Autotransplanted Patients Research Articles

Applying plastic surgery principles to ovarian tissue transplantation.

Ovarian tissue cryopreservation (OTC) and transplantation is an innovative procedure increasingly utilized to help preserve fertility after gonadotoxic treatments especially in cancer patients. Approximately 30% of autotransplanted patients are able to achieve live birth, typically with the help of in-vitro fertilization. Numerous techniques and grafting sites have been described to continue to increase this figure. In the field of plastic surgery, tissue grafting has been successful performed for thousands of years and knowledge in this area has been significantly refined. A qualitative review of the literature using PubMed, Cochrane, SCOPUS and Medline databases was performed to look for articles relating to ovarian tissue transplantation (OTT) and comparisons made to plastic surgery tissue grafting. Many parallels were found between the principles of grafting in plastic surgery and the principles of OTT, including pre-operative patient optimization, suitable donor site selection, tissue harvest and preparation, graft site choice, immobilization of the graft and post-operative care. Consideration of the benefits and risks of using orthotopic versus heterotopic recipient sites is also highly important with regards to graft take, morbidity and ease of access of oocyte collection. We believe that ongoing discussion between disciplines can have the potential to improve knowledge, surgical techniques and patient outcomes.

Up-regulation of activating and inhibitory NKG2 receptors in allogeneic and autologous hematopoietic stem cell grafts.

BackgroundHematopoietic Stem Cell Transplantation (HSCT) is known to induce the inhibitory immune receptor NKG2A on NK cells of donor origin. This occurs in allogeneic recipients, in both the haploidentical and HLA-matched settings.MethodsTo gain further insight, not only NKG2A, but also the activating receptors NKG2C and NKG2D were assessed by flow cytometry. Immunophenotyping was carried out not only on CD56+ but also on CD8+ lymphocytes from leukemia and lymphoma patients, receiving both HLA-matched (n = 7) and autologous (n = 5) HSCT grafts. Moreover, cognate NKG2 ligands (HLA-E, MICA, ULBP-1, ULBP-2 and ULBP-3) were assessed by immunohistochemistry in diagnostic biopsies from three autotransplanted patients, and at relapse in one case.ResultsAll the NKG2 receptors were simultaneously up-regulated in all the allotransplanted patients on CD8+ and/or CD56+ cells between 30 and 90 days post-transplant, coinciding with, or following, allogeneic engraftment. Up-regulation was of lesser entity and restricted to CD8+ cells in the autotransplantation setting. The phenotypic expression ratio between activating and inhibitory NKG2 receptors was remarkably similar in all the patients, except two outliers (a long survivor and a short survivor) who surprisingly displayed a similar NKG2 activation immunophenotype. Tumor expression of 2 to 3 out of the 5 tested NKG2 ligands was observed in 3/3 diagnostic biopsies, and 3 ligands were up-regulated post-transplant in a patient.ConclusionsAltogether, these results are consistent with a dual (activation-inhibition) NK cell re-education mode, an innate-like T cell re-tuning, and a ligand:receptor interplay between the tumor and the immune system following HSCT including, most interestingly, the up-regulation of several activating NKG2 ligands. Turning the immune receptor balance toward activation on both T and NK cells of donor origin may complement ex vivo NK cell expansion/activation strategies in unmanipulated patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0213-y) contains supplementary material, which is available to authorized users.

