Late-onset Post-transplant Lymphoproliferative Disorder Research Articles

Post-Transplant Lymphoproliferative Disorder in Lung Transplant Recipients – a Shift Lo Late Onset Disease

AbstractAbstract 5075 Background:Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication after solid organ transplantation. Most cases of PTLD arise within the first year from transplantation and are associated with EBV infection. However, there are increasing reports on a late onset form of PTLD. Methods:We reviewed all charts of patients undergoing either lung or heart-lung transplantation in a tertiary center in Israel between the years 1997 and 2012. PTLD was defined according to the WHO criteria. We analyzed baseline characteristics, clinical and pathological parameters as well as transplantation outcomes. Results:We identified 9 PTLD patients among cohort of 336 lung and heart-lung transplant recipients (incidence=2. 7%). Additional PTLD patient from another hospital was added for the clinical analysis (10 patients overall). Median age at transplantation of the PTLD patients was 50 (range 11–63) years, compared to 56 (2–69) among the non-PTLD patients (p=0. 04). Idiopathic pulmonary fibrosis was the leading etiology for transplantation among both PTLD and non-PTLD patients (50% vs. 37. 2%, respectively, p=0. 5), while relatively less COPD patients were observed among PTLD patients (10% vs. 34%, respectively, p=0. 28). Median time from transplantation to PTLD diagnosis was 41 (range 3–128) months, being among the longest to be reported in the literature among lung transplant recipients. Three patients developed early PTLD in our cohort, all were pre-transplant EBV seronegative and all were asymptomatic, diagnosed during surveillance chest imaging. In contrast, the seven late-onset PTLD cases were all EBV seropositive prior to transplantation, and were diagnosed after presenting with various symptoms, mainly B symptoms (71%). Overall extra-nodal involvement at presentation was very common for both PTLD forms (90%). While early onset PTLD uniformly involved the transplanted lung, this was relatively rare in the late-PTLD (100% vs. 14%, p=0. 03). According to the WHO classification, all PTLD specimens were monoclonal, based on molecular or light chain immuno-histochemistry. Eight (80%) cases were CD20 positive B cell lymphomas. EBV staining in the specimens was positive in 7 patients, including the 3 early-onset PTLD cases.All patients were treated with reduction of immunosuppression (Table). Other treatment modalities were diverse, including combination chemotherapy (6 patients), rituximab (6 patients), surgery (1 patient) and antiviral treatment (2 patients). 8 (80%) patients attained complete remission. With a median follow-up of 23 months, 6 patients died (3 from chronic rejection of the transplant, 1 from late chemotherapy toxicity, 1 from disease progression and 1 from unrelated cause). The median time from PTLD diagnosis to death was 19 months. Of the 8 patients attaining complete remission, only three patients are alive at the end of follow-up. Conclusion:Our cohort of lung transplant recipients demonstrates a trend of late-onset PTLD. This might be related to the high pre-transplant sero-prevalence to EBV in our cohort (96. 3%), as late-onset PTLD has been reported to be less associated with EBV proliferation. The majority of PTLD patients in our cohort died of treatment-related causes rather than disease progression.OutcomeStatus at end of treatmentTreatment givenHistologyStageExtranodal involvementPrimary site of involvementPresenting symptomsTime from transplantation to PTLD Dx (months)Age at transplantationSexCaseAliveCRRIS, RituximabMonoclonal PTLDIEYesTransplanted lungNone311F1AlivePDRIS, RituximabDLBCLIVEYesTransplanted lung, GITNone421F2DeadCRRIS, surgery, AcyclovirDLBCLIEYesTransplanted lungNone1049M3DeadCRRIS, AcyclovirDLBCLIEYesColonAbdominal pain, GI bleeding1863M4DeadCRRIS, R-CHOPDLBCLIEBYesTransplanted lungB symptoms, cough1860F5AliveCRRIS, R-CHOPDLBCLIIIAYeslymph nodesBack pain6453F6DeadPDRIS, CHOPPlasmabalstic lymphomaIEYesChest wallPalpable mass8926F7DeadCRRIS, GMALL 2002 protocol+rituximabDLBCLIVBYesBone marrowB symptoms, bone pain9153M8AliveCRRIS, R-CHOPDLBCLIEAYesStomachAbdominal pain10852M9DeadCRRIS, CHOPAnaplastic T cell lymphoma, ALK negativeIIIBNolymph nodesB symptoms, neck pain12815M10 Disclosures:No relevant conflicts of interest to declare.

EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

Serial EBV load monitoring of clinically asymptomatic pediatric thoracic organ transplant patients has identified three groups of children who exhibit undetectable (<100 copies/ml), chronic low (100-16,000 copies/ml), or chronic high (>16,000 copies/ml) EBV loads in peripheral blood. Chronic high EBV load patients have a 45% rate of progression to late-onset posttransplant lymphoproliferative disorders. In this article, we report that asymptomatic patients carrying EBV loads (low and high) expressed increased frequencies of EBV-specific CD8(+) T cells, as compared with patients with undetectable EBV loads. Although patients with low viral load displayed EBV-specific CD8(+) T cells with moderate signs of activation (CD38(+/-)/CD127(+/-)), programmed death 1 upregulation and effective IFN-γ secretion, high EBV load carriers showed significant CD38(+) upregulation, features of cellular exhaustion (programmed death 1(+)/CD127(-)) accompanied by a decline in IFN-γ release. Immunopolarization of EBV-specific CD8(+) T cells was skewed from the expected type 1 (IFN-γ) toward type 0 (IFN-γ/IL-5) in patients, and Tr1 (IL-10) in high load carriers. These results indicate the importance of chronic EBV load and of the levels of antigenic pressure in shaping EBV-specific memory CD8(+) T cells. Concomitant phenotypic and functional EBV monitoring is critical for identifying the complex "functional" versus "exhausted" signature of EBV-specific CD8(+) T cells, with implications for immunologic monitoring in the clinic.

Very late onset lymphoproliferative disorders occurring over 10 years post-renal transplantation: PTLD.Int. Survey

Knowledge of the significance of post-transplant lymphoproliferative disorders (PTLD) that occur "very late" or more 10 years after renal transplantation is limited. thus, we analysed and compared characteristics and prognosis of the disease in renal transplant patients with very late onset PTLD vs. early- and late-onset PTLD. Retrospective study of data obtained from comprehensive search of medical literature We searched for available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders occurring in renal transplant patients by disease presentation time. We analyzed data from 27 studies that included 303 patients with lymphoproliferative disorders after renal transplantation. Renal graft recipients with very late onset PTLD were significantly less likely to be under mycophenolate mofetil (MMF)- and/or tacrolimus (FK-506) (vs. azathioprine) -based immunosuppression (P=.035) and less likely to have a history of antibody induction immunosuppression (P<.001). Compared to "early onset" disease, "very late" onset PTLD is more likely to develop in older patients (P=.032). Survival analysis did not show any difference in outcome (P=.5). no organ involvement priority was found for this patient group (P>.1 for all). Older renal transplant patients are at increased risk for development of very late onset PTLD, and should be strictly followed. further multi-institutional prospective studies are needed to confirm our results.

Risk factors for early‐onset and late‐onset post‐transplant lymphoproliferative disorder in kidney recipients in the United States

Solid-organ transplant recipients have an elevated risk for some malignancies because of the requirement for immunosuppression [1]. In particular, non-Hodgkin's lymphoma (NHL) is common and comprises one end of a spectrum of post-transplant lymphoproliferative disorder (PTLD) ranging from benign hyperplasia to lymphoid malignancy [2]. PTLD risk is influenced by the type of organ transplanted, the age and Epstein-Barr virus (EBV) serostatus of the transplant recipient, and the intensity of immunosuppression [3-9]. PTLD incidence is high immediately after transplantation, decreases subsequently, and then rises again 4-5 years from transplantation [10,11]. This incidence pattern suggests the presence of separate early-onset and late-onset PTLD subtypes. Early-onset PTLDs tend to be EBV-positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ [12,13]. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal [13,14]. The Scientific Registry of Transplant Recipients (SRTR) includes data on a large number of solid-organ transplant recipients in the United States and information on malignancies diagnosed post-transplantation. We used these data to conduct a retrospective cohort study among kidney transplant recipients to examine differences in risk factors between early-onset PTLD and late-onset PTLD.

