Low Pre-Transplant Caveolin-1 Serum Concentrations Are Associated with Acute Cellular Tubulointerstitial Rejection in Kidney Transplantation.

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.

GFR estimation in lenalidomide treatment of multiple myeloma patients: a prospective cohort study.

BACKGROUND: The estimated glomerular filtration rate (eGFR) is clinically used to approximate renal function and adapt drug dosage. Multiple myeloma is a hematological disease; its prognosis is largely influenced by renal function. We evaluated two commonly used GFR estimations, CKD-EPI and MDRD (CKD Epidemiology Collaboration; Modification of Diet in Renal Disease) in myeloma patients undergoing treatment with lenalidomide, a renally excreted immunomodulatory drug. METHODS: We prospectively studied 130 myeloma patients receiving lenalidomide treatment at our institution. At baseline and after 3 months, GFR estimations were performed based on the CKD-EPI and MDRD equations. We compared eGFR-dependent CKD staging and lenalidomide dosage assignments. RESULTS: Initially, most patients were classified as CKD stage I/II, using both equations. Comparison of baseline renal function via CKD-EPI and MDRD induced concordance of CKD staging in 83% of patients, while CKD-EPI improved CKD staging in 16% of patients (p = 0.11). CKD-EPI assigned 3% of patients to higher lenalidomide dosing as opposed to MDRD. Both equations showed improved eGFR after 3 months of lenalidomide treatment. CONCLUSIONS: In our multiple myeloma patient cohort, CKD-EPI and MDRD led to similar CKD staging with minor differences in lenalidomide dosage assignment. Consistent with previous studies, eGFR improved under lenalidomide treatment. To standardize GFR estimation in myeloma patients, we suggest using the CKD-EPI equation.

Single cohort study: ABO-incompatible kidney transplant recipients have a higher risk of lymphocele formation.

PURPOSE: Since 2004, ABO-incompatible kidney transplantation (ABOi KTx) became an established procedure to expand the living donor pool in Germany. Currently, ABOi KTx comprises > 20% of all living donor KTx. Up to September 2015, > 100 ABOi KTx were performed in Freiburg. Regarding lymphocele formation, only scarce data exist. METHODS: Between April 2004 and September 2015, 106 consecutive ABOi and 277 consecutive ABO-compatible kidney transplantations (ABOc KTx) were performed. Two ABOi and 117 ABOc recipients were excluded due to differences in immunosuppression. One hundred-four ABOi and 160 ABOc KTx patients were analyzed concerning lymphocele formation. RESULTS: The incidence of lymphoceles in ABOi KTx was 25.2% and 10.6% in ABOc KTx (p = 0.003). A major risk factor appeared the frequency of ≥ 8 preoperative immunoadsorption and/or plasmapheresis sessions (OR 5.61, 95% CI 2.31-13.61, p < 0.001). Particularly, these ABOi KTx recipients had a distinctly higher risk of developing lymphocele (40.0% vs. 19.2%, p = 0.044). IA/PE sessions on day of transplantation (no lymphocele 20.0% vs. lymphocele 28.6%, p = 0.362) or postoperative IA/PE sessions (no lymphocele 25.7% vs. lymphocele 24.1%, p = 1.0) showed no influence on formation of lymphoceles. CONCLUSION: In ABOi KTx, the incidence of lymphocele formation is significantly increased compared to ABOc KTx and leads to more frequent surgical reinterventions without having an impact on graft survival.

Minimally Invasive Surgery (MIS) in Children and Adolescents with Pheochromocytomas and Retroperitoneal Paragangliomas: Experiences in 42 Patients.

BACKGROUND: Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access. MATERIALS: In the setting of a prospective study (1/2001-12/2016), 42 consecutive children and adolescents (33 m, 9 f) were operated on. Thirty-seven patients (88%) suffered from inherited diseases. Twenty-six patients had PH, 11 presented retroperitoneal PGL, and five patients suffered from both. Altogether, 70 tumours (mean size 2.7 cm) were removed (45 PH, 25 PGL). All operations were performed by a minimally invasive access (retroperitoneoscopic, laparoscopic, extraperitoneal). Partial adrenalectomy was the preferred procedure for PH (31 out of 39 patients). Twenty patients received α-receptor blockade preoperatively. RESULTS: One patient died after induction of anaesthesia due to cardiac arrest. All other complications were minor. Conversion to open surgery was necessary in two cases with PGL. Median operating time for unilateral PH was 55 min, in bilateral cases 125, 143 min in PGs, and 180 min in combined cases. Median blood loss was 20 ml (range 0-1000). Blood transfusion was necessary in two cases. Intraoperative, systolic peak pressure was 170 ± 39 mmHg with α-receptor blockade and 191 ± 33 mmHg without α-receptor blockade (p = 0.41). The median post-operative hospital stay was 3 days. After a mean follow-up of 8.5 years, two patients presented ipsilateral recurrence (after partial adrenalectomy). All patients with bilateral PH (n = 13) are steroid independent post-operatively. CONCLUSIONS: PH and PGL in children and adolescents should preferably be removed by minimally invasive surgery. Partial adrenalectomy provides long-term steroid independence in bilateral PH and a low rate of (ipsilateral) recurrence. α-Receptor blockade may not be necessary in these patients.

