Nicolaas A. Bakker

Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation

Post‐transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent introduction of anti B‐cell monoclonal antibody therapy (rituximab) for treatment of PTLD, mortality rates remain high. Because PTLD often presents in a nonspecific way in clinically unsuspected patients, it is a major challenge to diagnose PTLD at an early stage. Epstein–Barr virus (EBV)‐DNA load monitoring is a promising tool for the identification of patients at risk for PTLD development. However, there are some limitations of this method, and not all patients at risk for PTLD can be identified by EBV‐DNA measurements alone. Therefore, it is of major importance to recognize early clinical signs and symptoms of PTLD. In this review, risk factors for PTLD development, disease presentation, and methods for early detection will be discussed. Special attention is given to allograft and digestive tract localization and the relation with time of onset of PTLD. The value and pitfalls of EBV‐DNA load monitoring are discussed. In addition, because fluorodeoxyglucose (FDG)‐positron emission tomography (PET) has shown to be a powerful tool for staging and response evaluation of malignant lymphoma, the role of FDG‐PET for early diagnosis and staging of PTLD is addressed.

Epstein-Barr virus-DNA load monitoring late after lung transplantation: A surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression

Background. Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006. Methods. From all patients visiting our outpatient clinic, EBV-DNA load was measured at least twice a year during the study period. In patients with positive results, measurements were repeated every two to four weeks. EBV reactivation was defined as two consecutive EBV-DNA load measurements with a rising trend; with the last measurement exceeding 10.000 copies/mL under stable immunosuppression. In such case, immunosuppression was reduced. Results. EBV reactivation was observed in 26/75 patients (35%). One (1.5%) of these patients developed PTLD during the study period. Acute rejection, acceleration of chronic allograft rejection, or worse survival were not observed after reduction of immunosuppression. Conclusions. Preemptive reduction of immunosuppression after lung transplantation guided by EBV-DNA load appears to be a safe approach for the prevention of PTLD in lung transplant recipients late after transplantation.

Early onset post-transplant lymphoproliferative disease is associated with allograft localization.

Abstract:  Post‐transplant lymphoproliferative disease (PTLD) is a major complication after solid organ transplantation. We analyzed incidence, patient characteristics, clinical presentation, and prognostic factors for treatment outcome and survival of PTLD patients transplanted at our center. Records from adult kidney and lung transplant recipients, transplanted between January 1985 and December 2002 with a histologically confirmed diagnosis of PTLD, were retrieved. Histology was reviewed and prognostic factors for treatment outcome were evaluated by multivariable analysis. Of 1354 kidney and 206 lung transplants, PTLD was diagnosed in 40 transplant recipients (2.6%). Lung transplant recipients had a significantly higher incidence of PTLD (8.3%) than kidney transplant recipients (1.7%). Sites of presentation were highly heterogeneous. Notably, PTLD localized in the allograft occurred significantly earlier after transplantation than PTLD localized outside the allograft (p = 0.001). This was true for lung (p = 0.006) as well as for kidney transplant recipients (p = 0.03). In multivariable Cox regression, performance status (p = 0.01) and advanced stage (p = 0.04) were factors negatively predictive for response to first‐line treatment. Only performance status remained as negative predictive factor for survival (p = 0.002) and freedom from tumor progression (p = 0.01). In conclusion, the allograft is significantly more often involved as primary site of PTLD presentation during the first post‐transplant year. This may have clinical consequences and give new insights in pathogenesis of PTLD. Performance status and stage are important risk factors for outcome of PTLD.

Chronic subdural hematoma: a systematic review and meta-analysis of surgical procedures

OBJECT In this paper the authors systematically evaluate the results of different surgical procedures for chronic subdural hematoma (CSDH). METHODS The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other databases were scrutinized according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, after which only randomized controlled trials (RCTs) and quasi-RCTs were included. At least 2 different neurosurgical procedures in the management of chronic subdural hematoma (CSDH) had to be evaluated. Included studies were assessed for the risk of bias. Recurrence rates, complications, and outcome including mortality were taken as outcome measures. Statistical heterogeneity in each meta-analysis was assessed using the T(2) (tau-squared), I(2), and chi-square tests. The DerSimonian-Laird method was used to calculate the summary estimates using the fixed-effect model in meta-analysis. RESULTS Of the 297 studies identified, 19 RCTs were included. Of them, 7 studies evaluated the use of postoperative drainage, of which the meta-analysis showed a pooled OR of 0.36 (95% CI 0.21-0.60; p < 0.001) in favor of drainage. Four studies compared twist drill and bur hole procedures. No significant differences between the 2 methods were present, but heterogeneity was considered to be significant. Three studies directly compared the use of irrigation before drainage. A fixed-effects meta-analysis showed a pooled OR of 0.49 (95% CI 0.21-1.14; p = 0.10) in favor of irrigation. Two studies evaluated postoperative posture. The available data did not reveal a significant advantage in favor of the postoperative supine posture. Regarding positioning of the catheter used for drainage, it was shown that a frontal catheter led to a better outcome. One study compared duration of drainage, showing that 48 hours of drainage was as effective as 96 hours of drainage. CONCLUSIONS Postoperative drainage has the advantage of reducing recurrence without increasing complications. The use of a bur hole or twist drill does not seem to make any significant difference in recurrence rates or other outcome measures. It seems that irrigation may lead to a better outcome. These results may lead to more standardized procedures.

International subarachnoid aneurysm trial 2009: endovascular coiling of ruptured intracranial aneurysms has no significant advantage over neurosurgical clipping.

In the May 2009 issue of The Lancet Neurology, the 5-year follow-up results of the International Subarachnoid Aneurysm Trial (ISAT) were published. The authors concluded that, although the significant difference between coiling and neurosurgical clipping of ruptured intracranial aneurysms in terms of death and severe disability after 1 year has vanished (primary endpoint), coiling should still be favored over neurosurgical clipping because mortality rates significantly favored coiling. In this commentary, it is this particular conclusion that is challenged by combining data from previous ISAT publications with the current 5-year follow-up results. This modified intent-to-treat analysis clearly demonstrates that the significant advantage in terms of mortality in favor of the endovascularly treated patients is no longer present, with a hazard ratio of 0.80 in favor of endovascular treatment (95% confidence interval: 0.60-1.05; P = .10). Therefore, for everyday clinical practice and decision making, coiling and clipping are to be considered equivalent in the long term.

Hla antigens and post renal transplant lymphoproliferative disease : HLA-B matching is critical

Although several risk factors for posttransplant lymphoproliferative disease (PTLD) after solid organ transplantation have been identified, the immunosuppressive regimen probably as most important one, their exact pathogenic role and relevance is still unclear. In hematopoietic stem cell transplantation, HLA mismatching also is a risk factor. We analyzed factors possibly associated with development of PTLD in patients receiving a kidney transplant at our hospital between 1985 and 2002. PTLD was observed in 20 out of 1,013 patients (2.0%). Mismatches at the HLA-B locus, but not at the HLA-A or HLA-DR loci, and anti T-cell antibody therapy were both independently associated with development of PTLD. Hazard ratios increased from 1.4 (0.5–4.1) with one mismatch to 5.1 (1.4–19.0) in case of two HLA-B mismatches. Decreased surveillance by T-cells with dual specificity for Epstein-Barr virus (EBV) as well as for allo HLA antigens on the allograft might facilitate clonal expansion of B-cells latently infected with EBV.

Immediate placement of dental implants in the esthetic zone: a systematic review and pooled analysis

BACKGROUND Research interest on immediate placement of dental implants has shifted from implant survival toward optimal preservation of soft and hard tissues. The aim of this study is to systematically assess the condition of implant survival, peri-implant hard and soft tissue changes, esthetic outcome, and patient satisfaction of immediately placed single-tooth implants in the esthetic zone. METHODS MEDLINE, EMBASE, and CENTRAL databases were searched for publications up to June 2013. Studies reporting on implant survival, changes in hard and soft peri-implant tissues, esthetic outcome, and patient satisfaction were considered. A pooled analysis was performed to identify factors associated with survival and peri-implant tissue changes after immediate implant placement. RESULTS Thirty-four studies were considered eligible. Immediate placement of single-tooth implants in the esthetic zone was accompanied by excellent 1-year implant survival (97.1%, 95% confidence interval [CI]: 0.958 to 0.980). Mean marginal peri-implant bone loss was 0.81 ± 0.48 mm, mean loss of interproximal peri-implant mucosa level was 0.38 ± 0.23 mm, and mean loss of peri-implant midfacial mucosa level was 0.54 ± 0.39 mm. Regression analysis revealed that delayed provisionalization (odds ratio [OR] 58.03, 95% CI: 8.05 to 418.41, P <0.000), use of a flap (OR 19.87, 95% CI: 10.21 to 38.66, P <0.000), and use of a connective tissue graft (OR 4.56, 95% CI: 1.72 to 12.08, P <0.002) were associated with marginal peri-implant bone-level change >0.50 mm. Because of underreporting, esthetic results and patient outcome did not allow for reliable analysis. CONCLUSION Immediate placement with immediate provisionalization of dental implants in the esthetic zone results in excellent short-term treatment outcome in terms of implant survival and minimal change of peri-implant soft and hard tissue dimensions.

Predictive Factors for Rebleeding After Aneurysmal Subarachnoid Hemorrhage: Rebleeding Aneurysmal Subarachnoid Hemorrhage Study

Background and Purpose— Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke associated with high morbidity and mortality. One of the most feared complications is an early rebleeding before aneurysm repair. Predictors for such an often fatal rebleeding are largely unknown. We therefore aimed to determine predictors for an early rebleeding after aSAH in relation with time after ictus. Methods— This observational prospective cohort study included all consecutive patients admitted with aSAH between January 1998 and December 2014 (n=1337) at our University Neurovascular Center. Clinical predictors for rebleeding ⩽24 hours were identified using multivariable Cox regression analyses. Kaplan–Meier analyses were applied to evaluate the time of rebleeding ⩽72 hours after aSAH. Results— A modified Fisher grade of 3 to 4 was a predictor for an in-hospital rebleeding ⩽24 hours after ictus (adjusted hazard ratio, 4.4; 95% confidence interval, 2.1–10.6; P<0.001). The numbers needed to treat to prevent 1 rebleeding ⩽24 hours was calculated 15 (95% confidence interval, 10–25). Also, the initiation of external cerebrospinal fluid-drainage (adjusted hazard ratio, 1.9; 95% confidence interval, 1.4–2.5; P<0.001) was independently associated with a rebleeding ⩽24 hours. Cumulative in-hospital rebleeding rates were 5.8% ⩽24 hours, and 1.2% in the time frame 24–72 hours after ictus. Conclusions— In our opinion, timing of treatment of aSAH patients, especially those with an modified Fisher grade of 3 or 4 in a good clinical condition, should be reconsidered. These aSAH patients might be regarded a medical emergency, requiring aneurysm repair as soon as possible. In this respect, our findings should provoke the debate on timing of aneurysm repair, especially in patients considered to be at high risk for rebleeding.

Feasibility of magnetic resonance angiography (MRA) follow-up as the primary imaging modality after coiling of intracranial aneurysms.

Background: Digital subtraction angiography (DSA) is still regarded as the gold standard for detecting residual flow in treated aneurysms. Recent reports have also shown excellent results from magnetic resonance angiography (MRA) imaging. This is an important observation, since DSA is associated with a risk of medical complications, is time consuming, and is more expensive. Purpose: To determine whether MRA could replace conventional DSA and serve as the primary postinterventional imaging modality in patients with coiled intracranial aneurysms. Material and Methods: We studied a prospectively enrolled cohort of 190 patients treated endovascularly for a first-ruptured and/or unruptured intracranial aneurysm between January 2004 and December 2008. The imaging protocol included a 1.5T time-of-flight (TOF) MRA and a DSA at 3 months (on the same day) and, depending on comparability, a 1.5T TOF-MRA or DSA 1 year after treatment. All images were evaluated by a multidisciplinary panel. Results: In 141/190 patients, both an MRA and DSA were performed after 3-month follow-up. In 2/141 patients (1.4%), (small) neck remnants gave false-negative MRA results. In one patient (0.7%), this led to additional neurosurgical clipping of the aneurysm. In 25/141 patients, future follow-up (>3 months) consisted of DSA because of various reasons. In 24/25 of these patients, primary MRA images alone would invariably have led to additional DSA imaging. Conclusion: The present study shows that 1.5T TOF-MRA is a feasible primary follow-up modality after coiling of intracranial aneurysms. Given our data, we now suggest that, in every patient with a coiled intracranial aneurysm, the first follow-up, 3 months after coiling, should be an MRA study. Only when this MRA is inconclusive (e.g., because of coil artifacts), or in the case of suspicion of recanalization, should DSA be performed additionally.

Quantification of Epstein-Barr virus-DNA load in lung transplant recipients: A comparison of plasma versus whole blood

BACKGROUND Monitoring of the Epstein-Barr virus-DNA load is frequently used to identify patients at risk for post-transplant lymphoproliferative disease (PTLD). Epstein-Barr virus DNA can be measured in the plasma and whole blood serum compartments. METHODS We compared levels of Epstein-Barr virus DNA in whole blood and plasma using a real-time TaqMan polymerase chain reaction assay in 100 consecutive paired whole blood and plasma samples from 25 lung and heart-lung transplant recipients with detectable whole blood Epstein-Barr virus-DNA load (>2,000 copies/ml). RESULTS A correlation (r2) of 0.58 (p < 0.001) was observed between both measurements, whereas of the positive whole blood samples (>2,000 copies/ml), only 17 samples (18%) were also positive in plasma. CONCLUSION These results indicate that by virtue of its sensitivity, whole blood rather than plasma may be the preferable specimen for the detection of Epstein-Barr virus DNA in lung transplant recipients.