Ethical issues in solid organ transplantation: transfusion-free transplantation in Jehovah's witness patients.

PURPOSE OF REVIEW: Jehovah's Witnesses do not accept transfusion of major allogeneic blood fractions. Successful solid organ transplantation is challenging for Jehovah's Witnesses when anemia, coagulation disturbances, and difficult technical aspects co-exist, and key blood bank resources cannot be utilized. Organ availability for transplantation is limited and demand exceeds supply for all organ types. Historically, the likelihood of poor outcomes in Jehovah's Witnesses patients placed ethical limitations on transplant candidacy for this population violating the precept of maximal utilization of a limited resource. The review's purpose is to describe advancements and strategies that make Jehovah's Witnesses transplant outcomes comparable to transfusion-eligible patients and allay the ethical concerns of their candidacy. RECENT FINDINGS: Immunomodulation from allogeneic transfusion is a cause of significant postop morbidity. Blood conservation strategies have led to improved outcomes across different medical and surgical cohorts and set the stage for expanded utility in Jehovah's Witnesses with organ insufficiency.Published single-center series with descriptions of specific peri-operative strategies describe the path to major blood product avoidance. SUMMARY: Comparable outcomes in solid organ transplantation for Jehovah's Witnesses without allogeneic transfusion are possible when inclusion-exclusion criteria are respected, and blood conservation strategies employed.

Transfusion-free Strategies in Liver and Pancreatic Surgery: A Predictive Model of Blood Conservation for Transfusion Avoidance in Mainstream Populations.

OBJECTIVE: The objective of this study is to (1) describe the techniques and prove the feasibility of performing complex hepatobiliary and pancreatic surgery on a Jehovah Witness (JW) population.  (2) Describe a strategy that offsets surgical blood loss by the manipulation of circulating blood volume to create reserve whole blood upon anesthesia induction. BACKGROUND: Major liver and pancreatic resections often require operative transfusions. This limits surgical options for patients who do not accept major blood component transfusions. There is also growing recognition of the negative impact of allogenic blood transfusions. METHODS: A 23-year, single-center, retrospective review of JW patients undergoing liver and pancreatic resections was performed. We describe perioperative management and patient outcomes. Acute normovolemic hemodilution (ANH) is proposed as an important strategy for offsetting blood losses and preventing the need for blood transfusion. A quantitative mathematical formula is developed to provide guidance for its use. RESULTS: One hundred one major resections were analyzed (liver n=57, pancreas n=44). ANH was utilized in 72 patients (liver n=38, pancreas n=34) with median removal of 2 units that were returned for hemorrhage as needed or at the completion of operation. There were no perioperative mortalities. Morbidity classified as Clavien grade 3 or higher occurred in 7.0% of liver resection and 15.9% of pancreatic resection patients. CONCLUSIONS: Deliberate perioperative management makes transfusion-free liver and pancreatic resections feasible. Intraoperative whole blood removal with ANH specifically preserves red cell mass, platelets, and coagulation factors for timely reinfusion. Application of the described JW transfusion-free strategy to a broader general population could lessen blood utilization costs and morbidities.

Review of Oncology and Transplant Literature for the Management of Hepatic and Pancreatic Resections in Jehovah's Witnesses.

Jehovah's Witnesses undergoing liver or pancreas surgery represent a unique medical and ethical challenge. For hepatic and pancreatic malignancies, resections are currently the only curative treatment. These surgeries pose a risk for significant blood loss, for which blood transfusions are traditionally given. However, blood transfusions are considered unacceptable to many Jehovah's Witnesses patients. As the technology of surgery as well as development of new products continue to evolve, transfusion-less surgery modalities have been utilized for Jehovah's Witnesses. The use of these transfusion-less techniques is not yet standardized for hepatic and pancreatic resections. We aimed to review both oncology and transplant medical literature on pancreatic and hepatic resection to develop guidelines for the management Jehovah's Witnesses patients.

Dynamic liver test patterns do not predict bile duct stones.

