Drug-Eluting Embolic Loaded with Tyrosine Kinase Inhibitor Targeted Therapies for Transarterial Chemoembolization in a VX2 Model.

Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.

Delayed gastric emptying is associated with increased risk of mortality in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma.

Delayed gastric emptying (DGE) is common in patients undergoing pancreaticoduodenectomy (PD). The effect of DGE on mortality is less clear. We sought to identify predictors of mortality in patients undergoing PD for pancreatic adenocarcinoma hypothesizing DGE to independently increase risk of 30-day mortality. The ACS-NSQIP targeted pancreatectomy database (2014-2017) was queried for patients with pancreatic adenocarcinoma undergoing PD. A multivariable logistic regression analysis was performed. Separate sensitivity analyses were performed adjusting for postoperative pancreatic fistula (POPF) grades A-C. Out of 8011 patients undergoing PD, 1246 had DGE (15.6%). About 8.5% of patients with DGE had no oral intake by postoperative day-14. The DGE group had a longer median operative duration (373 vs. 362 min, p = 0.019), and a longer hospital length of stay (16.5 vs. 8 days, p < 0.001). After adjusting for age, gender, comorbidities, preoperative chemotherapy, preoperative radiation, open versus laparoscopic approach, vascular resection, deep surgical space infection (DSSI), postoperative percutaneous drain placement, and development of a POPF, DGE was associated with an increased risk for 30-day mortality (OR 3.25, 2.16-4.88, p < 0.001). On sub-analysis, grades A and B POPF were not associated with risk of mortality while grade C POPF was associated with increased risk of mortality (OR 5.64, 2.24-14.17, p < 0.001). The rate of DGE in patients undergoing PD in this large database was over 15%. DGE is associated with greater than three times the increased associated risk of mortality, even when controlling for POPF, DSSI, and other known predictors of mortality.

Intra-Operative Abdominal Drain Placement for Gallbladder Cancer Surgery and Risk of Infectious Complications.

Background: Routine intra-operative abdominal drain placement (IADP) is not beneficial for uncomplicated cholecystectomies though outcomes in gallbladder cancer surgery is unclear. This retrospective study hypothesized that patients with IADP (+IADP) for gallbladder cancer surgery have a higher risk of post-operative infectious complications (PIC) compared with patients without IADP (-IADP). Patients and Methods: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for +IADP and -IADP patients who had gallbladder cancer surgery. Post-operative infectious complications were defined as septic shock, organ/space infection (OSI), or percutaneous drainage. Multivariable analyses were performed to analyze the associated risk of PIC. Results: Of 385 patients, 237 (61.6%) were +IADP. The +IADP patients had higher rates of post-operative bile leak, OSI, re-admission, and increased length of stay (p < 0.05). The +IADP patients were not associated with increased risk of PIC (p > 0.05). Bile leak (odds ratio [OR], 10.61; p < 0.001), peri-operative blood transfusion (OR, 3.77; p = 0.003), biliary reconstruction (OR, 2.88; p = 0.018), and pre-operative biliary stent placement (OR, 3.02; p = 0.018) were the strongest associated risk factors of PIC. Patients with drains in place at or longer than 30 days post-operatively had an increased associated risk compared with patients who did not (OR, 6.88; 95% confidence interval [CI], 2.16-21.86; p < 0.001). Conclusions: More than 60% of gallbladder cancer surgeries included IADP and was not associated with an increased risk of PIC. Intra-operative abdominal drain placement was not associated with an increased risk of PIC, unless drains were left in place for 30 days or longer. Increased risk of PIC was associated with bile leak, peri-operative blood transfusion, pre-operative biliary stent placement, and biliary reconstruction.

Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II. METHODS: This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria. RESULTS: Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m2 I.V. and 20 mg/m2 I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions. DISCUSSION: TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.

Perioperative blood transfusion is associated with an increased risk for post-surgical infection following pancreaticoduodenectomy.

BACKGROUND/PURPOSE: Perioperative blood transfusion is common after pancreaticoduodenectomy (PD) and may predispose patients to infectious complications. The purpose of this study is to examine the association between perioperative blood transfusion and the development of post-surgical infection after PD. METHODS: Patients who underwent PD from 2014 to 2015 were identified in the NSQIP pancreas-specific database. Logistic regression analysis was used to compute adjusted odds ratios (aOR) to identify an independent association between perioperative red blood cell transfusion (within 72 h of surgery) and the development of post-operative infection after 72 h. RESULTS: A total of 6869 patients underwent PD during this time period. Of these, 1372 (20.0%) patients received a perioperative blood transfusion. Patients receiving transfusion had a higher rate of post-operative infection (34.7% vs 26.5%, p < 0.001). After adjusting for significant covariates, perioperative transfusion was independently associated the subsequent development of any post-operative infection (aOR 1.41 [1.23-1.62], p < 0.001), including pneumonia (aOR 2.01 [1.48-2.74], p < 0.001), sepsis (aOR 1.62 [1.29-2.04], p < 0.001), and septic shock (aOR 1.92 [1.38-2.68], p < 0.001). CONCLUSION: There is a strong independent association between perioperative blood transfusion and the development of subsequent post-operative infection following PD.

