consecutive cases of cholangiocarcinoma were studied. Immunohistochemistry was performed using a monoclonal antibody to survivin. Survivin expression was described as absent or weak and strong., Results: Median age was 68 years (range 40 to 77). There were 16 females and 8 males. SEER (Surveillance, Epidemiology and End Results) staging was local in 2, regional in 15 and distant in 7. Treatments included chemotherapy (n=3), surgery (n=9), combined modality (n=10) or no therapy (n=2). Cytoplasmic and nuclear survivin expression was seen in 13 and 11 patients respectively. Strong cytoplasmic survivin expression was seen in 6 cases and strong nuclear survivin in 4. Patients with strong nuclear survivin had a median survival of 11 months, significantly lower than for patients with weak nuclear survivin expression (20 months, p=0.033). Multivariate analysis using the Cox-proportional hazards model identified 4 important prognostic predictors: nuclear survivin (P=0.022), presence of metastasis (P=0.025), age (P=0.019) and use of combined modality therapy (P=0.006)., Conclusions: Nuclear survivin expression in cholangiocarcinoma may identify those with a poor prognosis.

Diffuse proliferative lupus nephritis requires aggressive therapy. Patients with lupus nephritis may have concomitant hepatic involvement in the form of lesions that may be inflammatory or neoplastic in nature. In such situations, initiation of immuno-suppressive therapy may prove difficult without defining the nature of the lesion. This report describes the diagnostic dilemma that we encountered in a young patient with lupus nephritis who was discovered to have an incidental solitary liver mass on abdominal ultrasound. The literature of hepatic involvement in lupus is reviewed and discussed.

Background: Radiofrequency thermal ablation (RFA) of liver tumors is done by both radiologists and surgeons by using various techniques for a variety of indications. This report describes our initial experience with RFA in 45 patients with hepatic malignancies., Methods: Patients with primary or secondary hepatic malignancies who were not candidates for resection underwent ultrasound-guided RFA under general anesthesia. End points were recurrence within or adjacent to the ablation zone or new hepatic or extrahepatic lesions. Product limit survival estimates for both ablation site recurrence-free survival and disease-free survival were calculated and compared for tumor size (less than 4 cm or 4 cm or greater), operative approach (percutaneous, laparoscopy, or open), and tumor type (hepatocellular cancer, colorectal cancer, or other metastatic disease)., Results: Patients with hepatocellular cancer (n = 11) and with secondary hepatic malignancies (n = 34) had 84 lesions ablated with a median follow-up of 12 months. Largest ablated tumor size of 4 cm or greater (P <.001) and the percutaneous approach (P <.02) were associated with worse ablation site recurrence-free survival but not overall disease-free survival (P =.06). The 15 patients with colorectal cancer had worse disease-free survival compared with other tumor types (P <.01)., Conclusions: RFA of hepatic malignancies can be done by using a percutaneous, laparoscopic, or open approach. Local control appears superior for tumors less than 4 cm and when an open surgical approach is used. The difficulty in achieving prolonged disease-free survival, especially in colorectal cancer, underscores the need to investigate multimodality approaches that include local ablative techniques. Future RFA studies should consider tumor size, operative technique, and tumor type in trial design.

Background: Pancreatic cancer is the fifth leading cause of cancer death in the United States, with an overall 5-year survival rate of less than 5%. A minority of patients are candidates for surgical resection, but most treatment strategies focus on palliative care., Methods: We discuss strategies in the diagnosis and treatment of resectable and locally advanced pancreatic cancer by reviewing available phase II and phase III trials, as well as large retrospective studies., Results: Surgical resection for pancreatic cancer is done today with an operative mortality rate below 5% and a 5-year survival rate of approximately 25%. There is evidence that chemoradiation may improve survival and quality of life in both the adjuvant setting and for locally advanced disease. Operative, minimally invasive, and endoscopic techniques are successful in palliating pain and jaundice., Conclusions: The diagnosis and treatment of pancreatic cancer continue to improve although most patients will succumb to their disease. Novel methods of earlier detection and more effective systemic therapies are needed to significantly improve outcomes.

