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BACKGROUND: Neoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. METHODS: A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009–12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. RESULTS: Thirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50–58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14–563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9–71.1 vs. 4.0 months, 95% CI: 0.4–14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14–0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08–0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04–0.40) and adjusted models (HR =0.13, 95% CI: 0.03–0.52). CONCLUSIONS: For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

Background Neoadjuvant therapy (NAT) for T1/T2 pancreatic adenocarcinoma (PDAC) prior to pancreaticoduodenectomy remains controversial. We compared positive margin rates in patients with clinical T1&T2 tumors who did and did not receive NAT. Methods The National Cancer Database (NCDB) found clinical T1&T2 PDAC patients who underwent pancreaticoduodenectomy from 2004 to 2014. Univariate and multivariate regression determined factors associated with a positive margin and survival. Results 9795 patients underwent surgery for clinical T1 or T2 pancreatic head adenocarcinoma. 8472 patients had data regarding use of neoadjuvant and adjuvant therapies; of which, 774 (9.1%) received NAT and 435 (5.1%) received both chemotherapy and radiation therapy. NAT was found to lower positive margin rates from 21.8 to 15.5% (p, Highlights • Neoadjuvant therapy for resectable pancreas cancer is controversial • Neoadjuvant therapy can improve margin positivity • Margin positivity is associated with inferior survival • Even small, resectable pancreas cancers may benefit from neoadjuvant therapy

The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Purpose: According to the American Joint Committee on Cancer (AJCC) 7th edition, T1 staging of pancreatic adenocarcinoma (PC) is defined as tumor limited to the pancreas, ≤2 cm. The AJCC 8th edition subcategorizes T1 staging into T1a (≤5 mm), T1b (≤1 cm), and T1c (≤2 cm) for PC despite the absence of supporting evidence. We sought to determine whether this new subcategorization has prognostic significance. Methods: A retrospective review of patients undergoing definitive surgery for PC was performed by using the National Cancer Database (NCDB) from 2004 to 2014. Kaplan–Meier survival was computed for the subcategories. Multivariable analysis (MVA) was performed by using stepwise regression. Results: The NCDB captured 41,552 stages I and II patients who underwent definitive surgery for PC in this 10-year period. A total of 2090 of these patients were pathological T1N0. The 5-year overall survival (OS) for patients with T1a (n = 319), T1b (n = 296), and T1c (n = 1309) PC was 68.8%, 57%, and 46.6%, respectively. This subcategorization lost significance on MVA and when focused on T1N1-2 patients. Recategorizing T stage into T1a (≤1 cm) and T1b (≤2 cm) resulted in statistical significance on MVA. Conclusion: Subcategorization of the T1 stage into T1a, T1b, and T1c in resected PC does differentiate OS in patients with node-negative disease. We support the AJCC 8th edition T1 stage subcategorization, while understanding that it does not differentiate OS on MVA. When this is further subcategorized into T1a (≤1 cm) and T1b (≤2 cm), it predicts OS in resected, node-negative patients on MVA.

Many solid organ malignancies including colorectal cancer (CRC), neuroendocrine tumors, and ocular melanoma frequently spread to the liver. Liver metastases in patients with these diseases are associated with a poor prognosis. Effective treatment of isolated tumors has remained difficult despite advances in targeted agents and chemotherapy. Isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) are examples of liver-directed therapies which were developed to target hepatic metastases in such patients who are refractory to other treatments. The efficacy of these therapies is thought to be attributed to targeting the unique blood supply to hepatic metastases, the hepatic artery. This chapter will describe the techniques of both IHP and PHP and summarize the clinical data evaluating their effectiveness for patients with isolated liver metastases and the above malignancies.

Diffuse malignant peritoneal mesothelioma (MPM) is a rare cancer that is ultimately fatal in almost all afflicted individuals. Morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. Patients with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. MPM is considered a chemotherapy-resistant malignancy.

To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES).Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur.A prospective database was queried.A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did.These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation.

This study was designed to determine the clinical significance of preoperative thrombocytosis in patients with malignant peritoneal mesothelioma (MPM) undergoing operative cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been associated with prolonged survival in patients with MPM and is the preferred treatment in select patients. However, patient selection criteria remain ill-defined for this operation that is also associated with significant morbidity and mortality. Preoperative thrombocytosis has been associated with poor outcomes in various malignancies but never studied in MPM. Between January 2006 and December 2015, 100 patients with high-grade epithelioid MPM were evaluated and selected for CRS and HIPEC at our center (M: 53, F: 47; mean age: 54 years [range 17–81 years]). We analyzed various patient and treatment related factors potentially associated with overall survival (OS). The median actuarial overall survival was 32.8 months; the actuarial 1-, 3-, 5-year survivals were 70, 49, and 36%, respectively. On multivariate analysis, suboptimal resection (CCR > 1), high tumor burden (PCI > 20), and elevated preoperative platelet count (>367,000/mm3) were independently associated with shortened OS (P

Human immunodeficiency virus (HIV) patients are living longer due to the availability of antiretroviral therapies, and non-AIDS-defining cancers are becoming more prevalent in this patient population. A paucity of data remains on post-operative outcomes following resection of non-AIDS-defining cancers in the HIV population. The National Inpatient Sample was utilized to identify patients who underwent surgical resection for malignancy from 2005 to 2015 (HIV, N = 52,742; non-HIV, N = 11,885,184). Complications were categorized by international classification of disease (ICD)-9 diagnosis codes. Cohorts were matched on insurance, household income, zip code and urban/rural setting. Logistic regression assessed whether HIV was an independent predictor of post-operative complications. Descriptive statistics found HIV patients to have an increased rate of complications following select oncologic surgical resections. Univariate and multivariate logistic regression found HIV to only be an independent predictor of complications following pulmonary lobectomy (p = 0.011; OR 2.93, 95% CI 1.29–6.73). Length of stay was statistically longer following colectomy (2.61 days, 95% CI 1.98–3.44) in those with HIV. Our findings are hypothesis generating and highlight the potential safety of major cancer surgery in the HIV population. However, care providers need be cognizant of the potential increased risk of post-operative complications following pulmonary lobectomy and the potential for increased length of stay. These findings are an initial insight into quality of care and outcomes metrics on HIV patients undergoing major cancer operations.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal mesothelioma. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal surface malignancies of various causes. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence. This article serves as an introduction to this effort.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Highlights • Desmoid tumors are rare neoplasms with unpredictable clinical behavior. • Intra-abdominal desmoid tumors are uncommon in pregnancy. • Spontaneous regression of pregnancy-associated desmoid tumors may occur post-partum. • Desmoid tumors may be initially managed with observation alone. • Surgical resection may be required for large, symptomatic tumors., Introduction The clinical behavior of desmoid tumors can be unpredictable, particularly when they arise in the ante-partum or post-partum period. We present a case of an intra-abdominal desmoid tumor that was identified in the ante-partum period, progressed rapidly in the post-partum period, and was subsequently resected. Presentation of case The patient is a 19 year-old female who was found to have a 12 cm intra-abdominal mass on a fetal assessment ultrasound. The decision was made to observe the patient and monitor the mass for growth. However, the mass rapidly grew in the post-partum period. The patient was transferred to our institution after an exploratory laparotomy revealed a large intra-abdominal mass emanating from the small bowel mesentery. The 30 cm × 24 cm × 16 cm mass was successfully resected with negative margins, and the pathologic diagnosis of desmoid tumor was confirmed. The patient had an uncomplicated post-operative course and was discharged on post-operative day 6. Discussion The majority of pregnancy-associated desmoid tumors are in the abdominal wall, arising from the rectus abdominus muscle or from previous Cesarean section scars. These tumors may spontaneously regress in the post-partum period and therefore, patients with these tumors are often observed. Close follow-up is important so that rapid tumor progression, which may lead to unresectability, can be identified and managed appropriately. Conclusion A patient with a rare case of a giant pregnancy-associated, intra-abdominal desmoid tumor that rapidly progressed in the post-partum period and was successfully treated with surgical resection with negative margins.

// Jian Wang 1 , Peijun He 1 , Matthias Gaida 2 , Shouhui Yang 1 Aaron J. Schetter 3 , Jochen Gaedcke 4 , B. Michael Ghadimi 4 , Thomas Ried 5 , Harris Yfantis 6 , Dong Lee 6 , Jonathan M. Weiss 7 , Jimmy Stauffer 8 , Nader Hanna 9 , H. Richard Alexander 9 , S. Perwez Hussain 1 1 Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA 2 Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany 3 US Food and Drug Administration, Silver spring, MD, USA 4 Department of General, Visceral and Pediatric Surgery, University Medicine, Gottingen, Germany 5 Genetics Branch, CCR, NCI, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA 6 Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA 7 Cancer and Inflammation Program, CCR, NCI Frederick, MD, USA 8 Laboratory of Cell and Developmental Signaling, NCI Frederick, MD, USA 9 Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA Correspondence to: S. Perwez Hussain, email: hussainp@mail.nih.gov Keywords: NOS2, NO, PDAC, KPC mouse model Received: February 12, 2016 Accepted: June 12, 2016 Published: June 29, 2016 ABSTRACT Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients ( N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy.

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.

Potentiation of systemic dosing of gemcitabine using very low-dose fractionated radiotherapy may improve its effect in advanced pancreatic cancer without additional toxicity as suggested by the results of our multi-institutional phase II study. Future regimens combining low-dose fractionated radiotherapy (RT) with systemic chemotherapy should be assessed for improving the chemotherapeutic benefit. Until recently, gemcitabine was considered the standard treatment for advanced pancreatic cancer despite low response rates. Efforts to improve response rates by combination therapies have had limited success and have involved using sub-systemic dosing of gemcitabine as a sensitizer for radiation. A novel paradigm, utilizing low-dose fractionated radiotherapy (LDFRT) as a potentiator of full-dose gemcitabine instead, was explored to assess safety and efficacy in treating advanced pancreatic cancer. Patients with locally advanced and metastatic pancreatic cancer were treated with 4 cycles of gemcitabine and LDFRT in a multi-institutional phase II study. Gemcitabine (1250 mg/m2 over 2 h) was administered on days 1 and 8 of a 21-day cycle. LDFRT fields included the upper abdomen from the diaphragm to the iliac crest and were administered at 60 cGy per fraction twice daily on days 1, 2, 8, and 9, with the morning fraction being delivered prior to gemcitabine infusion on days 1 and 8. Primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Thirty-eight patients were enrolled in the trial, of which 23 had metastatic disease at time of enrollment. Objective response rate (CR + PR) was 8 %, and 61 % had at least stable disease. Overall median survival was 13 months and 1-year survival was 37 %. Patients with non-metastatic disease had a 1-year survival of 60 %. The most significant toxicity was hematologic, and only 3 patients were withdrawn from protocol due to toxicity. There was no reported febrile neutropenia. The use of LDFRT with systemic gemcitabine is safe, tolerable, and potentially effective. In advanced pancreatic cancer, where response rates with single-agent gemcitabine have been low, this chemopotentiation paradigm may improve survival among a poor prognostic patient cohort.

There are few studies addressing survival of diffuse peritoneal mesotheliomas (DPM).In this study, survival data were obtained retrospectively from 73 patients treated with intended cytoreductive surgery for DPM, with a mean follow-up of 42 months. Mesotheliomas were classified as well differentiated papillary (WDPM, n = 2), multicystic (MCM, n = 4), and epithelioid mesotheliomas were subclassified as tubulopapillary (TPM, n = 27), solid/deciduoid (S/DM, n = 34), and or biphasic mesothelioma (BPM, n = 6). Invasion was characterised as absent (grade 0), into stroma (grade 1), into fat (grade 2), and into adjacent structures (grade 3). Peritoneal cancer index (PCI) and completeness of cytoreduction (CCR) were assessed surgically.There were no deaths in the WDPM, MCM, and epithelioid DPM with ≤ grade 1 invasion. There was a stepwise decrease in overall survival from invasive TPM, S/DM, and BPM (p 0.0001). By univariate analysis, advanced age (p = 0.01), incomplete CCR (p 0.001), PCI (p = 0.004), mitotic count (p 0.001), nuclear grade (p 0.0001), stromal inflammation (p = 0.013), depth of invasion (p 0.0001), necrosis (p = 0.002), and sarcomatoid growth (p 0.0001) were associated with decreased overall survival. By multivariate analysis, only sarcomatoid growth (p = 0.0006), depth of invasion (p = 0.02), elevated CCR (CCR 2-3) (p = 0.02), and presence of inflammatory stroma (p = 0.04) were significant variables associated with decreased overall survival.DPM form a spectrum of indolent to highly aggressive tumours. Solid epithelioid/deciduoid tumours have a prognosis intermediate between biphasic mesotheliomas and invasive TPM. The presence and degree of invasion, sarcomatoid features, and inflammatory stroma are poor prognostic indicators.

Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM. The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is

Mesothelioma of the peritoneum is a distinct entity that requires multidisciplinary care to improve oncological outcomes. In this article, we review the current management strategies discussed at the PSOGI meeting in Washington DC 2016 and provide evidence based recommendations for diagnosis and management of this disease.

Up to 80% of colorectal, melanoma, and neuroendocrine liver metastases are unresectable due to excessive tumor burden. Isolated hepatic perfusion (IHP) administers intensive therapy to the liver while limiting systemic toxicity and thus may have an important role in the management of unresectable liver metastases. This review s describes the development of IHP, initial clinical results, open and percutaneous IHP techniques, and contemporary long-term treatment outcomes. IHP with melphalan or tumor necrosis factor α (TNFα) has been shown to achieve hepatic response rates of greater than 50% with progression-free survival of greater than 12 months among patients with refractory ocular melanoma liver metastases. The only series describing outcomes of IHP for neuroendocrine liver metastases notes an overall response rate of 50% and a median actuarial overall survival of 48 months after IHP treatment with melphalan or TNFα. The majority of studies that have evaluated IHP have been performed in patients with colorectal cancer liver metastases (CRCLM). In aggregate, survival results from retrospective studies and phase I/II clinical trials suggest that IHP demonstrated no significant survival benefit compared with systemic chemotherapy alone as first-line therapy. In contrast, IHP does improve outcomes relative to that provided by second-line chemotherapy for CRCLM, with overall response rates of 60% and median duration of liver response of 12 months. Continued evaluation of IHP for unresectable liver metastases is necessary to establish its role in multidisciplinary treatment approaches.

Summary Background Diffuse peritoneal mesothelioma (DPM) forms a spectrum of indolent surface tumours to malignant invasive cancers. There are few pathological series that span well and poorly differentiated lesions that show diffuse peritoneal spread. Methods Sixty-four DPM treated by initial cytoreductive therapy were retrospectively reviewed. Tumours were classified by surface and invasive growth pattern and correlated with riskfactors, peritoneal cancer index (PCI) and completeness of cytoreduction (CCR). Degree of invasion was quantitated as absent (0), into stroma (I), into fat (II), and into adjacent structures (III) and was correlated with cytological features. Selected immunohistochemical stains were performed. Results There were three well differentiated papillary mesotheliomas (WDPM; type A), four multicystic mesothelioma (type B), 22 tubulopapillary epithelioid mesotheliomas (type C), and 35 poorly differentiated epithelioid mesotheliomas with solid or sarcomatoid growth (Type D). Seven type D tumours had prominent sarcomatoid areas, 12 deciduoid areas, and four lymphohistiocytoid features. Risk factors were present in all groups except type A, and included prior abdominal surgery ( n = 24), asbestos exposure ( n = 5) and radiation ( n = 2). Extra-pleural mesothelioma was present in all groups except type B (total n — 7, 11%). Two type A and eight type C tumours lacked invasion; only type D showed level III invasion. The invasive portion of one type A tumour and two type B tumours showed adenomatoid features. PCI and CCR were greater in type D compared to the other groups ( p— 0.02), as well as mitotic rate, degree of necrosis, and nuclear pleomorphism ( p 0.001). Degree of invasion was strongly correlated with CCR (p — 0.007), necrosis ( p 0.0001), nuclear grade ( p 0.0001), and mitotic rate (p — 0.001), but not PCI (p — 0.1). Immuno- histochemical results were similar across groups, with frequent positivity for CA125 (94%), EGFR (94%) and calretinin (93%), followed by p16 (85%), cytokeratin 5,6 (76%), D2-40 (71%) and WT-1 (47%). PAX-8 was negative in all tumours, except one type A tumour that showed diffuse nuclear positivity. Conclusions Diffuse peritoneal mesotheliomas can be classified into four groups that reflect invasive potential, degree of adverse histological features, and amenability for CCR. Noninvasive tumours include both type A and type C tumours.