Pro-oxidative/antioxidative imbalance: a key indicator of adverse outcome in hematopoietic stem cell transplantation

Pretransplantation iron overload (IO) is considered as a predictor of adverse outcome in hematopoietic stem cell transplantation (HSCT). Peroxidative tissue injury caused by IO leads to progressive organ dysfunction. This is a retro-prospective study which explores the possible relationship between IO, oxidative stress and transplant outcome. Serum samples of 149 consecutive HSCT candidates were subjected to analysis of iron parameters, including nontransferrin bound iron (NTBI) and pro-oxidant/antioxidant status. Serum ferritin was found to be positively correlated with NTBI and negatively correlated with glutathione peroxidase (GPx) and superoxide dismutase (SOD). An inverse correlation of NTBI with SOD, total antioxidant potential (TAP) and malonyldialdehide (MDA) was also demonstrated. An adverse impact of serum ferritin level on early posttransplant complications including pulmonary toxicity, fungal infections and sinusoidal obstruction syndrome (SOS) was shown. A significant impact of NTBI on +30 day (P = 0.027) and +100 day survival (P = 0.028) was shown in auto-transplanted patients. MDA levels had a significant impact on +30 day and +100 day survival in autologous (P = 0.047; P = 0.026) and allogeneic (P = 0.053; P = 0.059) groups. GPx (P = 0.016) and MDA (P = 0.021) were identified as independent prognostic parameters for overall survival in allo-transplanted patients. Pretransplantation IO might be a major contributor to adverse outcome in HSCT recipients through an impaired pro-oxidative/antioxidative homeostasis. The reversible nature of IO and oxidative stress suggests that early preventive strategies might have a potential to improve transplant outcome.

Frontline High Dose Chemotherapy Supported by Autologous PBSCT Might Improve Survival In Elderly Patients (≥60 Years) with High Risk Diffuse Large B-Cell Lymphoma (DLBCL)

AbstractAbstract 5190Limited data is available concerning feasibility and efficacy of high dose therapy (HDT) supported by autologous PBSCT in elderly patients with non-Hodgkin lymphoma (NHL). In young patients with poor prognostic features intensification supported by PBSCT as a part of first-line treatment suggests survival benefit. It is not clear if the same strategy is applicable to the older patients.The Institute Paoli-Calmettes database was reviewed for all DLBCL patients who received BEAM followed by PBSCT in patients >=60 years old between January 1998 and January 2010 (13 years). All patients were HIV-negative and received BEAM intensification as a part of front-line treatment. All of them were in a complete response after CHOP or R-CHOP induction prior to autograft. Thirty six auto-transplanted patients were identified (median age 63 y, range 60–68). This cohort was compared with closely matched group of 43 patients of same age range, who received first-line CHOP or R-CHOP regimen without intensification in the same 13-year interval. Only patients in a complete response after first line were included.As frontline autoPBSCT was performed in high-risk patients, the group without HDT was naturally privileged in the terms of Ann-Arbor stage and aaIPI index. There was significant difference in the localised vs disseminated disease (stage I-II: 53,4% in no-HDT vs 14% in HDT group, p=0,00025) and aaIPI (0-1: 72% in no-HDT vs 28% in HDT, p=0,000086) between the two groups. Factors evaluated included treatment-related mortality (TRM), overall survival (OS) and event-free survival (EFS). There were no transplant-related deaths in the HDT group.The estimated 5-year OS was 81,3% (95% CI 62,5-91,9 %) and 10-year OS was 65% (95%CI 34,2-86,9%) for HDT group compared to 91,5% (95% CI 77,5-97,1%) and 58,4% (95% CI 20–88,8%) in the no-HDT group (p=NS). There were 8 events (6 relapses and 2 secondary malignancy deaths) in the HDT group and 11 events (9 relapses and 2 secondary malignancy deaths) in no-HDT (5-year EFS 77,6% (95% CI 60,3-88,8%) vs 78,3% (95%CI 62,3-88,8%), p=NS)).We conclude that front-line autologous PBSCT with BEAM conditioning can be safely performed in patients aged 60 years or above with DLBCL after CHOP of R-CHOP induction. There was no difference in OS and EFS between cohorts with and without intensification even if the auto-transplantation procedure was reserved for the high risk patients only. The first-line HDT with autologous PBSCT in older patients with high-risk IPI score might improve survival in this group and produce results similar to those in the low-risk group. Disclosures:No relevant conflicts of interest to declare.

