Malignant primary melanoma of the colon: a case report.

Melanoma is most associated with cancer of the skin. However, a small subset of these melanomas can be a primary malignancy of other mucosal membranes. A 55-year-old male presented to the gastroenterologist with 1 year of symptoms typical of colon cancer including bloating, abdominal pain and weight loss. He underwent colonoscopy and a mass was seen in the transverse colon that was later proven melanoma. A PET CT scan showed this was his only focus of disease. He then underwent a laparoscopic-assisted extended right hemicolectomy. He had an uneventful postoperative course. He was thoroughly examined for other sources of melanoma such as cutaneous, anal and uveal sources. He has recovered well at home and is receiving adjuvant pembrolizumab immunotherapy. Mucosal primary melanomas have a worse 5-year survival than primary cutaneous melanomas. A multi-disciplinary approach is necessary to treat and properly diagnose these malignancies.

Gastrointestinal Stromal Tumor in the Excluded Gastric Remnant After Roux-en-Y Gastric Bypass.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. Despite this, they rarely occur, accounting for only 1% to 3% of all gastrointestinal tumors. This report describes a 53-year-old female patient with surgical history of Roux-en-Y gastric bypass (RYGB) who presented with right upper quadrant abdominal pain. CT imaging revealed a large 20 × 12 × 16 cm mass in the excluded stomach remnant. Ultrasound-guided biopsy confirmed this mass to be a GIST. The patient was treated surgically with exploratory laparotomy with distal pancreatectomy, partial colectomy, partial gastrectomy, and splenectomy. There are currently only 3 known reported cases of GISTs after RYGB.

Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.

Background and Aims: Early-stage small intestinal neuroendocrine tumors (SI-NETs) are generally asymptomatic and difficult to diagnose. As a result, patients often present with late-stage incurable disease. SI-NETs originate from enterochromaffin (EC) cells, which develop enteroendocrine cell (EEC) clusters consisting of a subset of EC cells at the crypt bottom at an early stage of tumor progression. In a familial form of SI-NET, EEC clusters arise in a multifocal and polyclonal fashion. We sought to determine whether early detection and analysis of cryptal EEC clusters could provide insight into the development of SI-NETs and allow successful pre-symptomatic screening for at risk family members of patients with SI-NETs. Methods: Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations. Results: Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors. Conclusion: This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.

American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary.

Importance: Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications. Objective: To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy. Evidence Review: A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included. Findings: Patients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics. Conclusions and Relevance: Twenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in pediatric patients with peritoneal mesothelioma: a single institution experience and long term follow up.

INTRODUCTION: Malignant peritoneal mesothelioma (MPM) is a lethal cancer, with approximately 2% of diagnoses occurring in patients less than 40 years of age. The purpose of this study is to report the only long-term follow up and survival of pediatric patients with MPM after multi-modality therapy including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We retrospectively investigated a prospectively maintained database including patients <21 years old who underwent CRS and HIPEC from 1994 through 2014. Follow-up information was available through 2019 and is included in this report. RESULTS: Seven young patients underwent CRS and HIPEC. Final histology was epithelioid in all patients. Three patients had received neo-adjuvant systemic chemotherapy. At the time of the operation Peritoneal Cancer Index ranged from 6 to 25. Completeness of cytoreduction score after CRS was 0 in 4 patients, 1 in two patients, and 2 in one patient. Post-operative complications included acute kidney injury (n = 1), hyperbilirubinemia (n = 1), bilateral pleural effusions (n = 1) and pneumothorax requiring chest tube placement (n = 1). At last available follow-up, 71% of patients (n = 5) were alive with minimal or no evaluable disease. The remaining two patients had passed away from their disease at 14 and 26 months, respectively, following CRS and HIPEC. Overall survival ranged between 14 and 281 months. CONCLUSION: Our surgical experience shows that CRS and HIPEC is a feasible and safe treatment option in pediatric patients, potentially improving overall survival.

Long-term outcomes in patients with advanced adrenocortical carcinoma after image-guided locoregional ablation or embolization.