Immunologic and Virologic Analyses in Pediatric Liver Transplant Recipients with Chronic High Epstein‐Barr Virus Loads

Long-term Epstein-Barr virus (EBV) monitoring for potentially life-threatening posttransplant lymphoproliferative disorder (PTLD) has identified asymptomatic patients who maintain high EBV loads over long periods. Thirty-one pediatric liver transplant recipients were designated as 11 chronic high EBV load carriers (EBV DNA level >5000 copies/mL of whole blood for >6 months) and 20 control recipients. Serial quantification of EBV DNA, measurement of interleukin 10 (IL-10) concentrations, EBV-specific tetramer staining, and relative quantification of EBV gene expression in peripheral blood mononuclear cells were performed. Most of the chronic high EBV load carriers were seronegative at transplant, the median time to resolution of a chronic high EBV load was 23 months, and no recipient developed late-onset PTLD. EBV DNA was detected predominantly in CD19(+) cells. The plasma concentration of IL-10 and the EBV-specific CD8(+) cell frequency did not differ significantly between the chronic high EBV load carriers and the control recipients. Analysis of gene expression showed that EBV-encoded small RNA 1, BamHI A rightward transcripts, and latent membrane protein 2 were positive in peripheral blood mononuclear cells from chronic high EBV load carriers. EBV-infected cells in the blood of chronic high EBV load carriers expressed a highly restricted set of latency genes, suggesting that the EBV-infected cells escaped from a T cell response.

Post-transplant lymphoproliferative disorder after adult-to-adult living donor liver transplant: case series and review of literature

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplant. Although living donor liver transplant (LDLT) has been increasingly performed, PTLD after LDLT has not been well investigated. We aimed to determine the clinical characteristics of PTLD after LDLT. We investigated 323 consecutive patients undergoing adult-to-adult LDLT and identified three patients who developed biopsy-proven PTLD. All of them were seropositive for Epstein–Barr virus (EBV) and had hepatitis C virus-related cirrhosis at transplant. All three patients developed late-onset and monomorphic PTLD, including one diffuse large B-cell lymphoma and two Burkitt lymphomas with c-myc rearrangement. Two of them were EBV negative. The initial therapy included chemotherapy, rituximab, and immunosuppression withdrawal. One patient died of sepsis during treatment and two patients achieved complete responses. We showed a relatively low incidence and distinct clinicopathological features of PTLD after adult-to-adult LDLT, which might reflect the unique nature of LDLT.

Post‐transplant lymphoproliferative disorder following renal transplantation: A single‐center experience over 40 years

To investigate post-transplant lymphoproliferative disorder (PTLD) following renal transplantation at our institution. Medical records of 631 patients who underwent renal transplantation at Osaka University Hospital between March 1965 and December 2008 were reviewed. PTLD following renal transplantation was detected in 10 patients (five men, five women; mean age at transplantation, 38.5 years). Mean duration from renal transplantation to the onset of PTLD was 7.1 years (range, 5 months to 18 years, 9 months). Mean duration of observation was 3.9 years from the onset of PTLD. Immunosuppressant therapy comprised multidrug combination therapy, including cyclosporine in six patients and tacrolimus in four patients. In addition to a reduction in the immunosuppressant dose, which was performed in all patients, PTLD was treated with surgery in seven patients, radiotherapy in two patients, rituximab in five patients, and cytotoxic chemotherapy in four patients. A complete remission in eight patients and progressive disease in two were observed. At last follow up, seven patients were alive and five patients had functioning grafts. The incidence of PTLD following renal transplantation at our institution is 1.6% with onset occurring more than 5 years after transplantation in five patients. Consequently, with long-term renal graft survival now feasible, attention must be paid to detecting late-onset PTLD.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Reduction of Immunosuppression and Subsequent Rituximab Monotherapy or CHOP-Based Chemotherapy +/− Rituximab as a Treatment for PTLD Does No Impair the Renal Graft Function: A Matched Pair Control Analysis in 55 Renal Transplant Recipients with PTLD and 1075 Renal Transplant Controls

