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Background Failure to rescue (FTR) is a recently described outcome metric for quality of care. However, predictors of FTR have not been adequately investigated, particularly after pancreaticoduodenectomy. We aim to identify predictors of FTR after pancreaticoduodenectomy. Methods We reviewed all patients who developed serious morbidity after pancreaticoduodenectomy from 2005 to 2012 in the ACS-NSQIP database. Logistic regression was used to identify preoperative and postoperative risks for 30-day mortality within a development cohort (randomly selected 80%). A score was created using weighted beta coefficients. Predictive accuracy was assessed on the validation cohort (remaining 20%) using a receiver operator characteristic curve and calculating the area under the curve (AUC). Results The FTR rate was 7.2% after pancreaticoduodenectomy (n = 5,027). We identified 5 independent risk factors: age ≥65 and albumin ≤3.5 g/dL, preoperatively; and development of shock, renal failure, and reintubation, postoperatively. The generated score had an AUC = 0.83 (95% CI, 0.77–0.89) in the validation cohort. Using the score: 1*Albumin ≤3.5 g/dL + 2*Age ≥ 65 + 2*Shock + 5*Renal failure + 5*Reintubation, FTR rates increased with increasing score (p Conclusion FTR rates have previously been shown to be associated with hospital factors. We show that FTR is also associated with preoperative and postoperative patient-specific factors.

Background/aim We have tested whether the anticancer peptide, PNC-27, that kills cancer cells but not normal cells by binding to cancer cell membrane HDM-2 forming pores, kills CD44+ colon cancer stem cells. Materials and methods Flow cytometry determined the CD44 and HDM-2 expression on six-colon cancer cell lines and one normal cell line (CCD-18Co). MTT, LDH release, annexin V binding and caspase 3 assays were used to assess PNC-27-induced cell death. Bioluminescence imaging measured PNC-27 effects on in vivo tumor growth. Results High percentages of cells in all six tumor lines expressed CD44. PNC-27 co-localized with membrane HDM-2 only in the cancer cells and caused total cell death (tumor cell necrosis, high LDH release, negative annexin V and caspase 3). In vivo, PNC-27 caused necrosis of tumor nodules but not of normal tissue. Conclusion PNC-27 selectively kills colon cancer stem cells by binding of this peptide to membrane H/MDM-2.

Patients with epithelial ovarian cancers experience the highest fatality rates among all gynecological malignancies which require development of novel treatment strategies. Tumor cell necrosis was previously reported in a number of cancer cell lines following treatment with a p53-derived anti-cancer peptide called PNC-27. This peptide induces necrosis by transmembrane pore formation with HDM-2 protein that is expressed in the cancer cell membrane. We aimed to extend these studies further by investigating expression of membrane HDM-2 protein in ovarian cancer as it relates to susceptibility to PNC-27.Herein, we measured HDM-2 membrane expression in two ovarian cancer cell lines (SKOV-3 and OVCAR-3) and a non-transformed control cell line (HUVEC) by flow cytometric and western blot analysis. Immunofluorescence was used to visualize colocalization of PNC-27 with membrane HDM-2. Treatment effects with PNC-27 and control peptide were assessed using a MTT cell proliferation assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers; annexin V and caspase-3.HDM-2 protein was highly expressed and frequently detected in the membranes of SKOV-3 and OVCAR-3 cells; a prominent 47.6 kDa HDM-2 plasma membrane isoform was present in both cell lines whereas 25, 29, and 30 kDa isoforms were preferentially expressed in OVCAR-3. Notably, PNC-27 colocalized with HDM-2 in the membranes of both cancer cell lines that resulted in rapid cellular necrosis. In contrast, no PNC-27 colocalization and cytotoxicity was observed with non-transformed HUVEC demonstrating minimal expression of membrane HDM-2.Our results suggest that HDM-2 is highly expressed in the membranes of these ovarian cancer cell lines and colocalizes with PNC-27. We therefore conclude that the association of PNC-27 with preferentially expressed membrane HDM-2 isoforms results in the proposed model for the formation of transmembrane pores and epithelial ovarian cancer tumor cell necrosis, as previously described in a number of solid tissue and hematologic malignancies.

Background Zollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management. Case presentation The patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100–624 pg/mL; current 114 pg/mL). Conclusion Success of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

Objectives Pseudomyxoma peritonei (PMP) is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. Methods A total of 54 patients with appendix-derived PMP were included in the study. Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing), protein expression (immunohistochemistry), and gene amplification (C/fluorescent in situ hybridization). Results Targeted sequencing of 47 genes detected variants in KRAS (81%), GNAS (74%), SMAD4 (16%), and ATM (16%). Mutations were found at low frequencies (n=1 to 2) in APC, BRAF, PIK3CA, MLH1, and TP53. GNAS and KRAS co-occurrence was found in 87%. Protein overexpression was found in epidermal growth factor receptor (83%), cyclooxygenase-2 (73%), cMET (63%), cKIT (58%), and platelet-derived growth factor receptor alpha (58%). Immune checkpoint expression was found in 36% (programmed cell death protein 1) and 18% (programmed death-ligand 1). Surrogate markers of cell proliferation were found at low rates (TLE3 23%, TOP2A 22%), consistent with the slow-growing biology of PMP. Phosophatase and tensin homolog was intact (wild type [100%]) and positive (immunohistochemistry [80%]). Patients exhibited stable microsatellite status and mismatch repair proficiency (93%). Importantly, multidrug resistance protein expression was elevated (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1), and irinotecan (TOPO1) chemosensitivities were detected at favorable rates: 93%, 87%, 77% and 65%, respectively. Conclusions Molecular profiling by multiple platforms identified potential therapies for the nontargetable KRAS-mutated population. The role of cMET-targeted therapeutics and immune checkpoint inhibitors merits further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate efficacy to systemic treatment.