BACKGROUND: To evaluate outcomes and survival rates in patients with metastatic adrenocortical carcinoma (ACC) who were treated with image-guided locoregional treatments (IGLTs). PURPOSE: To evaluate the overall survival (OS) and clinical impact of IGLT in the management of patients with advanced metastatic ACC. METHODS: Retrospective review of 39 patients treated with IGLT between 1999 and 2018 was performed. Short- and long-term efficacy of treatments were defined based upon imaging and clinical data. Subgroup survival analysis was performed on patients with metastatic disease at diagnosis (N = 17) and compared with the same stage group from the most recent National Cancer Database (NCDB) report. Statistical analysis was performed using Cox proportional hazards model. RESULTS: Treatments were performed at different anatomic sites including liver (N = 46), lung (N = 14), retroperitoneum (N = 5), bone (N = 4), subcutaneous (N = 2), and intracaval (N = 1). Radiofrequency, microwave, cryoablation, or a combination of two modalities (45, 18, 3, 3, respectively) were used in 69 ablation sessions. Intra-arterial procedures were performed in 12 patients in 18 treatment cycles (range 1-3 per patient). As of a 2019 analysis, 11 patients were alive with a mean follow-up of 169 months (range 63-292 months) from diagnosis. Two- and 5-year OS rates for all patients were 84.5% and 51%, respectively, and 76.5% and 59% for patients with metastatic disease at diagnosis (N = 17). This compares favorably with an NCDB report of 35% 5-year survival rate for patients with metastatic disease. Female gender and longer time from diagnosis to first IGLT were found to be predictors of prolonged survival with hazard ratios of 0.23 (p < 0.001) and 0.66 (p = 0.001), respectively. CONCLUSION: IGLT may be associated with prolonged life expectancy in select patients with metastatic ACC.

Racial disparities and treatment trends among young-onset colorectal cancer patients: An analysis of a hospital cancer registry.

BACKGROUND: There is an increasing trend of colorectal cancer (CRC) incidence and mortality in individuals under the age of 50. The impact of age on the outcomes of CRC remains controversial. This study examined the characteristics and treatment trends of young-onset CRC by comparing patients < 50 years of age to those ≥50. METHODS: Data were retrospectively obtained from one of the largest hospital systems in Virginia. The sample included patients diagnosed with CRC from 2008 to 2016. Bivariate analyses were used to describe patients' characteristics. Stratified and multivariate analyses were used to evaluate the association between treatments and age groups in different stages at diagnosis. RESULTS: Approximately 11.6 % (n = 522) of the cohort were younger than 50 years old at diagnosis with a mean age of 42.7 (SD = 5.9) years. Compared to their older counterpart (50 and older), young-onset patients were more likely to be African American (28.7 % (n = 150) vs. 23.7 % (n = 944)), to own private insurance (68.5 % (n = 313) vs. 27.6 % (n = 1032)), to have never used tobacco products (50.4 % (n = 237) vs. 43.8 % (n = 1616)), and to be late stage at diagnosis (68.6 % (n = 358) vs. 52.5 % (n = 2090)) (all p < 0.05). For early stage diagnosis, over 98 % of the young-onset treatments were surgery. For late stage diagnosis, the cancer treatment for young onset patients were a combination of surgery (89.4 %), radiation (82.5 %), and chemotherapy (86.3 %). The results of the analyses also demonstrated that patients with young-onset CRC have higher odds for surgery [OR = 1.76, 95 %CI (1.26, 2.47)], radiation [OR = 1.31, 95 %CI (1.17, 1.47)], and chemotherapy [OR = 3.34, 95 %CI (2.62, 4.25)]. CONCLUSIONS: Findings confirmed late-stage prevalence among young-onset as well as significant demographic differences with patients' age ≥50. This study is one of few to explore the characteristics and assess treatment of young patients with CRC using U.S hospital data. Moreover, further studies need to clarify the effects of biological properties like genetic influences and environmental factors between races on cancer patient outcomes.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization.

Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.

A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma.