Depth of response assessed by quantitative ASO‐PCR predicts the outcome after stem cell transplantation in multiple myeloma

Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real-time quantitative polymerase chain reaction by allele-specific primers (qASO-PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near-to-CR after autologous or allogeneic stem cell transplantation (SCT). Allele-specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71% (5/7 patients); the median sensitivity of PCR assay was <0.002%. The proportion of patients without detectable PCR target was 22% of all autotransplanted patients. A threshold level of 0.01% in the qASO-PCR assay 3-6 months after SCT was found to be a useful cut-off limit to divide the patients into two prognostic groups: MRD low/negative vs. MRD high. Low/negative MRD after SCT was a significant predictive factor for the prolongation of progression free (70 vs. 19 months; P = 0.003) and suggestively also for overall survival. We conclude that not only CR but also its depth is important for the long-term outcome in MM.

Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle

OBJECTIVECuring type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation.RESEARCH DESIGN AND METHODSThe current study presents a new experimental model that is found to be applicable to clinical islet transplantation. Islets were implanted into striated muscle and intraislet vascular density and blood flow were visualized with intravital and confocal microscopy in mice and by magnetic resonance imaging in three autotransplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody, and diabetes was induced by alloxan treatment.RESULTSContrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable with those of islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in autotransplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared with adjacent muscle tissue through high-resolution magnetic resonance imaging.CONCLUSIONSThis study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intraislet blood perfusion following transplantation to striated muscle under experimental and clinical situations.

Feasibility and Efficacy of BEAM as a Frontline High Dose Chemotherapy Supported by Autologous PBSCT in Elderly Patients (≥60 Years) with DLBCL

Limited data is available concerning feasibility and efficacy of high dose therapy (HDT) supported by autologous PBSCT in elderly patients with non-Hodgkin lymphoma (NHL). In young patients with poor prognostic features intensification supported by PBSCT as a part of first-line treatment suggests survival benefit. It is not clear if the same strategy is applicable to the older patients. The Institute Paoli-Calmettes database was reviewed for all DLBCL patients who received BEAM followed by PBSCT in patients >=60 years old between January 1998 and December 2006 (9 years). All patients were HIV-negative and received BEAM intensification as a part of front-line treatment. All of them were in a complete or partial response after CHOP or R-CHOP induction prior to autograft. Twenty seven auto-transplanted patients were identified (median age 63 y, range 60–68). This cohort was compared with closely matched group of 37 patients of same age range, who received first-line CHOP or R-CHOP regimen without intensification in the same 9-years interval. Only patients in a complete response after first line were included. As frontline autoPBSCT was performed in high-risk patients, the group without HDT was naturally privileged in the terms of Ann-Arbor stage and aaIPI index. There was significant difference in the localised vs disseminated disease (stage I–II: 54% in no-HDT vs 26% in HDT group, p=0.03)) and aaIPI (0–1: 66% in no-HDT vs 37% in HDT, p=0.046) between the two groups. Factors evaluated included treatment-related mortality (TRM), overall survival (OS) and event-free survival (EFS). TRM in the HDT group (1/27 pts (3,7%)) was comparable with previously published data. The estimated 5-year OS was 75,5% (95%CI 52–90 %) for HDT group compared to 79,9% (95%CI 58–92%) in the no-HDT group (p=0,75). There were 8 events (1 TRM and 7 relapses) in the HDT group and 11events (all relapses) in no-HDT (5-year EFS 49,4% vs 64,2%, p=0.45). We conclude that frontline autologous PBSCT with BEAM conditioning can be safely performed in patients aged 60 years or above with DLBCL after CHOP of R-CHOP induction. There was no difference in OS and EFS between cohorts with and without intensification even if the auto-transplantation procedure was reserved for the high risk patients. We conclude that first-line HDT with autologous PBSCT in older patients with high-risk IPI score might improve survival in this group and produce results similar to those in the low-risk group.