Background: Sentinel lymph node (SLN) mapping by lymphoscintigraphy has changed the surgical management of regional lymph node metastases for melanoma. SLNs lying outside of traditional nodal basins are now being identified. Our hypothesis is that when preoperative lymphoscintigraphy identifies aberrant SLNs, these nodes should be excised and, if histologically positive, lymphadenectomy of the aberrant nodal basin should be performed., Methods: Patients with melanomas 1 mm or larger Breslow thickness and clinical stage N0M0 underwent lymphoscintigraphy and excision with SLN biopsy. Preoperative lymphoscintigraphy, intraoperative gamma probe, and intraoperative injection of isosulfan blue were performed to identify the SLN. Aberrant SLNs were defined as epitrochlear, supraclavicular, or popliteal nodes for extremity lesions and intramuscular nodes for truncal and head and neck lesions., Results: Thirty-two patients were entered into the protocol. Seven (22%) were found to have aberrant nodes. Five of 19 patients with extremity melanoma had an aberrant SLN; 2 of 13 patients with truncal and head and neck melanoma had an aberrant SLN., Conclusions: This study demonstrates that (1) aberrant SLNs are encountered with similar frequency for extremity and truncal lesions, (2) biopsy should be performed on aberrant SLNs with intraoperative lymph node mapping with the gamma probe and blue dye, and (3) lymphadenectomy of the aberrant region should be considered if the aberrant SLN is positive.

Background: Metastatic disease is detected infrequently by computed tomography (CT) in early stage melanoma. The diagnostic yield of routine CT for stage III melanoma is less established, despite extensive use in clinical practice., Methods: Charts from 347 asymptomatic patients with stage III melanoma were reviewed. Findings suggestive of metastatic melanoma identified by head or body CT, chest radiography, bone scan, or liver function studies were confirmed histologically or by progression of disease., Results: Individual CT scans identified 33/788 (4.2%) instances of metastatic melanoma, with 66/788 (8.4%) false positive studies. No metastases were identified among 104 head CT scans. Chest CT had the highest yield in patients with cervical adenopathy (7/35, 20%), and the lowest yield with groin adenopathy (1/50, 2%). Pelvic CT diagnosed metastases in 7/94 (7.4%) patients with groin adenopathy, but no patients with palpable axillary (n = 76) or cervical (n = 21) nodes. Metastatic melanoma was diagnosed in 11/136 (8.1%) patients having complete body CT imaging (chest, abdomen, and pelvis), including six patients (4.4%) identified by CT alone., Conclusions: Routine CT in patients with clinical stage III melanoma infrequently identifies metastatic disease. Head CT in the asymptomatic patient, chest CT in patients with groin adenopathy, and pelvic CT in the presence of axillary or cervical adenopathy are not indicated. Selective use of chest CT in patients with cervical adenopathy or pelvic CT in the presence of groin disease may be useful.

Modern radiologic diagnostic approaches that identify patients with high bile duct cancer can predict resectability and provide information for biliary-enteric bypass in the case of irresectability. Twenty percent to 40% of patients are resectable by local excision with or without hepatic resection, and this represents the only opportunity for cure. Operative mortality is now acceptable and resection is associated with a median survival of approximately 35 months. Numerous palliative operative and nonoperative approaches are available, including biliary-enteric bypass, transtumoral stenting, and percutaneous endoprostheses. The role of both intraluminal and external beam radiotherapy also is discussed.