BACKGROUND: Recurrent adrenocortical carcinoma (ACC) is an aggressive disease with few options offering durable survival benefit. Despite metastasectomy, recurrence is common. Cytoreduction and intraperitoneal chemotherapy have offered improved survival in other advanced cancers. We sought to evaluate the use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of recurrent intraperitoneal ACC. METHODS: A phase II, single institution clinical trial was approved for patients with radiographic evidence of resectable ACC limited to the peritoneum. Patients underwent treatment if optimal cytoreduction was deemed possible at exploratory laparotomy. Primary outcome was intraperitoneal progression-free survival. Secondary outcomes were treatment-related morbidities and overall survival. RESULTS: Sixty-three patients were evaluated, of whom 11 met eligibility criteria. Nine patients underwent cytoreduction and HIPEC, including one patient who recurred and was re-treated (n = 10 treatments). One patient could not be optimally cytoreduced for HIPEC and therefore did not receive intraperitoneal chemotherapy. There was no perioperative mortality; perioperative comorbidities were limited to Clavien-Dindo grade 2 or 3 and included hematologic, infectious, and neurologic complications. Seven patients experienced disease recurrence and two patients died of disease during follow-up (median 24 mo). Intraperitoneal progression-free survival was 19 mo, and median overall survival has not yet been reached. CONCLUSIONS: Cytoreduction and HIPEC can be performed safely in selected patients. Patients with recurrent ACC confined to the peritoneal cavity can be considered for regional therapy in experienced hands. However, disease recurrence is common, and other treatment options should be explored.

A Rare Adrenal Incidentaloma That Mimics Adrenocortical Carcinoma.

OBJECTIVE: We present a case of an adrenal hemangioma, an uncommon cause of an adrenal mass, and review the clinical presentation, work-up, and management of adrenal incidentalomas. BACKGROUND: A 64-year-old male was found to have a right adrenal incidentaloma during work-up for elevated liver transaminase levels, later found to be from hepatitis C. The mass was suspicious for adrenocortical carcinoma on CT imaging. Biochemical evaluation revealed no evidence of function. He underwent an open right adrenalectomy. The mass was found to be an adrenal hemangioma on histopathologic analysis. METHODS: This is a case report with pertinent review of the diagnosis and management of adrenal incidentalomas. RESULTS: Adrenal hemangiomas are rare, benign, nonfunctional tumors typically found during imaging for other reasons. As illustrated by this case, they appear similar to adrenocortical carcinoma on CT imaging. The diagnosis is usually not made prior to surgical resection. CONCLUSION: Adrenal hemangioma is a rare nonfunctional adrenal incidentaloma that displays atypical features on CT imaging. The suspicion for adrenocortical carcinoma usually prompts adrenalectomy.

Routine Computer Tomography Imaging for the Detection of Recurrences in High-Risk Melanoma Patients.

BACKGROUND: The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. METHODS: A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. RESULTS: The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CONCLUSIONS: CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.

Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. METHODS: Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. RESULTS: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). CONCLUSIONS: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. LAY SUMMARY: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01853618.

Metastasectomy Following Immunotherapy with Adoptive Cell Transfer for Patients with Advanced Melanoma.

BACKGROUND: Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. METHODS: Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. RESULTS: Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. CONCLUSIONS: Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease.

Multiple Origins of Virus Persistence during Natural Control of HIV Infection.

Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.

Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma.

PURPOSE: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. PATIENTS AND METHODS: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. RESULTS: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. CONCLUSION: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs. METHODS: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA. RESULTS: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs. CONCLUSIONS: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.

Significance of preoperative radiographic pancreatic density in predicting pancreatic fistula after surgery for pancreatic neuroendocrine tumors.

BACKGROUND: Postoperative pancreatic fistula remains the most severe and worrisome complication after surgery. Predictive preoperative assessment remains challenging. The authors examine the role of pancreatic computed tomography density in predicting postoperative pancreatic fistula after surgery for pancreatic neuroendocrine tumors. METHODS: A single institutional retrospective review of pancreatic surgery for neuroendocrine tumors between 1998 and 2010 was conducted. Preoperative contrast-enhanced computed tomography scans were reviewed, with mean region of interest measurements of pancreatic parenchymal density obtained from 10-mm thick axial computed tomography images. RESULTS: A total of 119 patients were identified: 59 with enucleations and 60 with resections. Decreased preoperative pancreatic density was significantly associated with an increased grade of postoperative pancreatic fistula (P < .01). Subgroup analyses revealed that decreased gland density was associated with increased grade of postoperative pancreatic fistula in the resection (P < .01) but not in the enucleation group (P = .34). CONCLUSIONS: A significant association between postoperative pancreatic fistula grade and preoperative pancreatic computed tomography density is observed in patients undergoing resection for pancreatic neuroendocrine tumors.

Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases.

PURPOSE: There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. PATIENTS AND METHODS: A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. RESULTS: hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC. CONCLUSION: This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver.