Xavier Martin

Human hand allograft: report on first 6 months

BACKGROUND Long-term survival of animal limb allografts with new immunosuppressant combinations and encouraging results of autologous limb replantations led us to believe that clinical application of hand transplantation in human beings was viable. METHODS On Sept 23, 1998, we transplanted the right distal forearm and hand of a brain-dead man aged 41 years on to a man aged 48 years who had had traumatic amputation of the distal third of his right forearm. The donors arm was irrigated with UW organ preservation solution at 4 degrees C, amputated 5 cm above the elbow, and transported in a cool container. We dissected the donor limb and the recipients arm simultaneously to identify anatomical structures. Appropriate lengths of viable structures were matched. Transplantation involved bone fixation, arterial and venous anastomoses (ischaemic time 12.5 h), nerve sutures, joining of muscles and tendons, and skin closure. Immunosuppression included antithymocyte globulins, tacrolimus, mycophenolic acid, and prednisone. Maintenance therapy included tacrolimus, mycophenolic acid, and prednisone. Follow-up included routine post-transplant laboratory tests, skin biopsies, intensive physiotherapy, and psychological support. FINDINGS The initial postoperative course was uneventful. No surgical complications were seen. Immunosuppression was well tolerated. Mild clinical and histological signs of cutaneous rejection were seen at weeks 8-9 after surgery. These signs disappeared after prednisone dose was increased (from 20 mg/day to 40 mg/day) and topical application of immunosuppressive creams (tacrolimus, clobetasol). Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress (Tinels sign) was excellent and reached the wrist crease (20 cm) on day 100 for the median and ulnar nerves, and at least 24 cm to the palm by 6 months when deep pressure, but not light touch sensation, could be felt at the mid palm. INTERPRETATION Hand allotransplantation is technically feasible. Currently available immunosuppression seems to prevent acute rejection. If no further episode of rejection occurs, the functional prognosis of this graft should be similar to if not better than that reported in large series of autoreconstruction.

Whole-gland Ablation of Localized Prostate Cancer with High-intensity Focused Ultrasound: Oncologic Outcomes and Morbidity in 1002 Patients

BACKGROUND High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa). OBJECTIVE The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study. DESIGN, SETTING, AND PARTICIPANTS Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence. INTERVENTION Whole-gland prostate ablation with transrectal HIFU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2-13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression. RESULTS AND LIMITATIONS A total of 1002 patients were included. The median nadir prostate-specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA ≤0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients. CONCLUSIONS HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity.

Clinicopathologic monitoring of the skin and oral mucosa of the first human face allograft: Report on the first eight months

Background. The first human face allograft was performed in France on November 27, 2005. We report herein the clinicopathologic findings from the skin and oral mucosa of this allograft during the first eight months. Methods. Sequential biopsies were taken from the facial skin (n=3), oral mucosa (n=20), and sentinel skin graft (n=11) from day 3 to day 220 postgraft and examined (immuno)histologically, using a pathological score previously proposed for evaluation of rejection in composite tissue (hand) transplantation. Results. The patient developed clinically rejection episodes at day 20 and during the eighth month postgraft, manifesting with redness and edema of the facial skin, oral mucosa, and sentinel graft skin. Pathologically, changes suggestive of rejection grades 0, I, II, and III were seen in 1, 1, 1, and 0 biopsies of facial skin, 7, 2, 1, and 1 biopsies of sentinel skin graft and 3, 5, 8, and 4 biopsies of oral mucosa, respectively. Pathological changes were generally more severe in the oral mucosa than in facial and sentinel graft skin (mean scores 1.85, 0.64, and 1, respectively). Conclusions. As it happens with other composite tissue allografts, close clinicopathologic monitoring of the skin (and oral mucosa) seems to be the most reliable way to detect rejection in the setting of human facial tissue allotransplantation. Apart from these rejection episodes, the skin and mucosa maintained a normal microscopic structure, paralleling functional recovery.

Surgical Management of Complex Renal Cysts: A Series of 32 Cases

PURPOSE The differentiation between benign cysts of the kidney and those that require surgical exploration remains difficult. The accuracy of radiological techniques (ultrasound, computerized tomography [CT], angiography, magnetic resonance imaging, cyst puncture and intraoperative pathological examination) is analyzed. MATERIALS AND METHODS Surgical exploration was performed in 30 patients with 32 asymptomatic renal cysts, and the pathological specimens were compared retrospectively to the radiological findings. The classification of Bosnaik was used to categorize the ultrasound and CT findings. RESULTS Of our complex renal cysts 41% proved to be malignant. Our results suggest that the radiological techniques are not well suited for characterization of these cysts. None of the Bosnaik types was sufficiently predictive of the lesion. Only a Bosnaik score of 4 (the sum of ultrasound and CT Bosnaik types) was not associated with renal cell carcinoma. According to the radiological findings, 1 patient was under treated (recurrent renal cell carcinoma) and 4 were over treated (radical nephrectomy for benign lesions). CONCLUSIONS A practical therapeutic strategy is described in which radical nephrectomy is performed when malignant lesions are detected either by preoperative or intraoperative techniques. Conservative surgery is indicated for benign cysts according to the clinical status and risks of nephron sparing surgery.