Purpose: Post transplant lymphoproliferative disorder (PTLD) is a serious and often devastating complication after solid organ transplantation. The initial therapeutic action is reduction of immunosuppression (IR). Patients not responding to IR usually are treated with rituximab monotherapy and/or CHOP-based chemotherapy. The impact of treatment on the renal graft function is to be analyzed.Methods: A retrospective data analysis was performed on adult renal transplant recipients with PTLD requiring further therapy after failing to respond to IR. All patients gave their informed consent to this study and all had been treated within one of the prospective German PTLD Study Group protocols: PT-LPD-1 (rituximab monotherapy), PTLD-1 (sequential treatment with rituximab and CHOP chemotherapy) or PTLD D2006–2012 (different treatment protocols). Renal graft function was analyzed 6 months (6m) before, during and up to 2 years after treatment of PTLD. From our renal transplant database altogether 1075 transplant recipients that had transplantation between January 1998 and June 2008 served as a control. Controls were matched for sex, patient age, transplant age and transplant function at time of diagnosis of PTLD.Results: Median age at diagnosis of PTLD was 49 years. 38/55 pts. were male, 43/55 had late onset PTLD. 53/55 had B-cell PTLD: 2 polymorphic, 37 aggressive B-cell, 3 Hodgkin or Hodgkin-like PTLD and 11 others. 2/55 had T-cell PTLD. 34/55 had an advanced stage of disease and 26/51 had elevated LDH levels. 1 patient had renal graft involvement. Renal transplantation for endstage renal disease was either due to autoimmune disorders (26/55), to diabetes (4/55), to cystic renal degeneration (5/55) or to metabolic dysfunction (1/55, 19 others). At diagnosis of PTLD 10 patients were on calcineurin-inhibitor (CNI) therapy only, 16 were on CNI plus mycophenolate mofetil (MMF), 13 were on CNI plus azathioprin (AZA), 4 were on CNI plus mTor-inhibitor, 4 were on mTor-inhibitor plus MMF or AZA and 7 were on single agent immunosuppression with MMF, AZA or prednisone. Immunosuppression was reduced in all patients immediately after diagnosis of PTLD. 15/55 patients received further therapy with single agent rituximab, 40/55 patients received CHOP or CHOP-like chemotherapy +/− rituximab. 36/53 (68%) patients reached a complete remission (CR). At a median follow up of >2 years 4 patients relapsed and 17 died: 5 from PTLD, 7 from infections, 1 from myocardial infarction and 3 of unknown reason. Matching criteria were equally distributed in the patient and control group. After successful treatment of PTLD 4 of 38 PTLD survivors (10%) had failed renal allografts and recommenced hemodialysis: 1 due to a haemolytic uremic syndrom, 1 due to acute renal failure after a septic complication, 2 due to chronic transplant dysfunction. With a mean transplant age of 6.2 years transplant survival at 1 year after diagnosis of PTLD is 92% in the stable CR group. In a longitudinal analysis in 27 and 44 patient pairs evaluable not requiring hemodialysis we found a drop in eGFR values from 50.9 ml/min 6m before diagnosis of PTLD to 46.8 ml/min at time of diagnosis of PTLD that was statistically significant (p=0.04) suggesting a negative impact of the lymphoma (and/or of IR) to the graft function. With treatment of PTLD the graft function improved up to a mean eGFR of 56.3 ml/min 4 weeks after completing therapy (p=0.014). In subsequent subgroup analyses we found this effect to be restricted to and more durable in patients that had been treated with chemotherapy resulting in an eGFR of 57.6 ml/min, 55.7 ml/min and 58.6 ml/min 4 weeks, 6 months and 12 months after therapy, respectively. The graft function in this subgroup of patients was even superior to controls (p=0.012 at 6m, p=0.004 at 12m), which may result from the immunosuppressive effect of chemotherapy.Conclusion: PTLD may be associated with a worsening of graft function in renal transplant recipients but the graft often ameliorates during therapy. Beside rare acute complications like acute renal failure during septic complications there is no evident negative impact of therapy on renal graft function with rituximab and chemotherapy based 1st-line protocols in PTLD. Transplant survival in the disease free survival group is excellent.

Post Transplant Lymphoproliferative Disorders (PTLD): Prevalence, Clinical Features and Outcome.