Malignant peritoneal mesothelioma (MPM) is a primary cancer that arises diffusely from the mesothelial cells lining the peritoneum. Morbidity and mortality are almost invariably owing to locoregional progression. Cytoreduction surgery (CRS) with intraoperative or perioperative high-dose regional chemotherapy has been established as the preferred approach in selected patients. This study was performed to identify factors associated with long-term outcome.Between January 1992 and 2010, 211 patients with MPM treated at 3 major referral centers with operative CRS and hyperthermic intraoperative peritoneal chemotherapy (HIPEC) were analyzed.The median, actuarial overall survival was 38.4 months; the actuarial 5- and 10-year survivals were 41% and 26%, respectively. On multivariate analysis, factors independently associated with favorable outcome were younger age60 years (P.01), complete or near complete (R0-1) versus incomplete (R2-3) resection (P.02), low versus high histologic grade (P.01), and the use of cisplatin versus mitomycin-C during HIPEC (P.01). There was a trend toward female sex and improved survival (male hazard ratio, 1.46; 95% confidence interval, 0.89-2.41; P = .13).Operative CRS with HIPEC is associated with prolonged survival in patients with MPM. Factors associated with survival include age, complete or near complete gross tumor resection, histologic tumor grade, and HIPEC with cisplatin. Cisplatin (versus mitomycin-C) was independently associated with improved survival and demonstrates a salutary effect for HIPEC with cisplatin in the management of patients with MPM.

High-grade appendiceal adenocarcinoma is a rare malignancy with propensity for peritoneal metastases (PM). The impact of neoadjuvant chemotherapy on operative cytoreduction (CRS) and intraperitoneal chemotherapy (HIPEC) and patient survival was reviewed. A total of 45 patients with PM from high-grade appendiceal adenocarcinoma were identified from a prospective database. All patients had laparotomy with intent to undergo CRS and HIPEC. Operative parameters, complications, and survival outcomes were analyzed. Of the 45 patients (male: 27, female: 18; median age: 55 years), 26 received neoadjuvant chemotherapy ± bevacizumab. Of the 26, 15 (58 %) had a response based on improvement in imaging, biomarkers, or both and 9 (34 %) had stable disease. The median peritoneal cancer index (PCI) was 27. Also, 30 (67 %) had a completeness of cytoreduction score (CCR) of ≤1 and 37 (82 %) received HIPEC. There were no differences in PCI, CCR score, operative blood loss, or major organ resection between those who received or did not receive neoadjuvant chemotherapy. Operative time was significantly shorter in those who did not receive neoadjuvant chemotherapy. Major complications and length of hospital stay were similar between the groups. The median actuarial overall survival calculated from the date of initial therapeutic intervention was not different in those treated with or without neoadjuvant therapy. Neoadjuvant chemotherapy has marked clinical activity in patients with PM from high-grade appendiceal adenocarcinoma and does not adversely affect operative outcomes. These data support conducting a prospective clinical trial to define the role of neoadjuvant chemotherapy in this clinical setting.

Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance.We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation.The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery.Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.

Malignant peritoneal mesothelioma is a rare disease, with approximately 800 new patients per year in the United States. Its natural history is defined by progression restricted to the peritoneal space. In the past, patients with this disease had a limited lifespan of approximately 1 year. Numerous single-institution studies as well as a systematic review have reported median survival of 3 to 5 years with a combination of cytoreductive surgery and hyperthermic perioperative chemotherapy. These markedly improved survival statistics were achieved in experienced centers with 1% mortality and 20% morbidity rates. Data have shown that knowledgeable patient selection is required to prevent patients unlikely to benefit from undergoing these interventions. The conclusion is that patients with peritoneal mesothelioma can experience long-term progression-free survival or significant palliation with cytoreductive surgery plus hyperthermic perioperative chemotherapy. This management plan should be considered the standard of care for properly selected patients with malignant peritoneal mesothelioma at experienced centers around the world.

MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.

To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies.Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group.Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results.Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60%1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival.Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

SUMMARY Peritoneal carcinomatosis is an insidious condition that afflicts up to 20% of patients with colorectal cancer annually. Symptoms are related to disease progression in the peritoneal cavity such as bloating and intermittent abdominal pain; diagnostic imaging studies will frequently underestimate the extent of disease. The strategy of operative cytoreduction and hyperthermic intraperitoneal chemotherapy has become increasingly utilized as a therapeutic approach, however, most of the data regarding its efficacy come from single-institution studies. With increased understanding of optimal patient selection and treatment parameters, cytoreduction with hyperthermic intraperitoneal chemotherapy will likely become increasingly accepted as part of an integrated multimodal strategy to treat patients with peritoneal carcinomatosis from colorectal cancer in the future.

Importance Zollinger-Ellison syndrome (ZES) is a life-threatening disease caused by a malignant tumor that secretes gastrin (gastrinoma). Gastrinomas typically occur in the pancreas or the duodenum. Objective To describe the incidence and prognosis of very unusual gastrinomas originating in the hepatobiliary tract. Design, Setting, and Participants This study included 223 consecutive patients at the National Institutes of Health and Stanford University Hospital who were enrolled in a prospective protocol to treat ZES using proton pump inhibitors to control acid hypersecretion and surgical resection to ameliorate the tumoral process. Data were collected from June 1982 to August 2017. Main Outcomes and Measures Incidence, location, surgical results, and cure rate and overall survival among patients with gastrinomas that originate in the liver or bile ducts. Cure was defined as serum gastrin levels within the reference range, negative results of a secretin test, and no tumor found on imaging. Results Of the 223 patients who underwent surgery to remove gastrinomas, 7 (3.1%) had liver or biliary tract primary tumors, including 5 men and 2 women (mean age at diagnosis, 43 years; range 27-54 years). The mean serum gastrin level was 817 pg/mL (range, 289-2700 pg/mL). Each patient had positive results of a secretin test. None had evidence of multiple endocrine neoplasia 1. Four patients had primary tumors in the liver (1 in segment II, 2 in segment IV, and 1 in segment V); 3, in the bile duct (1 in the right hepatic duct, 1 in the left hepatic duct, and 1 in the common hepatic duct). Surgical resection required 1 right hepatic lobectomy, 1 left lateral segmentectomy, 2 left hepatic lobectomies, 1 central hepatectomy, and 2 bile duct resections. Four patients had nodal metastases, and no patient had distant metastases. No operative deaths occurred, but 3 patients had complications, including bile duct stricture, portal vein stricture, and biliary fistula. Each patient was disease free in the immediate postoperative period, and 3 had recurrences in the liver and portal lymph nodes (at 3, 11, and 15 years). Three patients (43%) remained free of disease at follow-up ranging from 24 months to 26 years. Conclusions and Relevance Primary gastrinomas of the hepatobiliary tract are uncommon (3%), but the hepatobiliary system is the second most frequent extraduodenopancreatic primary location (after the lymph nodes). These tumors can occur outside the gastrinoma triangle and must be specifically considered. Furthermore, their discovery changes the operative approach because aggressive liver or bile duct resection is indicated, with high rates of long-term cure and survival and acceptable rates of complications. In addition, their discovery dictates that lymph nodes in the porta hepatis should be routinely excised because nearly 50% of patients will have lymph node metastases.