Stem cell transplantation in poor‐risk chronic lymphocytic leukemia: assessment of post‐transplant minimal residual disease using four‐ and six‐color flow cytometry and allele‐specific RQ‐PCR

A total of 178 bone marrow samples were taken for minimal residual disease (MRD) analysis after 34 stem cell transplantations for poor-risk chronic lymphocytic leukemia, and 86 of them were analyzed in parallel by flow cytometry and allele-specific oligonucleotide-PCR (ASO-PCR). ASO primer was successfully designed for all patients whose frozen diagnosis samples were available. Flow cytometry and ASO-PCR were concordant, i.e. both either positive or both negative, in 78% of the analyses. Flow cytometry did not detect MRD in any of the samples that were PCR-negative cases. In contrast, ASO-PCR detected MRD in samples that were negative for MRD by flow cytometry in 22% of the analyses. In one patient, the immunophenotype but not the IgV(H) gene sequence had changed during a course of the disease, and MRD could not be followed by flow cytometry. In the remaining cases, the discrepancy was due to a higher sensitivity of ASO-PCR. Autologous stem cell transplantation resulted in clinical complete response in 87% (20/23) of the patients. By flow cytometry, 35% (8/23) of autotransplanted patients became MRD-negative, but only 12.5% (2/16) PCR-negative (sensitivity of ASO-PCR <0.001 and <0.01, respectively). All allotransplanted patients achieved or maintained hematological CR, and five out of nine patients (56%) became PCR-negative (sensitivity of PCR between <0.001 and <0.003), two of them having non-myeloablative conditioning. None of the patients who became PCR-negative after allogeneic transplantation have relapsed.

Early clinical impact of iron overload in stem cell transplantation. A prospective study

Toxic-infectious complications may be related with iron toxicity after a stem cell transplant (SCT). Eighty one patients who underwent SCT were prospectively evaluated over 3 months for mucositis, bacteraemia and febrile days. Pre-SCT transferrin saturation (TS), ferritin level and the number of days with TS >or= 80% after transplant were determined. A ferritin level >1,500 microg/l predicted the appearance of severe mucositis, bacteraemia and days with fever in univariate (P = 0.03, P = 0.03 and P = 0.03) and multivariate analysis (P = 0.03, P = 0.006 and P = 0.002). Nevertheless, further statistical studies revealed that the predictive value of pre-SCT ferritin levels was restricted to AUTO-transplanted patients in both univariate (P = 0.05, P = 0.05 and P < 0.001) and multivariate (P = 0.03, P = 0.05 and P < 0.001) analysis, in contrast with the ALLO-transplanted group where this variable did not reach statistical significance. In conclusion, iron burden seems to influence the appearance of toxic-infectious complications during the first 3 months after transplant in AUTO-transplanted patients.

CD34+ dose‐driven administration of granulocyte colony‐stimulating factor after high‐dose chemotherapy in lymphoma patients

Our goal was to optimize use of granulocyte colony-stimulating factor (G-CSF) after high-dose chemotherapy and autologous peripheral blood stem-cell transplantation in lymphoma patients, limiting G-CSF administration to patients infusing a suboptimal CD34(+) cell number. Of 124 consecutive patients with histologically proven Hodgkin's and non-Hodgkin's lymphoma from January 2001 to June 2004, 60 patients (group 1) given > or = 5 x 10(6)/kg CD34(+) cells received no G-CSF; 64 patients (group 2) given < or = 5 x 10(6)/kg CD34(+) cells received G-CSF from day +5 after stem-cell reinfusion. The median times to reach 0.5 x 10(9)/L and 1.0 x 10(9)/L neutrophils were, respectively, 3 and 4 d shorter in G-CSF group and this difference was statistically significant (P = 0.0014; P = 0.0001). In terms of antibiotic and antimycotic requirements, gastrointestinal toxicity, days of hospitalization, and transfusion requirements, no differences were demonstrated between the two groups. No statistically significant difference was demonstrated for the total number of febrile episodes (52 for group 1; 53 for group 2; P = 0.623) and the median number of febrile days (2 d for both groups). Myeloid reconstitution values for both groups agree with published results for autotransplanted patients treated with G-CSF from 7 to 14 d. Also, major clinical events, antibiotic, antimycotic, and transfusion requirements, and hospital stay were similar to published findings. Our data suggest that G-CSF administration can be safely optimized, used only for patients infused with a suboptimal CD34(+) cell dose.