BACKGROUND: Numerous models have been developed to predict choledocholithiasis. Recent work has shown that these algorithms perform suboptimally. Identification of clinical predictors with high positive and negative predictive value would minimize adverse events associated with unnecessary diagnostic endoscopic retrograde cholangiopancreatography (ERCP) while limiting the use of expensive tests including magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) for indeterminate cases. METHODS: Consecutive unique inpatients who received their first ERCP at Los Angeles County Medical Center between January 2010 and November 2016 for suspected bile duct stones were reviewed. The primary outcome was the proportion of patients with specific combinations of liver enzyme patterns, transabdominal ultrasound, and clinical features who had stones confirmed on ERCP. As a secondary outcome, we assessed the performance of the American Society for Gastrointestinal Endoscopy (ASGE) risk stratification algorithm in our population. RESULTS: Of the 604 included patients, bile duct stones were confirmed in 410 (67.9%). Detailed assessment of liver enzyme patterns alone and in combination with clinical features and imaging findings yielded no highly predictive algorithms. Additionally, the ASGE high-risk criterion had a positive predictive value of only 68% for stones. For the 236 patients for whom MRCP was performed, this imaging modality was shown to have highest predictive value for the presence of stones on ERCP. CONCLUSION: Exhaustive exploration of various threshold values and dynamic patterns of liver enzymes combined with clinical features and basic imaging findings did not reveal an algorithm to accurately predict the presence of stones on ERCP. The ASGE risk stratification criteria were also insensitive in our population. Though desirable, there may be no "perfect" combination of clinical features that correlate with persistent bile duct stones. MRCP or EUS may be considered to avoid unnecessary ERCP and associated complications.

Kidney transplantation in the Hispanic population.

Hispanic race and low socioeconomic status are established predictors of disparity in access to kidney transplantation. This single-center retrospective review was undertaken to determine whether Hispanic race predicted kidney transplant outcomes. A total of 720 patients underwent kidney transplantation from January 1, 2004 to December 31, 2013, including 398 Hispanic patients and 322 non-Hispanic patients. Hispanic patients were significantly younger (p < 0.0001), on hemodialysis for longer (p = 0.0018), had a greater percentage with public insurance (p < 0.0001), more commonly had diabetes as the cause of end-stage renal disease (p = 0.0167), and had a lower percentage of living donors (p = 0.0013) compared to non-Hispanic patients. There was no difference in one-, five-, and 10-yr graft (97%, 81%, and 61% vs. 95%, 76%, and 42% p = 0.18) or patient survival (98%, 90%, and 84% vs. 97%, 87%, and 69% p = 0.11) between the Hispanic and non-Hispanic recipients. Multivariate analysis identified increased recipient age and kidney donor profile index to be predictive of lower graft survival and increasing recipient age to be predictive of lower patient survival. In the largest single-center study on kidney transplantation outcomes in Hispanic patients, there is no difference in graft and recipient survival between Hispanic and non-Hispanic kidney transplant patients, and in multivariate analysis, Hispanic race is not a risk factor for graft or patient survival.

Blood Conservation Strategies and Liver Transplantation Transfusion-Free Techniques Derived from Jehovah's Witness Surgical Cohorts.

Red blood cell and component transfusions are a frequent and widely accepted accompaniment of surgical procedures. Although the risk of specific disease transmission via allogeneic blood transfusions (ABT) is very low, the occurrence of transfusion related immune modulation (TRIM) still remains a ubiquitous concern. Recent studies have shown that ABT are linked to increased morbidity and mortality across various specialties, with negative outcomes directly correlated to number of transfusions. Blood conservation methods are therefore necessary to reduce ABT. Acute normo-volemic hemodilution (ANH) along with pre-operative blood augmentation and intraoperative cell salvage are blood conservation techniques utilized in tertiary and even quaternary (transplantation) surgery in Jehovah's Witnesses with excellent outcomes. The many hematologic complications such as anemia, thrombocytopenia and coagulopathies that occur with liver transplantation present a significant barrier when trying to avoid ABT. Despite this, living donor liver transplantation (LDLT) has been successfully performed in a transfusion-free environment, providing valuable insight into the possibilities of limiting ABT and its associated risks in all patients.