PTLD is a life threatening complication developing in 1–5% of transplant (Tx) recipients. Epstein Barr (EBV), Cytomegalovirus (CMV) and immunosuppression (IS) were identified as risk factors. Aggressive evolution and therapy related toxicity generate poor prognosis. We retrospectively analyzed data from 18 PTLD patients (pts) diagnosed at our hospital between March 1994- June 2007. All of them were at least one graft recipient and were under IS.RESULTS: Out of 1206 adult Tx recipients, 18 (1,5%) developed PTLD. Ninety-four percent were men, mean age 42,9 years (range: 18–72). Our study comprises 10 heart, 2 kidney, 2 lung, 1 heart-lung, 1 liver and 2 non related allogeneic bone marrow (BM) recipients. IS protocols included Cyclosporin A (16 pts), Azathioprine (8), Mycophenolate mofetil (7), Tacrolimus (4) and antitymocyte globulin (2). Pretx recipients serology for EBV and CMV were positive in 87 and 94% respectively. Sixty-six percent (12/18) disclosed late onset PTLD (median 49 months), all of them were solid organ (SO) recipients. BM recipients developed the disease within the first 6 months after Tx. Fifty percent presented extranodal involvement, 3/18 with BM infiltration and 3/18 showed lymphoma in the graft. Histologycal findings: 15/18 B cell lymphoma (8/15 large cell lymphoma), 1 peripheral T cell lymphoma, 1 early lesion infectious mononucleosis-like PTLD, 1 polymorphic hyperplasia PTLD. Immunophenotype: 89% were CD20+. Fifty percent of the group achieved response, 7/9 with complete response(CR). Three/9 pts obtained CR with reduction of IS alone.Treatment included Rituximab (63% pts), CHOP (56%) and radiotherapy (25%). Eleven/18 pts died, 4 due to disease progression, 6 by sepsis and 1 because of underlying hematological disease relapse.CONCLUSIONS: In our experience, PTLD was an uncommon complication. The late onset of the disease was the most frequent form of presentation among SO recipients. B cell lymphoma was the main diagnosis (83%). Fifty percent (9/18) achieved response and 78% of them showed CR. Disease progression and sepsis were the most important causes of death.

Evidence for Genetic Susceptibility Towards Development of Posttransplant Lymphoproliferative Disorder in Solid Organ Recipients

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after organ transplantation. The identification of risk factors for PTLD development is important for disease management. It has been shown that cytokine gene polymorphisms are associated with lymphoma and Epstein-Barr virus (EBV)-associated diseases in nonimmunosuppressed patients. In the present case-control study, we analyzed the impact of -1082 interleukin (IL)-10, -308 tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 (codon 10, 25), and +874 interferon (IFN)-gamma gene single-nucleotide polymorphisms on the late onset EBV-associated PTLD. Out of 1,765 solid organ recipients, 38 patients with late-onset EBV-associated PTLD and 408 matched solid organ recipients were selected and enrolled in the study. Single nucleotide polymorphisms (SNPs) for -1082IL-10, -308TNF-alpha, TGF-beta1 (codon 10, 25), and +874IFN-gamma genes were analyzed by a sequence specific primer polymerase chain reaction and were related to the PTLD development, and the disease course and outcome. The TGF-beta1 (codon 25) GG genotype was detected more frequently in controls than in PTLD patients (odds ratio=0.34, 95% confidence interval: 0.17-0.69, P=0.0022). The frequency of -1082 IL-10 GG genotype was also significantly higher in controls than in PTLD patients (odds ratio=0.5, 95% confidence interval: 0.25-1.0, P=0.044). There were no associations between -308TNF-alpha, TGF-beta1 codon 10, and +874IFN-gamma SNPs and PTLD. Disease course and outcome were not associated with any cytokine SNPs. Polymorphisms in two key anti-inflammatory cytokines, IL-10 and TGF-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.

Post-Transplant Lymphoproliferative Disorders Occurring After Renal Transplantation in Adults: Report of 230 Cases From the French Registry

Post-transplant lymphoproliferative disorders (PTLD) are a rare but serious complication after organ transplantation. A French Registry of PTLD was set up in a nationwide population of kidney transplant recipients. We prospectively enrolled all adult kidney recipients developing PTLD between January 1, 1998, and December 31, 2003. We analyzed the incidence, risk and prognostic factors of PTLD by Kaplan-Meier and Cox analyses. Totally 230 cases of PTLD were referred to the French Registry. Cumulative incidence was 1.18% after 5 years. Older age (per year, AHR = 2.19, CI = 1.22-3.94) and recipient Epstein-Barr virus seronegativity (AHR = 3.01, CI = 1.57-5.08) were associated with an increased risk of PTLD. Patients with PTLD had a reduced survival rate (61% at 5 years). Graft PTLD had the best prognosis with an 81% survival rate after 5 years. Infection with hepatitis C or B virus (HCV or HBV), late-onset PTLD, multiple sites involvement and high Ann Arbor staging were risk factors for patient death. Use of azathioprine was associated with a poorer survival rate. PTLD incidence and risk factors in French recipients are in line with the international or American PTLD series. We highlighted the role of HBV or HCV in patient mortality and described the relevant prognosis factors for patients with post-transplant lymphoproliferations.