No Polarization of Type 1 or Type 2 Precursor Dendritic Cells in Peripheral Blood Stem Cell Collections of Non-Hodgkin's Lymphoma Patients Mobilized with Cyclophosphamide Plus G-CSF, GM-CSF, or GM-CSF Followed by G-CSF

Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a role in immune reconstitution after autologous transplantation. Recent reports suggest that mobilization with granulocyte colony-stimulating factor (G-CSF) containing regimens polarizes DCs into pDC2, which could potentially result with increased Th2 response and decreased graft-versus-host disease (GVHD) in allogeneic transplantation and with decreased cytotoxic Th1 response and graft versus tumor effect, which in autologous transplantation could translate into increased relapse rate. Previously, we have shown that non-Hodgkin's lymphoma (NHL) patients receiving cyclophosphamide (CTX) plus granulocyte- macrophage (GM)-CSF, G-CSF or GM-CSF followed by G-CSF for stem cell collection, mobilize up to five-fold more mature CD80(+) DCs compared to CTX plus G-CSF mobilized patients. Here, we analyzed samples from the same study for the number of pDC1 and pDC2 subsets in blood and apheresis products obtained from these patients. Samples from 29 patients were collected. Patients mobilized with CTX plus G-CSF collected a mean of 1.2 +/- 0.4 x 10(6) pDC1/kg per day and 2.2 +/- 1 x 10(6) pDC2/kg per day, whereas patients mobilized with CTX plus GM-CSF collected a mean of 1.1 +/- 0.5 x 10(6) pDC1 and 1.5 +/- 0.9 x 10(6) pDC2/kg per day. Patients mobilized with CTX plus GM-CSF followed by G-CSF collected 2.5 +/- 1.1 x 10(6) pDC1 and 2 +/- 0.5 x 106 pDC2/kg per day, with significantly higher levels of pDC1 +/- pDC2 cells. No significant difference was observed in pDC1/pDC2 ratio between the three mobilization arms. Patients mobilized with the GM-CSFcontaining regimen had a higher probability for survival compared to patients receiving G-CSF alone (median of 55 months vs. 15 months; p = 0.02). These results support the hypothesis that higher levels of DCs in the graft might be associated with prolonged survival of autotransplanted NHL patients. Further similar studies are merited in a larger population of NHL patients.

Cellular Composition of Allogeneic and Autologous PBPC Grafts and Patient Engraftment.