Hodgkin's disease after transplantation

Hodgkins disease (HD) has seldom been reported after transplantation. Epstein-Barr virus (EBV) is present in about 50% of Reed-Sternberg cells in HD developing in immunocompetent individuals, but is more frequently found in HD of acquired immune deficiency syndrome patients. We report 7 cases of HD that occurred in transplant recipients. Clinical and pathological data and studies of EBV reveal specific features of HD after transplantation. Six patients received kidney transplants and 1 patient received combined kidney and pancreas transplantation. Immunosuppressive therapy consisted of cyclosporine, steroids, azathioprine, and antilymphocyte globulins. One patient received, in addition, anti-CD3 mAb therapy and an EBV+ B cell lymphoma developed. Retrospective EBV serological data from patients were collected. Tumors were classified according to pathology. EBV studies were conducted by immunohistochemical methods with monoclonal antibodies to EBV-latent membrane protein (LMP) or EBV-nuclear antigen 2 (EBNA2), and by in situ hybridization for latent nuclear EBV-early RNAs (EBERs). The mean lapse of time between transplantation and HD was 49 months. Six patients presented with enlarged lymph nodes and 1 patient presented with liver involvement. HD was classified as IA in 2 patients, IIA in 3 patients, IIIB in 1 patient, and IVB in 1 patient. Four patients had primary EBV infection after graft, before HD, and the others reactivated latent EBV infection. Histological subtypes were mixed cellularity in 6 cases and lymphocytic depletion in 1 case. Latent EBV infection was detected with EBERs in all tumors. Reed-Sternberg cells expressed LMP, and were negative for EBNA2 expression. Six patients were treated: 2 patients at stage I received radiotherapy, and relapsed within 1 year with a more advanced stage of HD; chemotherapy was indicated as primary therapy in 5 patients, and as salvage therapy in 2 patients; it was associated with radiotherapy in 4 patients. Immunosuppressive therapy was reduced in all patients. Four patients were alive and in complete remission 18, 25, 31, and 67 months after chemotherapy, with a functioning graft in 3 patients. Two patients died of infection. Mixed cellularity is the most frequent histological subtype observed in HD occurring in transplant patients. EBV is present in all Reed-Sternberg cells. Posttransplant HD shows similarities with human immunodeficiency virus-associated HD. These facts argue for a role of EBV infection and immunosuppression in the progression of HD after transplantation.

IGL‐1 solution in kidney transplantation: first multi‐center study

Abstract:  IGL‐1 solution is characterized by inversion of K+ and Na+ concentrations in the University Wisconsin (UW) solution and polyethylene glycol 35 (PEG 35) substitution for hydroxy ethyl starch. In this prospective study, 121 patients transplanted with kidneys preserved in IGL‐1 solution were compared to 102 patients grafted with kidneys preserved in UW solution. Serum creatinine and creatinine clearance, delayed graft function (DGF) and rejection episodes, patient and graft survival were evaluated in the first post‐transplant year. Groups were comparable regarding to donor and recipient characteristics. Median creatinine levels were significantly lower in IGL‐1 group from day 6 to day 14 and it decreased more rapidly in the IGL‐1 group (from day 4 to day 15: p < 0.05). Creatinine clearance values were usually higher in the IGL‐1 group for the first 15 d. During the follow‐up period serum creatinine concentrations were lower in IGL‐1 group at one, three, six and 12 months after transplantation (p = 0.04; p = 0.06, p = 0.01 and p = 0.08, respectively) while creatinine clearance values were similar during the follow‐up. No significant difference in DGF and rejection rates as well as in patient and graft survival was shown between the two groups. Kidneys preserved in IGL‐1 solution showed to have the same function as kidneys preserved in UW solution.