Background The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use. Objective To evaluate published and ongoing clinical trials seeking to better define role of CRS/HIPEC in the treatment of peritoneal surface malignancies. Methods Systematic review by PubMed search was performed using terms "Clinical trial," "intraperitoneal chemotherapy," and "HIPEC." ClinicalTrials.gov and EudraCT registries were searched for active clinical trials. Eligibility included CRS/HIPEC trials investigating adult patient populations from published clinical reports and/or trials currently accruing or at completion. Results Thirteen published trials and 57 active clinical trials were included for review. Conclusions Published and ongoing U.S. and international clinical trials for CRS and HIPEC are defining important parameters that include improving patient selection, strategic sequences of treatment, cytoreductive strategies, chemotherapeutics, optimal hyperthermic temperature and timing, and toxicity profiles. Main barriers or limitations to trial development remain patient enrollment, trial design, and oncologic community collaboration. Overall progress is positive with increasing number of clinical trials throughout the world. Collaboration between surgeons and the wider oncologic community will be crucial to validate this important treatment strategy.

Introduction. Recurrence of gastrointestinal stromal tumors (GISTs) after surgical resection and imatinib mesylate (IM) adjuvant therapy poses a significant treatment challenge. We present the case of a patient who underwent surgical resection after recurrence and review the current literature regarding treatment. Case Presentation. A 58-year-old man with a large intra-abdominal jejunal GIST was treated with complete surgical resection followed by IM. The patient experienced disease recurrence 3.5 years later and underwent IM dose escalation and reresection. Conclusion. Current strategies to treat recurrent GIST include dose escalation, modifying adjuvant tyrosine kinase inhibitor therapy, and surgery. High-level evidence will be required to better define the combinatory roles of tyrosine kinase inhibitor therapy, guided by molecular profiling, and surgery in the management of recurrent GIST.

Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC), the National Comprehensive Cancer Network (NCCN) suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring6.2×3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles), intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.

Background Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear. Case presentation We report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component. Conclusion This study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression.

Treatment failure in pseudomyxoma peritonei (PMP) is partly attributed to the ineffective delivery of therapeutics through dense mucinous tumor barriers. We modified the surface of Poly (lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG-NPs) with a low-density, second PEG layer (PLGA-TPEG-NPs-20) to reduce their binding affinity to proteins and improve diffusion through mucin. Nanoprecipitation was used to fabricate PLGA-PEG-NPs. To construct the second PEG layer of PLGA-TPEG-NPs-20, PEG-Thiol was conjugated to PLGA-PEG-NPs composed of 80% methoxy PLGA-PEG and 20% of PLGA-PEG-Maleimide. DiD-labeled nanoparticles (NPs) were added to the inner well of a trans-well system containing cultured LS174T or human PMP tissue. Diffusion of NPs was measured via fluorescence signal in the bottom well. In an ex vivo rat model, small intestine was treated with DiD-labeled NPs. In an in vivo murine LS174T subcutaneous tumor model, Nu/Nu nude mice received supratumoral injections (subcutaneous injection above the tumor) of DiD-labeled NPs. Thirty minutes after injection, mice were sacrificed, and tumors were collected. All tissue was cryosectioned, mounted with DAPI-containing media, and inspected via confocal microscopy. Diffusion profiles of NPs through PMP and cultured LS174T cells were generated. PLGA-TPEG-NPs-20 diffused faster with ~ 100% penetration versus PLGA-PEG-NPs with ~ 40% penetration after 8 h. Increased diffusion of PLGA-TPEG-NPs-20 was further observed in ex vivo rat small intestine as evidenced by elevated luminal NP fluorescence signal on the luminal surface. Subcutaneous LS174T tumors treated with PLGA-TPEG-NPs-20 demonstrated greater diffusion of NPs, showing homogenous fluorescence signal throughout the tumor. PLGA-TPEG-NPs-20 can be an effective mucin penetrating drug delivery system.

The authors wish to make the following corrections to this paper [...]

Key Clinical Message Appendiceal mucoceles (AMs) infrequently arise from an underlying malignancy. Treatment has progressed toward a less aggressive approach over time; they can be managed by appendectomy‐only unless pathology reveals malignancy. The ultimate goal of management is to prevent AM rupture, avoiding the syndrome of pseudomyxoma peritonei.