We studied the influence of graft populations on the hematological recovery of PBPC transplants. The data shown is a retrospective study of 36 patients (median age 41, range 16–67) who underwent allogeneic transplant from HLA-matched siblings and 29 patients (median age 25, range 20–68) who underwent autologous PBPC transplants between June 2002 and July 2005. The cell populations studied were: total nucleated cells (TNC), CD34+ cells, T cells (CD3+) and NK cells (CD3−/CD56+). The hematological engraftment was evaluated by the following parameters: time to absolute neutrophil count (ANC)>0.5x109/L, platelets>20x109/L, absolute lymphocyte count (ALC)>0.5x109/L and ALC at day +15. The median cell doses infused in patients are summarised in Table 1Table 1-PBPC cell population infused per Kg of patient body weightTNC x 108CD34+ cells x 106T cells x 108NK cells x 106Allogeneic12.8 *7.53.236.83.6 – 30.7 **3.4 – 10.50.7 – 9.84.2 – 136.6Autologous123.263.5294.1– 51.02.2 – 7.00.1– 0.47.4 – 351*median **rangeSpearman correlation analysis showed for the allogeneic PBPC grafts, correlation between TNC and NK cells collected (p=0.002), whereas for the autologous grafts there was correlation between TNC and NK cells (p=0.000) and CD34+ cells (p=0.004) collected.To asses the importance of cell dose infused in the hematologic engraftment of the two patient groups, neutrophil, platelet and lymphocyte recovery was determined (Table 2).Table 2-Patient engraftmentDay to ANC>0.5x109/LDay to platelets>0.2x109/LDay to ALC>0.5x109/LALC day +15 cell/μlAllogeneic11 *12117158 – 15 **8 – 292 – 14190 – 4670Autologous11111211787 – 138 – 1810 – 21230 – 4410*median **rangeFor both groups of patients, engraftment occurred within the expected time and ALC day +15 cell/μl was different (median 715 cell/μl and 1178 cell/μl for allogeneic and autotransplanted patients respectively).For the allogeneic transplanted patients, Spearman correlation analysis showed that the dose of NK cells infused was significantly correlated with ALC at day +15 (p=0.021). There was also correlation between the time to platelets and ANC engraftment (p=0.008) and time to platelets engraftment and ALC at day +15 (p=0.046).For the autologous patients there was no correlation between cell populations of the grafts and the hematologic engraftment. Our data provide evidence that in allogeneic transplants the NK dose influences early ALC recovery. However, it is important to continue this study to balance the importance of cell population doses both in allogeneic and autologous transplants.

Peripheral blood stem cell contamination evaluated by a highly sensitive molecular method fails to predict outcome of autotransplanted multiple myeloma patients.

To evaluate the clinical impact of minimal residual disease in multiple myeloma, apheretic products from 51 autotransplanted patients were tested by fluorescent (GeneScan) polymerase chain reaction (PCR). Sixty-nine per cent of harvests were contaminated when evaluated for IgH rearrangement. Forty-six patients responded to transplant, with 52.9% achieving complete response (CR). The clinical response of patients was significantly influenced by the number of re-infused CD34+ cells. Positive PCR results of re-infused harvests were not significantly related to patient outcome. Median overall survival (OS) was 33 months, and a significant advantage for patients transplanted by 12 months from diagnosis was observed. Moreover, OS was longer for patients receiving PCR-negative stem cells, with 72% of patients surviving to 70 months in the group receiving PCR-negative harvests vs 48% in the group transplanted with contaminated precursors (not statistically significant). Ex vivo purging caused a reduction of contamination of up to 3 logs; nevertheless, 80% of purged harvests remained PCR-positive and the purging procedure did not alter response or survival rates. Thus, the failure of a predictive role for this highly sensitive molecular method could be explained by the assumption that in vivo persisting malignant cells are the true source of relapse in MM.

Markers of endothelial function in pediatric stem cell transplantation for acute leukemia.