Lipoprotein turnover and possible remnant accumulation in preeclampsia: insights from the Freiburg Preeclampsia H.E.L.P.-apheresis study.

BACKGROUND: Preeclampsia is a life-threatening disease in pregnancy, and its complex pathomechanisms are poorly understood. In preeclampsia, lipid metabolism is substantially altered. In late onset preeclampsia, remnant removal disease like lipoprotein profiles have been observed. Lipid apheresis is currently being explored as a possible therapeutic approach to prolong preeclamptic pregnancies. Here, apheresis-induced changes in serum lipid parameters are analyzed in detail and their implications for preeclamptic lipid metabolism are discussed. METHODS: In the Freiburg H.E.L.P.-Apheresis Study, 6 early onset preeclamptic patients underwent repeated apheresis treatments. Serum lipids pre- and post-apheresis and during lipid rebound were analyzed in depth via ultracentrifugation to yield lipoprotein subclasses. RESULTS: The net elimination of Apolipoprotein B and plasma lipids was lower than theoretically expected. Lipids returned to previous pre-apheresis levels before the next apheresis even though apheresis was repeated within 2.9 ± 1.2 days. Apparent fractional catabolic rates and synthetic rates were substantially elevated, with fractional catabolic rates for Apolipoprotein B / LDL-cholesterol being 0.7 ± 0.3 / 0.4 ± 0.2 [day- 1] and synthetic rates being 26 ± 8 / 17 ± 8 [mg*kg- 1*day- 1]. The distribution of LDL-subclasses after apheresis shifted to larger buoyant LDL, while intermediate-density lipoprotein-levels remained unaffected, supporting the notion of an underlying remnant removal disorder in preeclampsia. CONCLUSION: Lipid metabolism seems to be highly accelerated in preeclampsia, likely outbalancing remnant removal mechanisms. Since cholesterol-rich lipoprotein remnants are able to accumulate in the vessel wall, remnant lipoproteins may contribute to the severe endothelial dysfunction observed in preeclampsia. TRIAL REGISTRATION: ClinicalTrails.gov, NCT01967355 .

Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin.

BACKGROUND: Hemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst. METHODS: To elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher's exact test and student's t-test. RESULTS: As a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts. CONCLUSIONS: We therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.

Targeting mTOR Signaling Can Prevent the Progression of FSGS.

Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both Raptor alleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just one Raptor allele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatment with the mTORC1 inhibitor rapamycin efficiently diminished disease progression. Mechanistically, complete pharmacologic inhibition of mTOR in immortalized podocytes shifted the cellular energy metabolism toward reduced rates of oxidative phosphorylation and anaerobic glycolysis, which correlated with increased production of reactive oxygen species. Together, these data suggest that podocyte injury and loss is commonly followed by adaptive mTOR activation. Prolonged mTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition.

One hundred ABO-incompatible kidney transplantations between 2004 and 2014: a single-centre experience.

BACKGROUND: ABO-incompatible kidney transplantation (ABOi KTx) expands the living donor transplantation options. However, long-term outcome data, especially in comparison with ABO-compatible kidney transplantation (ABOc KTx), remain limited. Since the first ABOi KTx in Germany on 1 April 2004 at our centre, we have followed 100 ABOi KTx over up to 10 years. METHODS: One hundred ABOi KTx and 248 ABOc KTx from 1 April 2004 until 28 October 2014 were analysed in this observational, single-centre study. Three ABOi KTx and 141 ABOc KTx were excluded because of cyclosporine A-based immunosuppression, and 1 ABOc KTx was lost to follow-up. RESULTS: Median estimated 10-year patient and graft survival in ABOi KTx was 99 and 94%, respectively, and surpassed ABOc-KTx patient and graft survival of 80 and 88%, respectively. The incidence rate of antibody-mediated rejections was 10 and 8%, and that of T-cell-mediated rejections was 17 and 20% in ABOi KTx and ABOc KTx, respectively. Infectious and malignant complications in ABOi KTx were not more common than in ABOc KTx. However, postoperative lymphoceles occurred more frequently in ABOi KTx. Subgroup analysis of ABOi-KTx patients revealed that patients with high-titre isohaemagglutinins before transplantation had equal long-term results compared with low-titre isohaemagglutinin patients. CONCLUSION: Taken together, long-term outcome of ABOi KTx is not inferior to ABOc KTx. Incidences of rejection episodes, infectious complications and malignancies are not increased, despite the more vigorous immunosuppression in ABOi KTx. Our data provide further evidence that ABOi KTx with living donation is a safe, successful and reasonable option to reduce the organ shortage.