To study the influence of extrapancreatic neural and cholinergic activity on the pancreatic response to cholecystokinin (CCK), six dogs underwent creation of Herrera pancreatic fistulas, placement of Thomas gastric cannulas, and distal pancreatectomies (innervated; INN). Six additional dogs were prepared similarly, with the addition of total extrinsic pancreatic denervation (denervated; DEN). The pancreatic protein and bicarbonate response to graded 12.5 to 200 ng/kg/h CCK doses was determined for INN and DEN animals both alone and with 10 micrograms/kg/h atropine infusion. The influence of extra-pancreatic neural and cholinergic activity on secretin's potentiation of the CCK-induced pancreatic response was then determined by repeating the studies with a 125 ng/kg/h secretin infusion. The latter results were compared to those predicted by summating the responses seen during separate 12.5-200 ng/kg/h CCK dose-response and 125 ng/kg/h secretin studies. Unstimulated protein output was diminished by atropine in INN animals (78 +/- 21 vs. 39 +/- 9 mg/15 min; p < 0.05) but not in DEN animals. Unstimulated bicarbonate outputs, integrated bicarbonate and protein outputs, and bicarbonate and protein dose-response curves were unaffected by denervation or atropine. Potentiation of CCK-induced bicarbonate output by secretin was also unaffected by atropine and denervation. We conclude that cholinergic elements are involved in unstimulated, but not CCK-induced, enzyme secretion. Further, potentiation of CCK-induced bicarbonate output by secretin does not depend on extrinsic neural or cholinergic elements.

Twelve patients with irresectable or recurrent hilar cholangiocarcinoma were treated with internal biliary drainage followed by intraluminal (iridium-192) and external-beam radiotherapy. Biliary drainage was accomplished by means of a combined surgical and interventional radiological approach. Initial biliary decompression was performed surgically by tumour resection, intrahepatic biliary enteric bypass or distal biliary-enteric anastomosis with a temporary stent. Maintenance of internal biliary drainage and application of intraluminal radiotherapy were accomplished radiologically with the use of percutaneous dilatation and metallic expandable biliary endoprostheses. Median survival was 14.5 months; all 12 patients survived for at least 6 months. Early complications during radiotherapy were minor and included two patients with cholangitis and one with transient haemobilia. Jaundice was relieved in ten of 12 patients, while episodes of cholangitis were seen during long-term follow-up in 11 (median 1.5 episodes per patient). Internal biliary drainage, in conjunction with radiotherapy, appears to be safe and effective palliation of irresectable or recurrent hilar cholangiocarcinoma. Patients can maintain a reasonable quality of life with an acceptable incidence of cholangitis, without the hindrance of external drainage devices.

Although somatostatin is a potent inhibitor of pancreatic exocrine secretion in vivo, its mechanism of action remains unclear. The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion was studied in conscious dogs. Chronic pancreatic fistulae were created in six mongrel dogs, and a second group of six dogs also underwent complete pancreatic denervation. The pancreatic responses to graded doses of cholecystokinin (12.5-200 ng/kg/h) and bethanechol (57-916 micrograms/kg/h), both alone and during background infusion of somatostatin-14 (800 pm/kg/h), were determined in all dogs. The cholecystokinin dose-response with a somatostatin-14 background was then repeated with the addition of atropine (10 micrograms/kg/h). In both groups of animals, cholecystokinin elicited a dose-dependent increase in pancreatic protein secretion that was inhibited significantly by somatostatin-14. Regardless of the status of extrapancreatic nerves, atropine further inhibited cholecystokinin-induced protein secretion beyond that evoked by somatostatin-14. In both innervated and denervated animals, cholinergic stimulation with bethanechol elicited a dose-dependent increase in pancreatic protein secretion that was unaffected by somatostatin-14. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Somatostatin-14 appears to inhibit cholecystokinin-induced pancreatic secretion by an intrapancreatic cholinergic mechanism.

The influence of extrapancreatic nerves and intrapancreatic adrenergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/h) and cholecystokinin (CCK; 50 ng/kg/h) was administered over 2 h. An infusion of PYY (400 pmol/kg/h) was then given randomly, during either the first or second experimental hour. The experiments were then replicated after establishing adrenergic blockade with continuous background infusions of either phentolamine (0.2 mg/kg/h), propranolol (0.5 mg/kg bolus) or a combination of phentolamine and propranolol. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. Adrenergic blockade failed to eliminate the inhibitory effects of PYY. We conclude that extrapancreatic neural pathways, including adrenergic mechanisms, do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an indirect nonadrenergic mechanism.

