Kadiyala V. Ravindra

Experience with more than 500 minimally invasive hepatic procedures.

Objective:To evaluate our experience with more than 500 minimally invasive hepatic procedures. Summary Background Data:Recent data have confirmed the safety and efficacy of minimally invasive liver surgery. Despite these reports, no programmatic approach to minimally invasive liver surgery has been proposed. Methods:We retrospectively reviewed all patients who underwent a minimally invasive procedure for the management of hepatic tumors between January 2001 and April 2008. Patients were divided into 3 groups: laparoscopy with intraoperative ultrasound and biopsy only, laparoscopic radiofrequency ablation (RFA), and minimally invasive resection. To compare the various forms of surgery, we analyzed the incidence of complications, tumor recurrence, mortality, and cost. Statistical analysis was performed using χ2 analysis, Student t test, Kaplan-Meier survival analysis with the log-rank test, and multivariable Cox models. Results:A total of 590 minimally invasive hepatic procedures were performed during 489 operative interventions. The representative tumor histologies were: hepatocellular carcinoma (HCC; N = 210), colorectal carcinoma (N = 40), miscellaneous liver metastases (N = 42), biliary cancer (N = 20), and benign tumors (N = 176). Thirty-five patients underwent laparoscopic ultrasound and confirmatory biopsy alone; 201 patients underwent 240 laparoscopic RFAs, and 253 patients underwent 306 minimally invasive resections. Conversion rates to open surgery for the RFA and resection group were 2% overall. One hundred ninety-nine (40.6%) patients were cirrhotic; 31 resections were performed in cirrhotic patients. Complication and mortality rates for RFA and resection were comparable (11% vs. 16%, and 1.5% vs. 1.6%). However, complication rates (14% vs. 29%; P = 0.02) and mortality (0.3% vs. 9.7%; P = 0.006) rates were higher in the cirrhotic versus noncirrhotic resection group. Overall recurrence rates for RFA and resection groups were 24% and 23%, respectively. Local recurrence rates were higher in the RFA group (6.3% versus 1.5%; P < 0.06). Overall patient survival differed between HCC patients receiving RFA alone and those receiving RFA and OLT (P < 0.0001). Overall survival for cancer patients receiving RFA versus resection differed significantly when unadjusted for other covariates (P = 0.01), and remained marginally significant in a multivariable model (P = 0.056). Conclusions:Minimally invasive hepatic surgery has become a viable alternative to open hepatic surgery. Our present data are equivalent or superior to those encountered in any large open series. Our experience with RFA confirms a low local recurrence rate and an excellent technique for bridging patients to transplantation. Morbidity and mortality rates for minimally invasive hepatic resections in cirrhotics, is similar to other reported open resection series. This series confirmed excellent interim survival rates after laparoscopic HR and superiority over RFA in the treatment of cancer, with significantly lower local tumor recurrence rate.

Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation

Durable chimerism and donor-specific tolerance can be safely achieved without GVHD in HLA-mismatched donor/recipient pairs. Teaching Tolerance According to Greek mythology, the Chimera was a fire-breathing creature made of parts from different animals: the body of a lioness, a snake’s head at the end of the tail, and the head of the goat. Sightings of this fearsome beast portended any of a number of terrible disasters. In the context of organ transplantation, a “chimera” can indicate both desirable and disastrous outcomes. For example, hematopoietic chimerism, in which the immune cells in the graft recipient come from both the host and the donor, may promote graft tolerance, but may also cause graft-versus-host disease (GVHD), in which the donor immune cells attack the healthy tissue of the host. Leventhal et al. now report mixed chimerism and tolerance without the negative side effects of GVHD or engraftment syndrome in a phase 2 clinical trial of combined kidney and hematopoietic transplantation. Leventhal et al. used a combination of mobilized cells enriched for hematopoietic stem cells and graft-facilitating cells—which are composed largely of plasmacytoid precursor dendritic cells—with nonmyeloablative conditioning in conjunction with kidney transplant from major histocompatibility complex–mismatched, nonrelated donors and recipients. Five of eight kidney transplant recipients exhibited durable chimerism and were weaned off immunosuppressive therapies by 1 year after transplantation, with no signs of GVHD or engraftment syndrome. If confirmed in larger patient cohorts, this approach to transplantation could free some patients from the difficulties associated with lifelong immunosuppression and add transplantation as a viable option for patients for whom no matched donors exist. As with the Chimera of legend, mixed chimerism may be a harbinger of things to come—albeit hopefully a brighter future for transplant patients. The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)–mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.