Primary Nonresponse to Anti‐Cd20 Therapy in Gastrointestinal Posttransplant Lymphoproliferative Disorder

Primary Nonresponse to Anti‐Cd20 Therapy in Gastrointestinal Posttransplant Lymphoproliferative Disorder

Post‐transplant lymphoproliferative disorders after lung transplantation: first‐line treatment with rituximab may induce complete remission

Post-transplant lymphoproliferative disorders (PTLD) are potentially lethal complications of solid organ transplantation. We, here, report on our experience with rituximab, an anti-CD20 monoclonal antibody, as first-line treatment for PTLD in six lung transplant recipients. Two of the patients developed PTLD during the first year after transplantation, while four developed late-onset PTLD. One patient presented with PTLD localized to the graft, one had unilateral cervical lymph nodes, and the others presented with multi-organ involvement. All patients had diffuse large B-cell lymphoma. Immunosuppressive therapy was reduced and rituximab was administered at a dose of 375 mg/m(2)/wk for 4 wk. One patient did not respond to the first two courses of rituximab, received conventional chemotherapy, and achieved complete remission; four patients achieved complete remission after four courses with a median relapse-free survival of 34 months (range: 14-55); and one patient did not respond and died. The diagnosis of complete remission was established by conventional imaging techniques combined to whole-body positron emission tomography scan. We conclude that reduction in immunosuppression combined to first-line treatment with rituximab may induce long-term complete remission in lung transplant recipients presenting PTLD.

Epstein-Barr virus seronegativity is a risk factor for late-onset posttransplant lymphoroliferative disorder in adult renal allograft recipients.

Posttransplant lymphoproliferative disorder (PTLD) remains a difficult management issue; therefore, many studies focus on the identification of risk factors to allow for preventive strategies. We investigated risk factors for PTLD in the adult renal transplant setting. A single-center, matched case-control study design was used. Cases were identified from patients who underwent a first renal transplant between January 1, 1985, and December 1, 2001. Two controls were chosen per case, matched (+/-1 year) by date of transplant and graft survival. Clinical and demographic data were ascertained from medical records. Pretransplant serology for Epstein-Barr virus (EBV) and cytomegalovirus was confirmed on frozen, stored sera. Statistical analysis included univariate and multivariable examination of putative risk factors using conditional logistic regression. Twenty cases of PTLD were identified, an incidence of 2.4%. Median time from transplant to diagnosis was 55 months (range, 3-168 months), with 16 cases of late-onset PTLD (>1 year posttransplant). The only significant risk in univariate analysis was EBV-negative status at transplant (risk ratio 6.0, P=0.03). In multivariable analysis, EBV-negative status remained significant (adjusted risk ratio 8.9, P=0.01). The risk related to EBV status held true when late cases were analyzed separately (adjusted risk ratio 7.1, P=0.03). Pretransplant EBV-seronegative status is a strong risk for development of PTLD in adult renal allograft recipients, even in late disease. These results indicate that primary infection with EBV may have a pathogenic role in some cases of late PTLD.

Incidence and clinical characteristics of posttransplant lymphoproliferative disorders: report from a single center.

In the period 1973–1998, among 2 139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9 %): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy ± surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.

Clonus: the role of central mechanisms.

The peripheral and central components in sustained clonus were investigated. The excitability of the motoneurons responding to maintained stretch by clonus was examined by tendon taps, trains of vibratory stimuli and by H-reflex afferent volleys. Every burst of clonic discharge of the motoneurons was shown to be followed by a refractory period, which was followed by a shorter excitatory period. It was concluded that the motoneurons responding clonically to a continuous stretch cannot respond until their excitability has been regained after the refractory period. Attempts to change the rate of clonus in various ways failed to do so. Whether motoneurons of clonic muscles tend to respond maximally to other Ia volleys at the rate of clonus was examined by applying repeated taps to the tendon at rates from 1 to 15 Hz. There was a maximal response at the rate of clonus. Inputs other than those induced by stretch cause clonus; examples of cutaneous inputs causing it are given.