Endothelial cells and leukocytes intimately interact in inflammation and coagulation processes, so that dysregulation of their function may lead to both cellular damage and thrombosis, which may occur as complications of bone marrow transplantation (BMT). Partially conflicting evidence about endothelial markers and their relationships with clinical complications after BMT has been reported in the literature. Since almost all studies were carried out in adults, we evaluated some recent available markers of endothelial cell function in pediatric patients undergoing stem cell transplantation (SCT) for acute leukemia. We studied the variation in circulating serum endothelial-selectin (ES), leukocyte-selectin (LS), thrombomodulin (TM), von Willebrand factor (vWF), nitrate + nitrite (NO(2) (-)/NO(3) (-)), endothelin-1 (EN), and tissue factor (TF) in 21 pediatric patients undergoing SCT for acute leukemia. ES and LS significantly lowered following SCT and returned to pre-SCT levels 4 weeks after the procedure. NO(2) (-)/NO(3) (-) markedly increased following SCT. Also, TM and vWF increased, although such changes did not reach statistical significance. EN and TF did not appreciably change. A strong correlation was observed between white blood cell (WBC) count and both ES and LS, as well as between such selectins. TM significantly correlated with both selectins and NO(2) (-)/NO(3) (-). The pre-conditioning levels of TM and vWF in patients undergoing major complications, considered altogether, were significantly lower and higher, respectively, than in uncomplicated patients. NO(2) (-)/NO(3) (-) levels 3 and 4 weeks post-SCT were significantly lower in patients suffering from veno occlusive disease. Both selectins were significantly higher in allo- than in auto-transplanted patients 4 weeks after SCT. Our data support the hypothesis of severe endothelial damage after conditioning and SCT, particularly allogeneic. However, the increase in TM, which has strong anticoagulant properties, and metabolites of NO, involved also in protective actions, may reflect regeneration of the anti-thrombotic endothelial function. This could take place after transitory functional impairment, rather than pure endothelial damage.

Total parathyroidectomy without autotransplantation as a standard procedure in the treatment of secondary hyperparathyroidism.

Total parathyroidectomy with autografting of parathyroid tissue and subtotal resection of the parathyroid glands are currently considered as standard surgical procedures for the treatment of severe secondary hyperparathyroidism. However, a considerable recurrence rate following these procedures ranges from 5% to 80%. We present a retrospective analysis of the results of parathyroidectomy with autotransplantation to the forearm versus parathyroidectomy alone. We analyzed the clinical course of 11 consecutive patients who had undergone parathyroidectomy between 1995 and 1999, and who were not simultaneously autografted. Controls were 11 patients in whom autotransplantation of parathyroid tissue into the forearm had been routinely performed between 1993 and 1996 at our institution. Clinical symptoms and recurrence of hyperparathyroidism were assessed for comparison of the alternative treatment modalities. Recurrence of disease was defined by elevated parathormone (PTH) levels (>7.6 pmol/l) with clinical symptoms and/or need for reoperation. No recurrence of hyperparathyroidism was observed in patients without autotransplantation after a mean follow-up of 23 months (range 1-49). Measurement of intact serum PTH revealed residual PTH secretion even after removal of four glands (mean 2.02 pmol/l). Clinical symptoms improved substantially after surgery. In the historical control group 3 of the 11 autotransplanted patients (27%) required resection of transplanted tissue. Additionally, two patients (18%) presented with increased PTH secretion and clinical symptoms of recurrent hyperparathyroidism during follow-up. Thus, a total of five patients (45%) experienced relapsing hyperparathyroidism caused by the implanted tissue. Total parathyroidectomy without autotransplantation is a safe procedure with a low rate of recurrent hyperparathyroidism when compared to parathyroidectomy with autotransplantation to the forearm in a historical control. These preliminary results mandates further investigations including a randomized trial.

Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: Long-term follow-up of grafted parathyroid function

Background: Permanent hypoparathyroidism is a major complication of thyroidectomy. Autotransplantation of parathyroid glands has been attempted to prevent this complication. However, no direct data have been available to assess grafted parathyroid function after long-term follow-up in terms of the serum intact parathyroid hormone (PTH) concentration. Methods: Eighty-four consecutive patients with differentiated thyroid carcinoma who underwent total thyroidectomy and bilateral modified neck dissection from 1992 to 1996 were enrolled. They concomitantly underwent total parathyroidectomy and autotransplantation of all parathyroid glands to the pectoralis major muscle. The serum intact PTH concentration was periodically measured as an index of grafted parathyroid function. Results: The mean follow-up was 34 months. In all autotransplanted patients serum intact PTH concentrations fell below detectable limits immediately after surgery. They were restored to the normal range within 1 month postoperatively and were maintained during observation in 80 (95%) of 84 patients. Seventy-eight of 80 patients with normal intact PTH values were normocalcemic without any treatment and the remainder were normocalcemic with 1 μg of 1α-vitamin D3. Four hypoparathyroid patients were normocalcemic with 2 μg of 1α-vitamin D3. The postoperative average serum intact PTH concentration of patients having more than 2 autotransplanted parathyroid glands was almost equal to that of patients with preservation of the parathyroid glands in situ. The incidence of permanent hypoparathyroidism was inversely correlated with the number of autotransplanted parathyroid glands. Conclusions: The recovery patterns of the intact PTH concentration indicate that the glands were grafted successfully and functioned for a long period. This feasible method of parathyroid autotransplantation bears comparison with the previous reports in terms of the incidence of permanent postoperative hypoparathyroidism, and it can be performed simply and is reproducible. (Surgery 1999;125:504-8.)

Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: Long-term follow-up of grafted parathyroid function

Background: Permanent hypoparathyroidism is a major complication of thyroidectomy. Autotransplantation of parathyroid glands has been attempted to prevent this complication. However, no direct data have been available to assess grafted parathyroid function after long-term follow-up in terms of the serum intact parathyroid hormone (PTH) concentration. Methods: Eighty-four consecutive patients with differentiated thyroid carcinoma who underwent total thyroidectomy and bilateral modified neck dissection from 1992 to 1996 were enrolled. They concomitantly underwent total parathyroidectomy and autotransplantation of all parathyroid glands to the pectoralis major muscle. The serum intact PTH concentration was periodically measured as an index of grafted parathyroid function. Results: The mean follow-up was 34 months. In all autotransplanted patients serum intact PTH concentrations fell below detectable limits immediately after surgery. They were restored to the normal range within 1 month postoperatively and were maintained during observation in 80 (95%) of 84 patients. Seventy-eight of 80 patients with normal intact PTH values were normocalcemic without any treatment and the remainder were normocalcemic with 1 μg of 1α-vitamin D 3. Four hypoparathyroid patients were normocalcemic with 2 μg of 1α-vitamin D 3. The postoperative average serum intact PTH concentration of patients having more than 2 autotransplanted parathyroid glands was almost equal to that of patients with preservation of the parathyroid glands in situ. The incidence of permanent hypoparathyroidism was inversely correlated with the number of autotransplanted parathyroid glands. Conclusions: The recovery patterns of the intact PTH concentration indicate that the glands were grafted successfully and functioned for a long period. This feasible method of parathyroid autotransplantation bears comparison with the previous reports in terms of the incidence of permanent postoperative hypoparathyroidism, and it can be performed simply and is reproducible. (Surgery 1999;125:504-8.)

Quantitative and functional restorations and alterations of peripheral lymphocytes in patients with autologous spleen implantation

To reduce the risk of severe infections in splenectomized patients, new methods for splenic preservation or heterotopic autologous spleen implantation have been established. In the latter case, the immunological and functional benefits are still under discussion. In this study we compared immunological parameters in 16 splenectomized patients with and without heterotopic autologous spleen implantation with a nonsplenectomized control group. The total lymphocyte counts--T-cells, CD4+ -, as well as CD8+ - lymphocytes, CD16+ - and B-cells--were highly elevated in both groups, whereby the B-cells were relatively and absolutely higher in the implanted group than in the nonimplanted group. Splenectomized patients had a significantly reduced serum IgM level. The serum IgM of patients with splenic autotransplantation was not significantly lower than that of the controls. In contrast to the impaired in vitro immunoglobulin synthesis in the splenectomized group, the autotransplanted patients showed a normal PWM-induced IgG and IgM synthesis and an increased IgA production compared with the controls. The latter results support the findings of elevated serum IgA levels in this group. The mitogenic-induced proliferation with PHA, ConA, PWM, and OKT3 was not clearly different within the tested groups. The results may indicate a benefit of autologous spleen implantation in regard to the humoral immune response.