The influence of extrapancreatic nerves on the inhibition of meal- and secretogogue-induced pancreatic secretion by galanin was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs and a second group of five dogs also underwent complete pancreatic denervation. After recovery, galanin dose response (150-1,200 pmol/kg/h) revealed that 600 pmol/kg/h was the lowest dose of galanin to significantly inhibit pancreatic exocrine secretion. Pancreatic responses to a mixed meal, cholecystokinin (CCK) dose response (12.5-200 ng/kg/h), and secretin dose response (16-500 ng/kg/h) were determined. The experiments were then replicated with a continuous background infusion of galanin (600 pmol/kg/h). Galanin inhibited meal-, CCK-, and secretin-induced bicarbonate outputs in both the innervated and denervated pancreas. Galanin also inhibited meal- and CCK-induced protein responses in both groups. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of galanin.

Although vagal cholinergic stimulation is the predominant regulatory mechanism governing the release of pancreatic polypeptide (PP), recent studies suggest that cholecystokinin (CCK) is also an important mediator. The present study examined the role of cholinergic neural pathways in the PP response to exogenous CCK-8 using a selectively denervated canine pancreas model. Chronic denervated pancreatic preparations were created in five dogs, while five dogs underwent sham laparotomy as controls. On study days, the fasted animals were infused intravenous CCK-8 (40 or 400 pmole/kg/hr) for 60 min both with and without atropine (20 micrograms/kg/hr). Plasma was collected at 20-min intervals and PP levels were determined by radioimmunoassay. CCK-8 elicited a dose-dependent increase in circulating PP in dogs with a neurally intact pancreas. Atropine and pancreatic denervation eliminated the PP response to CCK-8 at 40 pmole/kg/hr (P < 0.01) and inhibited the PP response to CCK-8 at 400 pmole/kg/hr (P < 0.05). The high dose of CCK-8 still elicited a small PP response in the denervated dogs (P < 0.05), which was subsequently abolished by the addition of atropine. These findings suggest that extrapancreatic cholinergic nerves are essential components of CCK-stimulated PP release, and that intrapancreatic cholinergic activity may play a limited role.

To study neural involvement in potentiation of acid-induced pancreatic bicarbonate output, six dogs underwent extrapancreatic denervation and pancreatic fistula creation. Pancreatic responses to secretin (16 and 32 ng/kg/h) and cholecystokinin (50 ng/kg/h) were then assessed. The duodenum was then perfused with three sets of perfusates. The first set contained hydrochloric acid with either D- or L-phenylalanine. The second set contained bovine serum albumin and hydrochloric acid with or without oleic acid; the albumin and acid were varied so that each 50 ml contained 1, 2, or 4 meq titratable acid (pH 2.0-4.5). The third set was identical to the second except for initial pH of 3.5. Pancreatic responses predicted upon addition of cholecystokinin to secretin, L-phenylalanine to hydrochloric acid, or oleic acid to bovine serum albumin were compared with observed responses. At both doses, secretin-induced bicarbonate output was increased by cholecystokinin (16 ng/kg/h: 0.88 +/- 0.29 meq/15 min; 32 ng/kg/h: 1.01 +/- 0.23 meq/15 min). The latter significantly exceeded predicted output (16 ng/kg/h: 0.38 +/- 0.10 meq/15 min; 32 ng/kg/h: 0.58 +/- 0.15 meq/15 min), verifying potentiation. L-phenylalanine failed to potentiate bicarbonate output evoked by acidified D-phenylalanine. In contrast, addition of oleic acid to pH 2.0 or 3.5 bovine serum albumin potentiated bicarbonate output. These data suggest that enteropancreatic reflexes mediate potentiation of acid-induced pancreatic bicarbonate output by amino acids, but not by fatty acids.