Peripheral nerve regeneration in human hand transplantation

WHEN a major peripheral nerve is rejoined microsurgically after complete severance it may regenerate distally at a rate of up to 1 mm/d in adults. Regeneration can proceed steadily even through two completely severed and then meticulously individually repaired anastomoses along the same nerve. A long nerve homograft can also be expected to regenerate, but at a slighter slower rate. On September 23, 1998, a cadaver right distal forearm and hand were transplanted onto a 47-year-old amputee in Lyon, France. The different tissues were joined at different levels due to their anatomic location and condition. With a reference point at the wrist crease, the ulnar and median nerves were joined 20 and 21 cm, respectively, proximal to it. Sensory and motor nerve regeneration was assessed independently by a group of hand therapists—first by assessment of Tinel signs, followed by Semmes‐Weinstein microfilaments, NCS, pinprick, hot and cold, and light and deep pressure. Rapid regeneration was observed immediately postoperatively, with the Tinel sign advancing to the wrist crease by 100 days (200 and 210 mm, respectively, for the ulnar and median nerve). At 300 days, regeneration was at 330 mm and reached all fingertips (360 mm) at 365 days. Intrinsic muscle activity appeared into the abductor digiti minimi muscle at 12 months and was detected as very weak in the other intrinsic muscles at 16 months. Currently, muscle activity is also present in the first dorsal interosseous muscle. The remarkable speed of nerve regeneration may be due in part to the effect of FK 506, which serves not only as a very effective immunosuppressant drug but has a well-defined action in removing some of the inhibiting factors presently slowing normal nerve regeneration. FK 506 protects neural cells from ischemia and blocks neuronal apoptosis. Subsequent to protective sensation reaching to his fingertips at 1 year postoperatively, the patient has reported gradually more specific feeling, and at almost 2 years postoperation could discriminate pain, hot and cold, and “sharp” and “blunt” sensation in his palms and all digits. There have been several episodes during which the patient left the intensive care of our team (for periods of 3 months, several weeks, and lately for .3 months). Because routine blood drug levels and biopsies (with subsequent adjustments of dosages) were not possible, and as routine physiotherapy was also neglected for months at a time, recovery

Endocrinometabolic effects of whole versus segmental pancreas allotransplantation in diabetic patients : a two-year follow-up

We have investigated the metabolic effects of segmental (neoprene-injected) pancreas transplantation versus whole (enteric-diverted) pancreas transplantation. Seventeen uremic insulin-dependent diabetes mellitus (IDDM) patients received a simultaneous pancreaticorenal transplant: in a prospective, randomized study, 9 patients received a segmental neoprene-injected graft (group A) while 8 patients received a total pancreaticoduodenal graft, with enteric diversion (group B). The immunosuppressive therapy was based on ALG, CsA, azathioprine, and steroids. Three months after surgery, patients were submitted to the following metabolic investigation: i.v. and oral glucose tolerance tests, Hba1, i.v. arginine test, and a 24-hr metabolic profile. The OGTT, HbA1, and metabolic profile were repeated 12 and 24 months after transplantation. At 3 months after transplantation, the OGTT showed delayed insulin secretion and higher blood glucose levels in group A. Serum insulin levels after IVGTT or arginine were higher in group B than in group A. OGTT at 12 and 24 months were unchanged in group B, while in group A a higher incidence of impaired glucose tolerance (IGT) and diabetes mellitus response were observed. HbA1 and blood glucose levels during the 24-hr profile showed good metabolic control in both groups at 3, 12, and 24 months. We can conclude that both the segmental and total pancreas transplantation restore a good metabolic control in IDDM patients, though a higher incidence of IGT and DM responses were observed after OGTT in the patients receiving a segmental graft. These abnormalities do not seem to interfere with metabolic control in everyday life. These results seem to be the consequence of the different B cell masses transplanted with these two techniques.

Impact of pancreatic venous drainage site on long-term patient and graft outcome in simultaneous pancreas-kidney transplantation.

Abstract:  The impact of portal or systemic venous pancreas graft drainage on patient and graft outcome remains controversial. In the present study, the impact of venous drainage type on long‐term patient and graft survival is assessed. From July 1996 to December 2002 80 simultaneous pancreas‐kidney transplants were enrolled into a prospective study: 44 received a pancreas allograft with portal (P‐SPK group) and 36 with systemic venous drainage (S‐SPK group). Enteric exocrine drainage was performed in all recipients receiving the same immunosuppressive treatment. At one yr, the patient survival rates were 91.7% and 95.5% both for S‐SPK and P‐SPK groups, respectively; no significant difference in survival was shown at any time point of the follow‐up. The one‐, three‐, five‐, and eight‐yr pancreas survival rates were 75%, 60.6%, 56.7%, and 44%, respectively in the S‐SPK group compared to 88.6%, 84.1%, 78.4%, and 31.3% in the P‐SPK group. The one‐, three‐, five‐, and eight‐yr kidney survival rates were 91.7%, 78.15%, 74.1%, and 57.9%, respectively in the S‐SPK group compared to 93.2%, 88.6%, 78.4%, and 38.9% in the P‐SPK group. Comparing the two groups, no significant difference was shown in the total number of surgical complications as well as in the number of each complication. No significant difference in long‐term outcomes between the two groups was shown, even if in S‐SPK group a higher incidence of pancreas graft loss has been reported and it was in part correlated to a higher number of graft thromboses.

Pancreas retransplantation: a second chance for diabetic patients?

BACKGROUND If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome. METHODS Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated. RESULTS Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years). CONCLUSION Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.Background If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome. Methods Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated. Results Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years). Conclusion Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.