Laparoscopic Hand-Assisted Parenchymal-Sparing Resections for Presumed Side-Branch Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: The diagnosis of side-branch intraductal papillary mucinous neoplasms (IMPNs) is increasingly more common, but their appropriate management is still evolving. We recently began performing laparoscopic hand-assisted enucleation or duodenal-sparing pancreatic head resection for these lesions with vigilant postoperative imaging. MATERIALS AND METHODS: Seventeen patients with pancreatic cystic lesions were included in this single-center retrospective review from January 1, 2008 to March 30, 2013. Indication for surgical intervention was growth in size of the cyst, symptoms, cyst size >3 cm, and/or presence of a mural nodule. Twelve patients underwent laparoscopic hand-assisted enucleation, and 5 patients underwent laparoscopic hand-assisted pancreatic head resection. RESULTS: The mean age of patients was 64 years old. The most common presenting symptom was abdominal pain. The indication for surgical intervention was growth in the cyst or symptoms in the majority of patients. Fourteen lesions were in the head/uncinate, two were in the pancreatic body, and one was in the tail. Final pathology was consistent with side-branch IPMN in 13 patients (1 with focal adenocarcinoma). Three patients had serous cysts, and 1 had a mucinous cyst. Three patients developed pancreatic leaks, which were controlled with intraoperative placed drains, whereas 1 patient required additional drain placement. Median time from surgery to latest follow-up imaging is over 2 years. No patients have developed recurrent cysts or adenocarcinoma. CONCLUSIONS: Duodenal-sparing pancreatic head resection or pancreatic enucleation for patients with presumed side-branch IPMN is a safe and efficacious option, in terms of both operative outcomes and postoperative recurrence risk.

Surgical transgastric debridement of walled off pancreatic necrosis: an option for patients with necrotizing pancreatitis.

BACKGROUND: Transgastric debridement of walled off pancreatic necrosis (WOPN) is a surgical treatment option for patients requiring pancreatic debridement for necrotizing pancreatitis. The reported experience with surgical transgastric pancreatic debridement is limited, however, the lower incidence of postoperative pancreatic fistulae with this procedure compared to other options warrants further evaluation of this technique. METHOD: Retrospective chart review. RESULTS: Twenty-two patients underwent transgastric debridement with a cystogastrostomy for clinically symptomatic WOPN from January 1, 2005 to July 31, 2013. Eight cases were performed laparoscopically and 14 were performed by an open approach. The mean patient age was 50.9 (50.9 ± 14.5) and the median American Society of Anesthesiologist score was 3. The most common etiology for pancreatitis was gallstones and the median time from attack of pancreatitis to definitive surgical management was 60 days (range 22-300 days). Median operative time was 182 min (range 85-327 min) with 100 cc (range 20-500 cc) of blood loss. In seven patients the necrosis was infected and in 15 patients the necrosis was sterile as determined by the intraoperative culture of the necrotic material. The overall significant morbidity (Clavien type 3 or greater) was 13.6 % and the mortality was 0 %. The incidence of postoperative pancreatic fistula was 0 %. 20 patients (90 %) were symptom free during a median follow-up of 12 months. CONCLUSION: In selected patients with clinically symptomatic WOPN, surgical transgastric pancreatic debridement appears to be a safe procedure with a low morbidity and mortality. The low incidence of postoperative pancreatic fistulae warrants further evaluation.

Trisectionectomy for cholangiocarcinoma: is it worth it?

Many centers perform aggressive liver resection for patients with cholangiocarcinoma, because improved survival has been reported after resection with negative margins. Patients with extensive tumor burden sometimes require trisectionectomy for clearance of disease with increased risk of liver insufficiency and postoperative complications. A retrospective review was conducted examining records for 62 patients who were taken to the operating room for cholangiocarcinoma from January 1, 2000, to March 31, 2010. Thirty-eight patients underwent surgical resection: 17 patients underwent trisectionectomy and 21 patients underwent liver resections. No statistically significant differences were found between patients who underwent liver resection compared with those who underwent trisectionectomy with regard to demographics or complications. Pathology was rereviewed by a single pathologist, and no statistically significant differences were found between the two groups in any of the recorded pathology results. No significant differences in survival were found between the two groups. The median survival for liver resection patients was 2.9 years and for trisegmentectomy patients was 2.8 years. Complete resection with negative margins remains the current surgical goal in the treatment for cholangiocarcinoma. Performing trisectionectomy in an effort to clear all disease is safe with comparable outcomes to patients needing less extensive liver resections.