To study the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the pancreatic response to secretin, six dogs underwent extrapancreatic denervation and creation of pancreatic fistulae. A second group of six dogs had pancreatic fistulae created without pancreatic denervation. The pancreatic exocrine response to graded doses of secretin (16-500 ng/kg/h) was determined, both alone and during a background infusion of cholecystokinin-octapeptide (CCK8, 50 ng/kg/h). All studies were replicated during administration of atropine (10 micrograms/kg/h). Secretin-induced bicarbonate output was significantly inhibited by atropine in both the innervated and denervated groups. Combined secretin and CCK8 elicited a dose-dependent increase in bicarbonate output and a sustained increase in protein output in both groups, regardless of atropine. In addition, potentiation of secretin-induced bicarbonate output by CCK8 was observed despite both extrinsic pancreatic denervation and administration of atropine. We conclude that endogenous intrapancreatic cholinergic activity influences the pancreatic response to secretin. Potentiation of secretin-induced bicarbonate output by CCK, however, is not dependent on neural mediation.

Background: Somatostatin inhibits pancreatic exocrine secretion in intact animals but not in vitro, suggesting an indirect effect. The present study examined the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion in conscious dogs., Methods: Seven dogs underwent extrapancreatic denervation and creation of pancreatic fistulae, while a second group of 6 dogs had pancreatic fistulae created without denervation. The pancreatic responses to graded doses of secretin (16-500 ng.kg-1.h-1), both alone and during background infusions of somatostatin-14 (400 and 800 pmol/L.kg-1.hr-1), were determined in all dogs. The secretin dose response was then repeated with a continuous infusion of bethanechol (90 micrograms.kg-1.h-1) both with and without somatostatin-14 (800 pmol/L.kg-1.h-1)., Results: Secretin-induced bicarbonate and protein outputs were significantly inhibited by somatostatin-14 in both the innervated and denervated animals. The inhibitory effects of somatostatin-14 were partially reversed by bethanechol in the innervated animals and completely reversed in the denervated animals. Bethanechol alone potentiated secretin-induced bicarbonate output from both the innervated and denervated pancreas., Conclusions: The data suggest that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Rather, somatostatin-14 appears to inhibit secretin-induced pancreatic response by an intrapancreatic cholinergic mechanism.

The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/hr) and cholecystokinin (50 ng/kg/hr) was administered over 2 hr. An infusion of PYY (400 pm/kg/hr) was then given randomly, during either the first or second experimental hour. The experiments were then replicated with a continuous background infusion of (90 micrograms/kg/hr) bethanechol, a cholinergic agonist. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. In the denervated animals, bethanechol eliminated the inhibitory effects of PYY. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an intrapancreatic cholinergic mechanism.

Objective: This study determined whether there are any laboratory or other features that will enable prediction of spontaneous closure in patients with gastrointestinal cutaneous fistulas., Summary Background Data: Although the anatomic criteria for spontaneous closure of gastrointestinal cutaneous fistulas have been presented by several authors, less than 50% of such fistulas tend to close, even in the most recent series., Methods: A group of patients with gastrointestinal cutaneous fistulas with anatomical features favorable to study were investigated with respect to a series of parameters including the usual demographic parameters, plus fistula output, number of blood transfusions, presence of sepsis, as well as metabolic parameters including serum transferrin, retinol-binding protein, thyroxin-binding prealbumin, and serum albumin., Results: Of 79 patients with 116 fistulas, 16 (20.3%) died. Causes of death were uncontrolled sepsis in eight patients and cancer in five patients. Postoperative fistulas constituted 80% of the group. The presence of local sepsis, systemic sepsis, remote sepsis (such as pneumonia or line sepsis), the number of fistulas, fistula output, and the number of blood transfusions were not predictive of spontaneous closure, whereas serum transferrin was predictive of spontaneous closure. Serum transferrin, retinol-binding protein, and thyroxin-binding prealbumin were predictive of mortality., Conclusions: Serum transferrin does not appear to be an entirely independent variable, but seems to identify those patients with significant remote sepsis, systemic sepsis, and neoplasia in whom these processes are clinically significant. The results, if confirmed, and provided that nutritional needs are met, suggest that short-turnover proteins, particularly serum transferrin, might be useful in predicting which patients with gastrointestinal cutaneous fistulas should undergo surgery despite anatomic criteria favorable for spontaneous closure.