Spontaneous choledochoduodenal fistula in a patient with a bile duct injury following laparoscopic cholecystectomy.

We report a 67-year-old female that had a laparoscopic cholecystectomy complicated by common bile duct (CBD) and right hepatic artery injuries. A catheter was placed into the proximal common bile duct to create an external biliary fistula. The catheter eroded into the edge of the CBD and that irritation caused a choledochoduodenal fistula to form. To our knowledge, this is the first reported case in which an external biliary catheter caused the formation of a choledochoduodenal fistula after a bile duct injury from a laparoscopic cholecystectomy.

Bile Metabolism and Lithogenesis: An Update.

Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation. Various physiologic conditions and disease states alter bile composition and metabolism, thus increasing the risk of developing gallstones.

Systematic review of islet cryopreservation.

Pancreatic islet transplantation is being extensively researched as an alternative treatment for type 1 diabetic patients. This treatment is currently limited by temporal mismatch, between the availability of pancreas and isolated islets from deceased organ donor, and the recipient's need for freshly isolated islets. To solve this issue, cryopreservation of islets may offer the potential to bank islets for transplant on demand. Cryopreservation, however, introduces an overwhelmingly harsh environment to the ever-so-fragile islets. After exposure to the freezing and thawing, islets are usually either apoptotic, non-functional, or non-viable. Several studies have proposed various techniques that could lead to increased cell survival and function following a deep freeze. The purpose of this article is to critically review the techniques of islet cryopreservation, with the goal of highlighting optimization parameters that can lead to the most viable and functional islet upon recovery and/or transplant.

A case report on a rare anatomic variant of cystic duct insertion.

We report a case a 70-year-old female presenting with abdominal pain who has a cystic duct coursing medial to the common bile duct before anastomosing just proximal to the ampulla. Low medial insertion of the cystic duct is a rare anatomic variant that is easily misidentified on imaging studies and may complicate surgical and percutaneous intervention. It can be identified by pre-operative imaging modalities such as magnetic resonance cholangiopancreatography.

Management of an Accessory Bile Duct Leak Following Pancreaticoduodenectomy: A Novel Approach Utilizing a Percutaneous and Endoscopic Rendezvous.

Biliary leaks are uncommon but morbid complications of pancreaticoduodenectomies, which have historically been managed with percutaneous drainage, reoperation, or a combination of both. We report a de novo percutaneous-endoscopic hepaticojejunostomy from an anomalous right hepatic duct injured during pancreaticoduodenectomy to the afferent bowel limb. The percutaneous-endoscopic hepaticojejunostomy was stented to allow for tract formation with successful stent removal after 5.5 months. One year after the creation of the percutaneous-endoscopic hepaticojejunostomy, the patient remains clinically well without evidence of biliary leak or obstruction.

Development of Postoperative Diabetes Mellitus in Patients Undergoing Distal Pancreatectomy versus Whipple Procedure.

Because the islets of Langerhans are more prevalent in the body and tail of the pancreas, distal pancreatectomy (DP) is believed to increase the likelihood of developing new onset diabetes mellitus (NODM). To determine whether the development of postoperative diabetes was more prevalent in patients undergoing DP or Whipple procedure, 472 patients undergoing either a DP (n = 122) or Whipple (n = 350), regardless of underlying pathology, were analyzed at one month postoperatively. Insulin or oral hypoglycemic requirements were assessed and patients were stratified into preoperative diabetic status: NODM or preexisting diabetes. A retrospective chart review of the 472 patients between 1996 and 2014 showed that the total rate of NODM after Whipple procedure was 43 per cent, which was not different from patients undergoing DP (45%). The incidence of preoperative diabetes was 12 per cent in patients undergoing the Whipple procedure and 17 per cent in the DP cohort. Thus, the overall incidence of diabetes after Whipple procedure was 54 and 49 per cent in the DP group. The development of diabetes was unrelated to the type of resection performed. Age more than 65 and Caucasian ethnicity were associated with postoperative diabetes regardless of the type of resection performed.

Efficacy of Negative Pressure Wound Treatment in Preventing Surgical Site Infections after Whipple Procedures.