Outcomes after liver transplantation in patients achieving a model for end-stage liver disease score of 40 or higher.

BACKGROUND: Patients with Model for End-Stage Liver Disease (MELD) scores of 40 or higher are at high risk for liver transplantation. In some regions, the organ donor shortage has resulted in a substantial increase in the number of patients who underwent transplantation with MELD scores of 40 or higher. The objective of this study was to characterize the outcomes of liver transplantation in these patients. METHODS: A single-center retrospective study evaluating the outcome of liver transplantation in 38 consecutive patients achieving a MELD score of 40 or higher from January 1, 2006, to November 30, 2010, was conducted. Patient and graft survivals and independent risk factors for postoperative death or graft loss were determined. RESULTS: Kaplan-Meier-based 1-, 2-, and 3-year patient survival rates were 89%, 82%, and 77% with 1-, 2-, and 3-year graft survival rates of 84%, 75%, and 70.3%, respectively. One of three recipients was on a vasopressor before transplantation, and 13% were mechanically ventilated. Renal replacement therapy was used before operation in 90% of the recipients. Postoperative length of stay averaged 38 days. There was a 42% incidence of postoperative bacteremia and an 18% incidence of bile duct stricture within 6 months. Univariate analysis identified admission-to-transplantation time and recipient diabetes as risk factors for graft failure and patient death. Multivariate analysis confirmed recipient diabetes as a risk factor for patient survival and admission-to-transplantation time of more than 15 days as a risk factor for graft survival. CONCLUSIONS: Acceptable outcomes are achievable after liver transplantation in patients with MELD scores of 40 or higher but come at high pretransplantation and posttransplantation resource utilization.

Combined surgical resection and radiofrequency ablation as treatment for metastatic ocular melanoma.

PURPOSE: Ocular melanoma is a rare disease with a strong predilection for the liver. Systemic and locoregional treatments for metastatic ocular melanoma have had disappointing results, with an average survival of 5-7 months. Resection and/or radiofrequency ablation (RFA) of liver lesions were attempted to improve the patient outcomes. METHODS: Eight patients with liver metastasis from ocular melanoma underwent surgery and/or RFA at the University of Southern California, University Hospital from 1 January 2001 to 31 December 2009. Their charts were retrospectively reviewed. RESULTS: All patients had undergone eye enucleation as the primary treatment. Four patients had all metastatic liver lesions addressed: one patient underwent left lateral segmentectomy and three patients had combinations of left lateral segmentectomies, wedge resections and RFA of two to four lesions. Two patients underwent surgical biopsies for diagnosis, one patient was unresectable and one patient underwent RFA of a dominant lesion. The median survival was 36 months. The median survival of patients who underwent surgery alone or in conjunction with RFA to address all liver lesions was 46 months. CONCLUSIONS: There are few reports of RFA for metastatic ocular melanoma. RFA of liver lesions in addition to resection can perhaps lead to improved survival and may play a critical role in the future management of this disease.

The surgical management of pancreatic cancer.

There have been significant advances made over the years in the areas of critical care, anesthesia, and surgical technique, which have led to improved mortality rates and survival after resection for pancreatic cancer. The standard of care is currently PD or PPPD for pancreatic cancers of the head, uncinate process, or neck and DP for pancreatic cancers of the body or tail. Resections are performed with the goals of negative margins and minimal blood loss, and referral to high-volume centers and surgeons is encouraged. However, 5-year survival rate after curative resection still remains at less than 20%. In an effort to improve survival and extend the limits of resectability, many centers have attempted extended lymphadenectomy and portal venous and even arterial resection and reconstruction. Extended lymphadenectomy has not led to improved survival for these patients. Portal vein resection has increased the number of patients amenable to resection, with equivalent survival rates compared with those of standard resections. Portal vein invasion is thus no longer considered a contraindication to resection at many large centers. Resection and reconstruction of involved arteries have been rarely performed and are currently not considerations for most patients. It is likely that future improvements in survival lie in the realm of adjuvant therapy. As chemotherapeutic and other tumor-directed agents continue to evolve and advance, this will hopefully lead to improved survival for patients undergoing surgical resection for pancreatic cancer.

Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome.

Acute kidney injury (AKI) at the time of liver transplantation (LT) has been associated with increased morbidity and mortality. In patients with potentially reversible renal dysfunction, predicting whether there will be sufficient return of native kidney function is sometimes difficult. Previous studies have focused mainly on the effect of the severity of renal dysfunction or the duration of pretransplant dialysis on posttransplant outcomes. We performed a retrospective analysis of patients who underwent LT at our center after Model for End-Stage Liver Disease-based allocation so that we could determine the impact of the etiology of AKI [acute tubular necrosis (ATN) versus hepatorenal syndrome (HRS)] on post-LT outcomes. The patients were stratified according to the severity of AKI at the time of LT as described by the Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE) classification: risk, injury, or failure. The RIFLE failure group was further subdivided according to the etiology of AKI: HRS or ATN. The patient survival and renal outcomes 1 and 5 years after LT were significantly worse for those with ATN. At 5 years, the incidence of chronic kidney disease (stage 4 or 5) was statistically higher in the ATN group versus the HRS group (56% versus 16%, P < 0.001). A multivariate analysis revealed that the presence of ATN at the time of LT was the only variable associated with higher mortality 1 year after LT (P < 0.001). Our study is the first to demonstrate that the etiology of AKI has the greatest impact on patient and renal outcomes after LT.

Ischemic mass effect from biliary surgical clips.

Migrating surgical clips in the hepatic hilum are known causes of biliary stricture or obstruction, most often due to direct intraluminal obstruction or secondary stone formation. Two cases are reported on patients with previous cholecystectomies presenting with delayed symptoms of biliary tract stricture. Both patients were successfully treated with a resection of the strictured area and a Roux-en-Y hepatico-jejunostomy. Resected specimens grossly demonstrated surgical clips adjacent to the stricture, but not directly within the lumen, suggestive of an ischemic mass effect, which was supported by histology. In addition to the direct intraluminal obstruction and lithogenic effects of migratory surgical clips, "clipomas" due to an ischemic mass effect can also lead to biliary tract strictures.

The prevalence of colorectal neoplasia in patients with end-stage renal disease: a case-control study.

BACKGROUND AND PURPOSE: The scarcity of organs for transplantation has led to aggressive pretransplant evaluations. Many younger kidney transplant patients with end-stage renal disease, who would be ordinarily at average risk for colorectal cancer, undergo screening colonoscopy as part of this evaluation. The purpose of this study was to determine the prevalence of colorectal neoplasia in patients with end-stage renal disease who are potential transplant candidates. MATERIALS AND METHODS: We performed a retrospective chart review analysis on 57 kidney transplant candidates who underwent pretransplant screening colonoscopy between August 1999 and December 2004. The control group was comprised of 60 age- and gender-matched subjects without end-stage renal disease who underwent routine screening colonoscopy. RESULTS: The prevalence of polyps in end-stage renal disease patients was 37 vs 22% in the control group (p=0.07, not significant). None of the risk factors studied were found to predict the presence of polyps in the study group. CONCLUSION: These results suggest that screening guidelines for colorectal cancer for the general population should be adequate for potential kidney transplant recipients.

A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity.

BACKGROUND AND OBJECTIVE: Inosine 5'-monophosphate dehydrogenase 2 is required for purine synthesis in activated lymphocytes. Variants in the IMPDH2 gene may account for the large inter-individual variability in baseline enzyme activity, immunosuppressive efficacy and side effects in transplant recipients receiving mycophenolic acid. Therefore, the objective of this study was to identify and functionally characterize IMPDH2 variants. METHODS: DNA samples from 152 solid organ transplant patients were screened at exons and exon/intron junctions of the IMPDH2 genes by PCR amplification followed by bidirectional direct DNA sequencing. Genetic variant was constructed by site-directed mutagenesis and transformed to an inosine 5'-monophosphate dehydrogenase-deficient strain of Escherichia coli h712. Proteins were purified to homogeneity and the enzymatic activity was measured by reduced nicotinamide adenine dinucleotide production. RESULTS: Nine genetic variants were identified in the IMPDH2 gene, with frequencies of the rarer alleles ranging from 0.5 to 10.2%. A novel nonsynonymous variant L263F was identified, and the kinetic assay demonstrated that the inosine 5'-monophosphate dehydrogenase activity of L263F variant was decreased to 10% of the wild-type. The Ki for mycophenolic acid inhibition of the L263F variant was comparable with the wild-type, and the variant Km for inosine 5'-monophosphate and nicotinamide adenine dinucleotide did not change significantly. CONCLUSIONS: IMPDH2 has low genetic diversity, but the nonsynonymous variant L263F has a significant impact on inosine 5'-monophosphate dehydrogenase activity. This novel functional variant may be one of the factors contributing to the inter-individual difference of baseline inosine 5'-monophosphate dehydrogenase activity as well as drug efficacy and adverse events in transplant patients.