Background Obesity is a risk factor for pancreatic cancer which may be treated with Roux-en-Y gastric bypass and represents an increasing morbidity. Post-RYGB anatomy poses considerable challenges for reconstruction after pancreaticoduodenectomy (PD), a growing problem encountered by surgeons. We characterize specific strategies used for post-PD reconstruction in the RYGB patient. Methods PubMed search was performed using MeSH terms “Gastric Bypass” and “Pancreaticoduodenectomy” between 2000 and 2018. Articles reporting cases of pancreaticoduodenectomy in post-RYGB patients were included and systematically reviewed for this study. Results Three case reports and five case series (25 patients) addressed PD after RYGB; we report one additional case. The typical post-gastric bypass PD patient is a woman in the sixth decade of life, presenting most commonly with pain (69.2%) and/or jaundice (53.8%), median 5 years after RYGB. Five post-PD reconstructive options are reported. Among these, the gastric remnant was resected in 18 cases (69.2%), with reconstruction of biliopancreatic drainage most commonly achieved using the distal jejunal segment of the pre-existing biliopancreatic limb (73.1%). Similarly, in the eight cases where the gastric remnant was spared (30.8%), drainage was most commonly performed using the distal jejunal segment of the biliopancreatic limb (50%). Among the 17 cases reporting follow-up data, median was 27 months. Conclusion Reconstruction options after PD in the post-RYGB patient focus on resection or preservation gastric remnant, as well as creation of new biliopancreatic limb. Insufficient data exists to make recommendations regarding the optimal reconstruction option, yet surgeons must prepare for the possible clinical challenge. PD reconstruction post-RYGB requires evaluation through prospective studies.

Appendiceal mucoceles (AMs) are rare mucin-containing neoplasms with malignant potential. Lack of evidence-based data exists defining clinicopathological features for management. MEDLINE search between 1995 and 2015 was performed using search criteria "Appendix mucocele." Systematic review of patient-, pathologic-, and treatment-related characteristics was performed and data analyzed. Among 276 cases of non-perforated AMs, 163 (59%) patients were female, with variable and nonspecific presentation. Patients were treated with appendectomy (52.1%), right hemicolectomy (17.6%), partial cecectomy (17.2%), and ileocecetomy (13.1%). Pathologic evaluation revealed the following: cystadenoma/low-grade appendiceal mucinous neoplasm (54%), unspecified/benign (25%), retention cyst (14.1%), cystadenocarcinoma (4.2%), and mucosal hyperplasia (2.9%). All 11 (4.2%) patients with cystadenocarcinoma were female (P = 0.004), odds ratio for malignancy 1.07 times higher for women. Synchronous colonic malignancy was reported in three patients (27%) with cystadenocarcinoma (P = 0.007), odds ratio of 12.1. AMs have low risk for malignancy. Treatment should begin with appendectomy-only and subsequently guided by pathologic diagnosis.

Background Bloodless pancreatic surgery (BPS) is rarely performed and/or reported. We aim to characterize perioperative and anesthetic strategies in BPS. Materials and methods A literature search was performed on MEDLINE looking for case reports/case series using search terms (“Jehovah's Witness” [All Fields]) AND (“Pancreatic Surgery” [All Fields] OR “Pancreaticoduodenectomy” [All Fields] OR “Distal Pancreatectomy” [All Fields]). Data regarding categorical variables are reported as proportions and quantitative continuous variables as medians with ranges or means with standard deviation. Forty-one patients requiring BPS are reported in the literature with three additional cases from our institution (n = 44). The data analyzed included clinicopathologic factors, BPS strategies, patient complications, and in-hospital mortality. Results The most common procedure and diagnosis were pancreaticoduodenectomy (n = 34, 77.3%) and pancreatic ductal adenocarcinoma (n = 12, 27.3%), respectively. Transfusion reduction strategies in BPS fell into three categories: preoperative, intraoperative, and postoperative. Preoperative strategies included iron supplementation (n = 24, 54.5%) and erythropoietin administration (n = 14, 41.2%). Intraoperative strategies included acute normovolemic hemodilution (n = 30, 68%) and cell saver (n = 4, 9.1%). Postoperative strategies included erythropoietin (n = 16, 48.5%) and iron supplementation (n = 16, 48.5%). Complications occurred in 21 (60%) patients. There was no in-hospital mortality among the 44 patients in this cohort. Conclusions A broad spectrum of bloodless medicine and surgery practices were used based on patient selection, multidisciplinary practice, and preference. With careful perioperative and anesthetic management, BPS can be performed with good outcomes.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have gained momentum as a viable treatment option for primary or recurrent malignancies with peritoneal metastasis (PM). Despite significant progress over the last 30 years, this field has lacked in high-quality randomized, controlled trials, with most data supporting the use of CRS and HIPEC coming from smaller retrospective and prospective trials. Ultimately, validation of treatment efficacy and outcomes will require large, collaborative, well-organized, outcomes-based studies. Thus far, the use of CRS and HIPEC in metastatic gastric, ovarian, pancreatic, and other gastrointestinal malignancies has spurred further development of a growing number of prospective clinical trials to study outcomes and survival benefit. This chapter summarizes some of the notable, completed clinical trials and current trials being conducted.