Minimally Invasive Liver Resection for Metastatic Colorectal Cancer: A Multi-Institutional, International Report of Safety, Feasibility, and Early Outcomes

Objective:To evaluate a multicenter, international series on minimally invasive liver resection for colorectal carcinoma (CRC) metastasis. Summary Background Data:Multiple single series have been reported on laparoscopic liver resection for CRC metastasis. We report the first collaborative multicenter, international series to evaluate the safety, feasibility, and oncologic integrity of laparoscopic liver resection for CRC metastasis. Methods:We retrospectively reviewed all patients who underwent minimally invasive liver resection for CRC metastasis from February 2000 to September 2008 from multiple medical centers from the United States and Europe. The multicenter series of patients were accumulated into a single database. Patient demographics, preoperative, operative, and postoperative characteristics were analyzed. Actuarial overall survival was calculated with Kaplan-Meier analysis. Results:A total of 109 patients underwent minimally invasive liver resection for CRC metastasis. The median age was 63 years (range, 32–88 years) with 51% females. The most common sites of primary colon cancer were sigmoid/rectum (51%), right colon (25%), and left colon (13%). Synchronous liver lesions were present in 11% of patients. For those with metachronous lesions liver lesions, the median time interval from primary colon cancer surgery to liver metastasectomy was 12 months. Preoperative chemotherapy was administered in 68% of cases prior to liver resection. The majority of patients underwent prior abdominal operations (95%). Minimally invasive approaches included totally laparoscopic (56%) and hand-assisted laparoscopic (41%), the latter of which was employed more frequently in the US medical centers (85%) compared with European centers (13%) (P = 0.001). There were 4 conversions to open surgery (3.7%), all due to bleeding. Extents of resection include wedge/segmentectomy (34%), left lateral sectionectomy (27%), right hepatectomy (28%), left hepatectomy (9%), extended right hepatectomy (0.9%), and caudate lobectomy (0.9%). Major liver resections (≥3 segments) were performed in 45% of patients. Median OR time was 234 minutes (range, 60–555 minutes) and blood loss was 200 mL (range, 20–2500 mL) with 10% receiving a blood transfusion. There were no reported perioperative deaths and a 12% complication rate. Median length of hospital stay for the entire series was 4 days (range, 1–22 days) with a shorter stay in medical centers in the United States (3 days) versus that seen in Europe (6 days) (P = 0.001). Negative margins were achieved in 94.4% of patients. Actuarial overall survivals at 1-, 3-, and 5-year for the entire series were 88%, 69%, and 50%, respectively. Disease-free survivals at 1-, 3-, and 5-year were 65%, 43%, and 43%, respectively. Conclusions:Minimally invasive liver resection for colorectal metastasis is safe, feasible, and oncologically comparable to open liver resection for both minor and major liver resections, even with prior intra-abdominal operations, in selected patients and when performed by experienced surgeons.

Science of composite tissue allotransplantation.

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.

Hand transplantation in the United States: experience with 3 patients.

BACKGROUND Composite tissue allotransplantation (CTA) is a newly emerging field of transplantation that involves the simultaneous transfer of multiple tissues with differing antigenicity. Hand transplantation, the most widely recognized form of CTA, aims to improve function and the quality of life of upper limb amputees. METHODS In 1999, an institutional review board-approved hand transplantation protocol was implemented at the Jewish Hospital, University of Louisville. Suitable patients were evaluated and underwent hand transplantation. The surgical technique was akin to that used in limb reimplantation, and the immunosuppression protocol used was similar to renal transplantation. RESULTS Between 1999 and 2006, 3 patients underwent hand transplantation at our center. Although episodes of acute rejection were seen in all patients during the early postoperative period, only 1 immunologic event occurred after the first year. Graft function improved with time period. Carroll test scores were superior to those recorded with a prosthesis at the end of 1 year. Additionally, recovery of protective sensation was seen in all 3 patients and limited discriminatory sensation in 2. Complications related to immunosuppression have included cytomegalovirus infection in 2 patients, diabetes in 1, hyperlipidemia in 2, and osteonecrosis in 1. At a follow-up of 8, 6, and 1 year(s), all the recipients are healthy and have returned to a productive life. CONCLUSIONS The long-term success reported here should encourage wider application of the CTA in general and hand transplantation in particular. Methods of minimizing long-term immunosuppression need to be pursued.

West Nile Virus—Associated Encephalitis in Recipients of Renal and Pancreas Transplants: Case Series and Literature Review

Although West Nile fever is mild in the vast majority of infected persons, there is growing evidence that the disease may be more severe in the immunocompromised population. We describe 3 recipients of kidney or pancreas transplants who developed West Nile fever, 2 of whom had meningoencephalitis. As is the norm when treating serious infections in transplant recipients, a reduction of immunosuppression was pursued for these patients. Despite the severe nature of the disease in 2 patients, all recovered from the disease. The time course of neurologic recovery in the 2 patients with meningoencephalitis is highlighted. We also review the literature on West Nile fever in organ transplant recipients. In areas where West Nile virus is endemic, one must have a high index of suspicion for the illness when dealing with fever in transplant recipients.