Surgical site infections (SSIs) occur at an average rate of 21.1 per cent after Whipple procedures per NSQIP data. In the setting of adherence to standard National Surgery Quality Improvement Program (NSQIP) Hepatopancreatobiliary recommendations including wound protector use and glove change before closing, this study seeks to evaluate the efficacy of using negative pressure wound treatment (NPWT) over closed incision sites after a Whipple procedure to prevent SSI formation. We retrospectively examined consecutive patients from January 2014 to July 2016 who met criteria of completing Whipple procedures with full primary incision closure performed by a single surgeon at a single institution. Sixty-one patients were included in the study between two cohorts: traditional dressing (TD) (n = 36) and NPWT dressing (n = 25). There was a statistically significant difference (P = 0.01) in SSI formation between the TD cohort (n = 15, SSI rate = 0.41) and the NPWT cohort (n = 3, SSI rate = 0.12). The adjusted odds ratio (OR) of SSI formation was significant for NPWT use [OR = 0.15, P = 0.036] and for hospital length of stay [OR = 1.21, P = 0.024]. Operative length, operative blood loss, units of perioperative blood transfusion, intraoperative gastrojejunal tube placement, preoperative stent placement, and postoperative antibiotic duration did not significantly impact SSI formation (P > 0.05).

Global Estimation of Surgical Procedures Needed for Forcibly Displaced Persons.

INTRODUCTION: Sixty million people were displaced from their homes due to conflict, persecution, or human rights violations at the end of 2014. This vulnerable population bears a disproportionate burden of disease, much of which is surgically treatable. We sought to estimate the surgical needs for forcibly displaced persons globally to inform humanitarian assistance initiatives. METHODS: Data regarding forcibly displaced persons, including refugees, internally displaced persons (IDPs), and asylum seekers were extracted from United Nations databases. Using the minimum proposed surgical rate of 4669 procedures per 100,000 persons annually, global, regional, and country-specific estimates were calculated. The prevalence of pregnancy and obstetric complications were used to estimate obstetric surgical needs. RESULTS: At least 2.78 million surgical procedures (IQR 2.58-3.15 million) were needed for 59.5 million displaced persons. Of these, 1.06 million procedures were required in North Africa and the Middle East, representing an increase of 50 % from current unmet surgical need in the region. Host countries with the highest surgical burden for the displaced included Syria (388,000 procedures), Colombia (282,000 procedures), and Iraq (187,000). Between 4 and 10 % of required procedures were obstetric surgical procedures. Children aged <18 years made up 52 % of the displaced, portending a substantial demand for pediatric surgical care. CONCLUSION: Approximately three million procedures annually are required to meet the surgical needs of refugees, IDPs, and asylum seekers. Most displaced persons are hosted in countries with inadequate surgical care capacity. These figures should be considered when planning humanitarian assistance and targeted surgical capacity improvements.

Total pancreatectomy and islet autotransplantation: A decade nationwide analysis.

AIM: To investigate outcomes and predictors of in-hospital morbidity and mortality after total pancreatectomy (TP) and islet autotransplantation. METHODS: The nationwide inpatient sample (NIS) database was used to identify patients who underwent TP and islet autotransplantation (IAT) between 2002-2012 in the United States. Variables of interest were inherent variables of NIS database which included demographic data (age, sex, and race), comorbidities (such as diabetes mellitus, hypertension, and deficiency anemia), and admission type (elective vs non-elective). The primary endpoints were mortality and postoperative complications according to the ICD-9 diagnosis codes which were reported as the second to 25(th) diagnosis of patients in the database. Risk adjusted analysis was performed to investigate morbidity predictors. Multivariate regression analysis was used to identify predictors of in-hospital morbidity. RESULTS: We evaluated a total of 923 patients who underwent IAT after pancreatectomy during 2002-2012. Among them, there were 754 patients who had TP + IAT. The most common indication of surgery was chronic pancreatitis (86%) followed by acute pancreatitis (12%). The number of patients undergoing TP + IAT annually significantly increased during the 11 years of study from 53 cases in 2002 to 155 cases in 2012. Overall mortality and morbidity of patients were 0% and 57.8 %, respectively. Post-surgical hypoinsulinemia was reported in 42.3% of patients, indicating that 57.7% of patients were insulin independent during hospitalization. Predictors of in-hospital morbidity were obesity [adjusted odds ratio (AOR): 3.02, P = 0.01], fluid and electrolyte disorders (AOR: 2.71, P < 0.01), alcohol abuse (AOR: 2.63, P < 0.01), and weight loss (AOR: 2.43, P < 0.01). CONCLUSION: TP + IAT is a safe procedure with no mortality, acceptable morbidity, and achieved high rate of early insulin independence. Obesity is the most significant predictor of in-hospital morbidity.

Evolution in the Treatment of Delayed Postpancreatectomy Hemorrhage: Surgery to Interventional Radiology.