Objective: The purpose of this pilot study was to evaluate the feasibility and tolerability of weekly intratumoral TNFerade™ injections combined with concurrent capecitabine and radiotherapy in the treatment of patients with locally advanced rectal cancer. Methods: Patients with T3, T4, or N+ rectal cancer received radiotherapy to a total dose of 50.4–54 Gy in combination with capecitabine 937.5 mg/m2 p.o. b.i.d. TNFerade™ at a dose of 4 × 1010 particle units was injected into the rectal tumor on the first day of radiotherapy and weekly for a total of 5 injections. Surgery was performed 5–10 weeks after the completion of chemoradiation. Results: Nine patients were enrolled in this pilot trial. The stage was cT2 in 2 patients, cT3 in 6 patients, cT4 in 1 patient, N– in 7 patients and N+ in 2 patients. Eight patients completed all treatments. Grade 3 hematologic toxicity was observed in 2 patients. There was no toxicity directly attributable to the injection procedure. A complete pathologic response was observed in 2 of 9 patients. Conclusions: This study demonstrates the feasibility of weekly intratumoral TNFerade™ injections during chemoradiotherapy for locally advanced rectal cancer. Pathologic responses with this combination compare favorably to published rates.

Purpose In-transit disease afflicts approximately 10% of patients with extremity melanoma; no single treatment approach has been uniformly accepted as the most effective. We report long-term outcomes in patients with in-transit extremity melanoma who underwent isolated limb perfusion (ILP) in an era of increasingly accurate staging, uniform operative and treatment conditions, and regular long-term follow-up. Patients and Methods Between May 1992 and February 2005, 91 patients (median age, 57 years; 50 women, 41 men) underwent a 90-minute hyperthermic ILP (melphalan, 10 to 13 mg/L limb volume, tumor necrosis factor [TNF; n = 44], or interferon [n = 38]) using uniform operative technique and intraoperative leak monitoring. Patients were prospectively followed for response, in-field progression-free survival (PFS), and overall survival (OS). Parameters associated with in-field PFS and OS were analyzed by standard statistical methods. Results There was one operative death (1.1%). There were 62 complete responses (69%) and 23 partial responses (26%) in 90 assessable patients. At a median potential follow-up of 11 years, median in-field PFS was 12.4 months and median OS was 47.4 months; 5 and 10-year actuarial OS probabilities were 43% and 34%, respectively. Female sex and low tumor burden (≤ 20 lesions) were associated with prolonged in-field PFS (male:female hazard ratio [HR], 2.07; 95% CI, 1.27 to 3.38; 21+ v ≤ 20 tumors HR, 2.29; 95% CI, 1.21 to 4.34; P < .011 for both). Female sex was associated with improved OS (P = .027; male:female HR, 1.82; 95% CI, 1.07 to 3.09). Conclusion In appropriately selected patients, ILP has clinical benefit. The use of TNF was not associated with improved in-field PFS, while female sex was associated with better survival.

Context: Selective intraarterial calcium injection of the major pancreatic arteries with hepatic venous sampling [calcium arterial stimulation (CaStim)] has been used as a localizing tool for insulinomas at the National Institutes of Health (NIH) since 1989. The accuracy of this technique for localizing insulinomas was reported for all cases until 1996. Objectives: The aim of the study was to assess the accuracy and track record of the CaStim over time and in the context of evolving technology and to review issues related to result interpretation and procedure complications. CaStim was the only invasive preoperative localization modality used at our center. Endoscopic ultrasound (US) was not studied. Design and Setting: We conducted a retrospective case review at a referral center. Patients: Twenty-nine women and 16 men (mean age, 47 yr; range, 13–78) were diagnosed with an insulinoma from 1996–2008. Intervention: A supervised fast was conducted to confirm the diagnosis of insulinoma. US, computed tomography (CT), magnetic resonance imaging (MRI), and CaStim were used as preoperative localization studies. Localization predicted by each preoperative test was compared to surgical localization for accuracy. Main Outcome: We measured the accuracy of US, CT, MRI, and CaStim for localization of insulinomas preoperatively. Results: All 45 patients had surgically proven insulinomas. Thirty-eight of 45 (84%) localized to the correct anatomical region by CaStim. In five of 45 (11%) patients, the CaStim was falsely negative. Two of 45 (4%) had false-positive localizations. Conclusion: The CaStim has remained vastly superior to abdominal US, CT, or MRI over time as a preoperative localizing tool for insulinomas. The utility of the CaStim for this purpose and in this setting is thus validated.