A patient with a malignant extraadrenal retroperitoneal paraganglioma had elevated levels of immunoreactive neuropeptide Y (NPY) in the peripheral blood (5988 pg/ml; normal, 123 +/- 30 pg/ml [mean +/- standard error of the mean]). A 6-month course of chemotherapy allowed surgical removal of the previously unresectable primary tumor. Postoperatively, the plasma NPY level initially fell to 1089 pg/ml; continued chemotherapy caused an additional decrease to 440 pg/ml. Four months after surgery, the plasma NPY level increased to 940 mg/ml, coincident with hepatic metastases. This case is the first report of a NPY-secreting clinically nonfunctional malignant extraadrenal paraganglioma. Determination of circulating NPY levels may be useful in the diagnosis and follow-up of patients with neuroendocrine tumors.

Peptide YY (PYY) is released postprandially into both the circulation and the distal intestinal lumen. While circulating PYY inhibits pancreatic secretion and insulin release, the effects of intraluminal PYY on pancreatic function are unknown. The aim of the present study was to evaluate the effect of exogenous, intraileal luminal PYY on pancreatic exocrine function and fasting glucose levels. Chronic pancreatic and ileal fistulae (50 cm from the ileocecal valve) were created in nine mongrel dogs. The animals were given intravenous infusions of secretin (125 ng/kg/h) and cholecystokinin octapeptide (CCK-8, 50 ng/kg/h) for four hours. At the beginning of the second hour, either normal saline or PYY, at low [physiologic (2 ng/min)] or high [supraphysiologic (50 ng/min)] levels, was infused antegrade into the ileal fistula for two hours. Pancreatic juice was collected for PYY and glucose levels. Ileal luminal PYY infusions had no effect on pancreatic bicarbonate or protein output. Fasting serum PYY and glucose concentrations were unaffected by either dose of intraluminal PYY. We conclude that ileal luminal PYY does not influence pancreatic exocrine function or fasting glucose levels.

Peptide YY (PYY) release into the ileal lumen is stimulated by cholecystokinin (CCK) and glucose ingestion. Previous data have implicated vagal activity in the mediation of PYY release into both the systemic circulation and the ileal lumen. The present study was designed to evaluate extrinsic neural involvement in CCK and glucose-stimulated circulating and ileal intraluminal PYY release. Distal ileal Thiry-Vella loops (TVL) of 25 cm were created in seven mongrel dogs. On separate days fasted dogs were given continuous infusions of CCK at 500 ng/kg/hr during the first hour of the study or an oral glucose (1.5 g/kg) tolerance test (OGTT) was performed. Peripheral blood samples and ileal effusates were collected before tests and following either CCK or glucose stimulation for 120 min at 20-min intervals. Ileal PYY recoveries were measured by the instillation and collection of 20 cc of normal saline from the TVL for each 20-min period. The dogs were again tested after surgical denervation of the TVL. OGTT resulted in a significant rise of PYY recovery from the TVL (P less than 0.05), while not affecting circulating PYY. Intravenous CCK resulted in significant increases in both plasma and ileal PYY concentrations (P less than 0.05). Denervation of the TVL decreased PYY recovery from the TVL after both CCK and OGTT, whereas this procedure did not affect circulating PYY levels or basal luminal levels. These data demonstrate the inhibition of CCK- and glucose-stimulated ileal PYY recovery from denervated ileal loops. The extrinsic neural pathways are involved in the mediation of glucose- and CCK-stimulated mechanisms for ileal PYY release.