OBJECTIVES: We summarized a single center's evolution in the management of postpancreatectomy hemorrhage (PPH) from surgical toward endovascular management. METHODS: Between 2003 and 2013, 337 patients underwent Whipple procedures. Using the International Study Group of Pancreatic Surgery (ISGPS) consensus definition, patients with PPH were identified and retrospectively analyzed for the presentation of hemorrhage, type of intervention, and 90-day mortality outcome measures. RESULTS: Management evolved from operative intervention alone, to combined operative and on-table angiographic intervention, to endovascular intervention alone. The prevalence of PPH was 3.0%. Delayed PPH occurred with a mean of 13.8 days. On angiography, visceral arteries affected were the gastroduodenal artery, hepatic artery, jejunal branches of the superior mesenteric artery, pancreaticoduodenal artery, and inferior phrenic artery. Ninety-day mortality for PPH was 20%. From early to recent experience, the mortality rate was 100% for operative intervention alone, 25% for combined operative and on-table angiographic intervention, and 0% for endovascular intervention alone. CONCLUSIONS: Our 10-year experience supports current algorithms in the management of PPH. Key considerations include the recognition of the sentinel bleed, the presence of a pancreatic fistula, and the initial operative role of a long gastroduodenal artery stump with radiopaque marker for safe and effective embolization should PPH occur.

Vascular reconstruction plays an important role in the treatment of pancreatic adenocarcinoma.

OBJECTIVE: Previous studies have proved the feasibility of performing a pancreaticoduodenectomy (Whipple operation) in patients with portal vein-superior mesenteric vein and hepatic artery invasion. We report our institutional experience with the use of a variety of vascular reconstructive methods during pancreatic resections for adenocarcinoma. METHODS: A retrospective review was performed identifying all patients undergoing a Whipple operation or total pancreatectomy procedure from January 2003 to December 2013. All venous (portal vein-superior mesenteric vein) and arterial (superior mesenteric artery-hepatic artery) reconstructions were extracted and reviewed to determine survival and perioperative complications. RESULTS: During the 10-year study period, 270 Whipple and total pancreatectomy procedures were performed, of which 183 were for adenocarcinoma of the pancreas. Of the 183 operations, a total of 60 (32.8%) vascular reconstructions were found, 49 venous and 11 arterial. Venous reconstruction included 37 (61.7%) primary repairs, four (6.7%) reconstructions with CryoVein (CryoLife, Inc, Kennesaw, Ga), three (5.0%) repairs with autologous vein patch, three (5.0%) autologous saphenous reconstructions, and two (3.33%) portacaval shunts. In addition, there were 11 (18.3%) arterial reconstructions (seven hepatic artery and four superior mesenteric artery). The 1-year survival for all reconstructions was 71.1%, which is equivalent to T3 lesions that did not receive vascular reconstruction (70.11%), with a median survival time of 575.28 days and 12 patients still alive. Survival time was comparable with each type of venous reconstruction, averaging 528 days (11 of 49 patients still alive). There was a total thrombosis rate of seven of 60 (11.6%), all of which were portal vein thrombosis: three in the primary repair group and four delayed thromboses seen in primary repair, CryoVein repair, and vein patch repair. There was no thrombosis in any patients after arterial reconstruction. CONCLUSIONS: An aggressive approach for stage II pancreatic cancers with venous or arterial invasion can be performed with comparable results when it is executed by an experienced institution with skilled oncologic and vascular surgeons.

Composite liver tumors: a radiologic-pathologic correlation.

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.

Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib.

Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.

Advances in managing hepatocellular carcinoma.

Multiple modalities for treatment of hepatocellular carcinoma are available, depending on tumor size and number. Surgical resection remains the gold standard, so long as the residual liver function reserve is sufficient. In patients with advanced cirrhosis, liver transplantation is the preferred option, as these patients may not have adequate hepatic reserve after resection. Salvage liver transplantation has also become an option for a select few patients who recur after surgical resection. Ablative techniques have been used for palliation as well as to either completely destroy the tumor, act as an adjunct to resection, or downstage the tumor to meet Milan criteria such that a patient may be a candidate for liver transplantation. Radiofrequency ablation, microwave ablation, chemoembolization, radioembolization, and irreversible electroporation have all been used in this capacity. Currently, sorafenib is the only US Food and Drug Administration-approved chemotherapeutic for hepatocellular carcinoma. The efficacy of sorafenib, in combination with other agents, transarterial chemoembolization, and surgical resection is currently being investigated. Sunitinib and brivanib, tyrosine kinase inhibitors, have failed as potential first- or second-line options for chemotherapy. Bevacizumab in combination with erlotinib is also currently being studied. Final analysis for ramucirumab and axitinib are pending. Tivantinib, a selective mesenchymal-epithelial transition factor (MET) inhibitor, is also undergoing clinical trials for efficacy in MET-high tumors. This review serves to emphasize the current and new technologies emerging in the treatment of hepatocellular carcinoma.