Gallbladder mass with a carbohydrate antigen 19-9 level in the thousands: malignant or benign pathology? Report of a case.

Tumor markers such as carbohydrate antigen 19-9 (CA 19-9) are commonly measured in the serum of patients with suspected pancreaticobiliary malignancies. Moderate elevations of CA 19-9 may be seen in benign disease, but levels in the thousands are indicative of malignancy. We report the case of a 64-year-old man with an elevated CA 19-9 of 5791 U/ml and radiological findings suggestive of metastatic gallbladder carcinoma. The patient underwent cholecystectomy and excision of a common bile duct stricture, with hepaticojejunostomy and liver biopsy. The final surgical pathology was consistent with xanthogranulomatous cholecystitis (XGC) and the elevated CA 19-9 returned to normal postoperatively. Thus, an elevated CA 19-9 level, even in the thousands, should not preclude patients from an operation if a mass is deemed resectable. Thorough investigation and treatment may result in a curative operation even if unresectable malignant disease is initially suspected.

Left extended hepatectomy for a metastatic gastrointestinal stromal tumor after a disease-free interval of 17 years: report of a case.

Gastrointestinal stromal tumors (GISTs), although rare, are frequently diagnosed with liver metastasis. These metastatic GISTs are poorly responsive to conventional chemotherapy; however, recent studies report improved survival after complete surgical resection of liver metastases. On the other hand, few reports describe the treatment of delayed liver metastasis after resection of a primary GIST. We report the case of a 55-year-old woman found to have liver metastasis from a GIST after a 17-year disease-free interval. The patient underwent a left extended hepatectomy for a complete resection of the metastatic GIST and is alive and well 30 months later. To our knowledge, this is the longest disease-free interval reported in the literature, and emphasizes the importance of considering late metastasis when evaluating patients with a history of GIST. Thus, surgical resection of delayed liver metastasis from a GIST should be considered as primary therapy.

High seroprevalence of anti-HTLV-I/II antibodies among solid organ donors necessitates confirmatory testing.

BACKGROUND: Human T-cell lymphotrophic virus (HTLV) type I has been linked to adult T-cell leukemia/lymphoma (ATL) and HTLV-I associated myelopathy (HAM). Transmission of HTLV by blood and organ transplantation has been documented, with some infections leading to clinical disease. Organ donors are tested for anti-HTLV antibodies and donor suitability is determined primarily by results from enzyme immunoassays (EIA). Confirmatory testing is not routinely performed, and the number of false positive organ donors is unknown. METHODS: In order to investigate the contemporary seroprevalence of anti-HTLV I/II antibodies among solid organ donors and determine the number of false positive samples, we tested 1,408 specimens from prospective organ donors in 2002 and 2003. All specimens were tested for anti-HTLV antibodies by a commercial EIA. Repeatedly reactive specimens underwent confirmatory testing using a commercial Western blot. RESULTS: There were 22 repeatedly EIA reactive donor specimens (1.56%). Five specimens did not undergo further testing because of case shutdown or insufficient sample quantity. HTLV I/II western blot confirmed six positives, whereas five were negative and six were indeterminate. The majority of confirmed specimens were positive for antibodies to HTLV-II. CONCLUSIONS: Our data shows that 29% of initially reactive specimens were false positives. With the increasing demand for organs, the unnecessary rejection of organs that are falsely positive for HTLV antibodies becomes of tremendous importance and stresses the need for timely confirmatory testing for HTLV.