In two previous studies, postprandial pancreatic polypeptide (PP) release was inhibited when pancreatic denervation was combined with distal pancreatectomy. In contrast, postprandial PP release was unaffected by pancreatic denervation without a distal pancreatectomy. These findings suggested a role for the distal pancreas in regulation of postprandial PP release. To examine this possibility, we performed distal pancreatectomy on four mongrel dogs. Pancreatic polypeptide response to i.v. insulin (0.5 U/kg), a meal, and an infusion of cholecystokinin octapeptide (CCK-8; 50 ng/kg/h) were measured in conscious dogs before and after distal pancreatectomy. Insulin-induced hypoglycemia stimulated PP release both preoperatively (47.0 +/- 8.8 ng.[0-120]min/ml) and postoperatively (61.6 +/- 9.2 ng.[0-120]min/ml). Ingestion of a meal also evoked significant PP release preoperatively (85.8 +/- 22.1 ng.[0-180]min/ml) and postoperatively (105.8 +/- 42.2 ng.[0-180]min/ml). CCK-8 elicited only a small increase in circulating PP, which was not influenced by distal pancreatectomy. These findings demonstrate that distal pancreatectomy does not alter PP response to insulin, a meal, or CCK-8.

Peptide YY (PYY) and pancreatic polypeptide (PP) are related hormones released systemically after a meal. The effects of glucose stimulation and vagal involvement on circulating and ileal luminal PYY and PP concentrations were evaluated in awake dogs. An oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGT), 2-deoxyglucose bolus (2-DG), or atropine pretreatment prior to OGTT were administered to awake dogs with 25-cm ileal Thiry-Vella fistulas. Circulating and ileal intraluminal PYY and PP levels were measured by radioimmunoassay. No changes were noted in circulating PYY, and circulating PP increased (p less than 0.05) only after administration of 2-DG. Ileal luminal PP recovery was minimal (less than 60 pg/mL) and was unchanged after all tests. Ileal luminal PYY recovery increased significantly after both OGTT and IVGT. Pretreatment with atropine abolished the luminal PYY response to OGTT, and 2-DG did not affect luminal PYY recovery. Blood glucose and insulin levels were similar in all groups. Peripheral cholinergic control of luminal PYY release is suggested by our findings, whereas a central mediation of circulatory PP release is supported by 2-DG stimulation.

Somatostatin is known to inhibit the postprandial release of most gastrointestinal hormones. The aim of the present study was to evaluate the effect of an analog of somatostatin, SMS 201-995 (120 ng/kg/hr), on both meal-induced and cholecystokinin octapeptide (CCK-8, 500 ng/kg/hr)-induced peptide YY (PYY) release. Six mongrel dogs with distal ileal Thiry-Vella loops were used in this study. PYY was measured in both plasma and ileal luminal effluent. SMS 201-995 did not affect interdigestive plasma or ileal luminal PYY concentrations. CCK-8 and a fat meal both stimulated PYY release into the circulation. SMS 201-995 completely inhibited the CCK-8 and fat-stimulated circulatory release of PYY. Both CCK-8 and a mixed meal increased ileal luminal PYY recovery. SMS 201-995 inhibited CCK-8-induced, but not meal-induced, ileal luminal PYY recovery. These findings support previous studies that describe independent circulatory and ileal luminal PYY release. We conclude that both somatostatin and CCK may have a regulatory role in postprandial circulatory release of PYY.

1. A toxic extract has been isolated from the red-tide dinoflagellate Gonyaulax monilata by a phenol-water extraction. 2. The compound action potential in the desheathed frog sciatic nerve is irreversibly blocked by topical application of the extract in concentrations as low as 40 ppm (w/v) in frog Ringer solution. 3. The toxin liberated by this algae has the potential for causing the neurological symptoms exhibited by animals following the administration of the toxic extract.