Left hepatic trisectionectomy for hepatobiliary malignancy: results and an appraisal of its current role.

Objective:To analyze results of 70 patients undergoing left hepatic trisectionectomy and to clarify its current role. Summary Background Data:Left hepatic trisectionectomy remains a complicated hepatectomy, and few reports have described the long-term results of the procedure. Methods:Short-term and long-term outcomes of 70 consecutive patients who underwent left hepatic trisectionectomy from January 1993 to February 2004 were analyzed. Results:Of the 70 patients, 36 had colorectal liver metastasis, 24 had cholangiocarcinoma, 4 had hepatocellular carcinoma, and the remaining 6 had other tumors. Overall morbidity, 30-day and 90-day mortality rates were 46%, 7%, and 9%, respectively. Multivariate analysis disclosed that preoperative jaundice and intraoperative blood transfusion were positive independent predictors for postoperative morbidity; however, there were no independent predictors for postoperative mortality. Postoperative morbidity (87% versus 35%, P < 0.001) and mortality (20% versus 5%, P = 0.108) were observed more frequently in patients with preoperative obstructive jaundice than in those without jaundice. Each survival according to tumor type was acceptable compared with reported survivals. Survival for patients with colorectal liver metastasis undergoing left hepatic trisectionectomy with concomitant partial resection of the remnant liver was similar to those without this concomitant procedure. This concomitant procedure was not associated with postoperative morbidity and mortality. Conclusions:Left hepatic trisectionectomy remains a challenging procedure. Preoperative obstructive jaundice considerably increases perioperative risk. Concomitant partial resection of the remaining liver appears to be safe and offers the potential for cure in patients with colorectal metastasis affecting all liver segments.

Composite Tissue Transplantation: A Rapidly Advancing Field

Composite tissue allotransplantation (CTA) is emerging as a potential treatment for complex tissue defects. It is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed through 30 hand transplantation, 3 facial reconstructions, and vascularized knee, esophageal, and tracheal allografts. A major drawback for CTA is the requirement for lifelong immunosuppression. The toxicity of these agents has limited the widespread application of CTA. Methods to reduce or eliminate the requirement for immunosuppression and promote CTA acceptance would represent a significant step forward in the field. Multiple studies suggest that mixed chimerism established by bone marrow transplantation promotes tolerance resulting in allograft acceptance. This overview focuses on the history and the exponentially expanding applications of the new frontier in CTA transplantation: immunology associated with CTA; preclinical animal models of CTA; clinical experience with CTA; and advances in mixed chimerism-induced tolerance in CTA. Additionally, some important hurdles that must be overcome in using bone marrow chimerism to induce tolerance to CTA are also discussed.

Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis

BACKGROUND The goal of this study was to examine the safety and efficacy of selective internal radioembolization (SIR) for hepatocellular carcinoma (HCC) with portal vein or caval thrombosis (VT), or both. Recent reports have demonstrated that SIR is safe for patients with HCC, but the impact on efficacy of venous thrombosis is unknown. STUDY DESIGN Prospective single-arm study of the use of Therasphere in patients with unresectable HCC enrolled from January 2004 to June 2007. Patients were categorized into three groups based on VT status and therapy. RESULTS Fifty-two patients were enrolled: 20 patients without VT who received SIR, 15 patients with VT who were treated, and 17 patients (10 with VT) who were not treated because of preprocedure screening failure. Fifty-eight treatments were administered, with a median of two treatments per patient (range of one to three treatments). Childs score was different between groups. Of the VT patients treated, 67% had portal VT, 7% had cava VT, and 26% had both. There were no treatment-related deaths. There was no difference in complications among groups (p = 0.34). Treated patients without thrombosis had a median overall survival of 13.9 months versus 2.7 months for those treated with thrombosis and 5.2 months for the untreated group given best supportive care only (p = 0.01). CONCLUSIONS SIR is safe in patients with HCC. Although SIR can be delivered with minimal morbidity, there might be no benefit for patients with VT. Continued emphasis on multimodality therapy in this population is needed to improve survival.

Composite Tissue Allotransplantation: Past, Present and Future—The History and Expanding Applications of CTA as a New Frontier in Transplantation

Composite tissue allotransplantation (CTA) transplantation is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed in over 40 successful hand transplants, 3 facial reconstructions, and vascularized knee, esophageal, abdominal wall, and tracheal allografts. The toxicity of chronic, nonspecific immunosuppression remains a major limitation to the widespread availability of CTA and is associated with opportunistic infections, nephrotoxicity, end-organ damage, and an increased rate of malignancy. Methods to reduce or eliminate the requirement for immunosuppression would represent a significant step forward in the field. Mixed chimerism induces tolerance to solid organ and tissue allografts, including CTA. This overview focuses on the history and expanding applications of CTA as a new frontier in transplantation, and considers the important hurdles that must be overcome through research to allow widespread clinical application.