Secreted frizzled-related protein 4 predicts progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common autosomal dominant condition associated with renal cysts and development of renal failure. With the availability of potential therapies, one major obstacle remains the lack of readily available parameters that identify patients at risk for disease progression and/or determine the efficacy of therapeutic interventions within short observation periods. Increased total kidney volume (TKV) correlates with disease progression, but it remains unknown how accurate this parameter can predict disease progression at early stages. METHODS: To identify additional parameters that help to stratify ADPKD patients, we measured secreted frizzled-related protein 4 (sFRP4) serum concentrations at baseline and over the course of 18 months in 429 ADPKD patients. RESULTS: Serum creatinine and sFRP4 as well as TKV increased over time, and were significantly different from baseline values within 1 year. CONCLUSION: Elevated sFRP4 levels at baseline predicted a more rapid decline of renal function at 2, 3 and 5 years suggesting that sFRP4 serum levels may provide additional information to identify ADPKD patients at risk for rapid disease progression.

An update on ABO-incompatible kidney transplantation.

ABO-incompatible kidney transplantation is nowadays a well-established procedure to expand living donor transplantation to blood group incompatible donor/recipient constellations. In the last two decades, transplantation protocols evolved to more specific isohaemagglutinin elimination techniques and established competent antirejection protection protocols without the need of splenectomy. ABOi kidney transplantation associated accommodation despite isohaemagglutinin reappearance, C4d positivity of peritubular capillaries as well as the increased incidence of bleeding complications is currently under intense investigation. However, most recent data show excellent graft survival rates equivalent to ABO-compatible kidney transplantation outcome.

Molecular fingerprinting of the podocyte reveals novel gene and protein regulatory networks.

A thorough characterization of the transcriptome and proteome of endogenous podocytes has been hampered by low cell yields during isolation. Here we describe a double fluorescent reporter mouse model combined with an optimized bead perfusion protocol and efficient single cell dissociation to yield more than 500,000 podocytes per mouse allowing for global, unbiased downstream applications. Combining mRNA and miRNA transcriptional profiling with quantitative proteomic analyses revealed programs of highly specific gene regulation tightly controlling cytoskeleton, cell differentiation, endosomal transport, and peroxisome function in podocytes. Strikingly, the analyses further predict that these podocyte-specific gene regulatory networks are accompanied by alternative splicing of respective genes. Thus, our 'omics' approach will facilitate the discovery and integration of novel gene, protein, and organelle regulatory networks that deepen our systematic understanding of podocyte biology.

Stereotactic Body Radiotherapy for Renal Cell Carcinoma in Patients with Von Hippel-Lindau Disease-Results of a Prospective Trial.

Von Hippel-Lindau disease (VHL) is a hereditary disorder associated with malignant tumors including clear cell renal cell carcinoma (ccRCC). Partial nephrectomy is complicated by multilocular tumor occurrence and a high recurrence rate. The aim of this study was to evaluate the potential of stereotactic body radiotherapy (SBRT) as an alternative treatment approach in VHL patients with multiple ccRCC. Patients with VHL and a diagnosis of ccRCC were enrolled. SBRT was conducted using five fractions of 10 Gy or eight fractions of 7.5 Gy. The primary endpoint was local control (LC). Secondary endpoints included alteration of renal function and adverse events. Seven patients with a total of eight treated lesions were enrolled. Median age was 44 years. Five patients exhibited multiple bilateral kidney cysts in addition to ccRCC. Three patients underwent at least one partial nephrectomy in the past. After a median follow-up of 43 months, 2-year LC was 100%, while 2-year CSS, 2-year PFS and 2-year OS was 100%, 85.7% and 85.7%, respectively. SBRT was very well tolerated with no acute or chronic toxicities grade ≥ 2. Mean estimated glomerular filtration rate (eGFR) at baseline was 83.7 ± 13.0 mL/min/1.73 m2, which decreased to 76.6 ± 8.0 mL/min/1.73 m2 after 1 year. Although the sample size was small, SBRT resulted in an excellent LC rate and was very well tolerated with preservation of kidney function in patients with multiple renal lesions and cysts.

Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial).

BACKGROUND: The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. METHODS: For the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. RESULTS: DFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported. CONCLUSION: Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike. TRIAL REGISTRATION: DRKS00000163.

Risk Factors and Management of Leukopenia After Kidney Transplantation: A Single-Center Experience.

BACKGROUND: Leukopenia is a common complication after kidney transplantation. The etiology is multifactorial, with medication adverse effects and cytomegalovirus infection as main causes. Optimal strategies to prevent or treat posttransplant leukopenia remain unknown. We aimed to identify risk factors for leukopenia and to investigate the benefit of switching the immunosuppressive therapy to hydrocortisone as a continuous infusion. METHODS: We retrospectively evaluated all patients with leukopenia after kidney transplantation between 2007 and 2017 at our center relative to age- and sex-matched controls. RESULTS: Leukopenia was associated with the degree of rejection therapy before leukopenia, the immunosuppressive therapy before transplantation, and an induction therapy with rabbit antithymocyte globulin. Patients with leukopenia exhibited increased mortality, an increased incidence of bacterial and viral infections, and more acute rejections. Switching to hydrocortisone as a continuous infusion in patients with severe leukopenia decreased the duration of leukopenia and the incidence of subsequent viral infections, especially with cytomegalovirus. CONCLUSION: Leukopenia is a risk factor for infectious complications and mortality, and it is associated with acute rejection. Switching immunosuppressive therapy to hydrocortisone as a continuous infusion is a safe approach to reduce the duration of leukopenia and the incidence of viral infections.

Long-term Follow-up of ABO-Incompatible Kidney Transplantation in Freiburg, Germany: A Single-Center Outcome Report.

BACKGROUND: ABO-incompatible kidney transplantation (ABOi-KT) is an established way to enlarge the donor pool around the world. Comparability of long-term success and complications to ABO-compatible kidney transplantation (ABOc-KT) are still under debate. METHODS: We evaluated all patients with a living donor kidney transplantation performed between April 1, 2004, and March 31, 2019. RESULTS: A total of 137 ABOi-KT and 346 ABOc-KT were analyzed. We excluded 4 ABOi-KT recipients and 178 ABOc-KT recipients with cyclosporine A-based immunosuppression or without basiliximab induction. Three patients of the ABOi-KT cohort and 6 patients of the ABOc-KT cohort were lost to follow-up and therefore excluded. The patient characteristics were comparable except for the higher age of transplant recipients in the ABOc-KT cohort and longer follow-up of the ABOi-KT cohort. The mean estimated 15-year recipient survival was 89% in the ABOi-KT cohort and 91% in the ABOc-KT cohort (P = .39). Mean estimated graft survival was 71% in the ABOi-KT cohort and 87% in the ABOc-KT cohort (P = .68). The estimated glomerular filtration rate (Modification of Diet in Renal Disease) measured in the last follow-up was 51 mL/min/1.73 m2 in the ABOi-KT cohort and 50 mL/min/1.73 m2 in the ABOc-KT cohort (P = .36). The incidence for antibody-mediated rejection, T cell-mediated rejections, and infectious complications requiring hospitalization was not different between the cohorts. In the ABOi-KT cohort, we found significantly more lymphoceles and consequent surgical revision procedures. CONCLUSIONS: At our center, ABOi-KT has as good long-term results as ABOc-KT in terms of patient survival, graft survival, and complications, with the exception of increased lymphocele formation.

Thrombotic thrombocytopenic purpura associated to dual checkpoint inhibitor therapy for metastatic melanoma.

Dual checkpoint inhibitor therapy has known immune-related adverse events. However, checkpoint inhibitor-associated thrombotic thrombocytopenic purpura is very rarely reported. We present a case of a 70-year old man with advanced melanoma, presenting with severe thrombocytopenia, hemolytic anemia with schistocytes and suppressed ADAMTS-13 activity by ADAMTS-13 inhibitors. We discuss differential diagnoses and speculated mechanisms of this obviously therapy-related adverse event, which should be considered by clinicians prescribing these drugs.

Clinical decision making in small non-functioning VHL-related incidentalomas.

The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.84 tumours/patient, range 1-8). Mean age at diagnosis was 32 ± 16 years. Seventy-four percent of tumours were localised to the adrenals. Mean tumour diameter was 2.42 ± 2.27 cm, 46% were <1.5 cm. 24% of tumours were biochemically inactive. Inactive tumours were significantly smaller than active PHEO/PGL at diagnosis (4.16 ± 2.80 cm vs 1.43 ± 0.45 cm; P < 0.025) and before surgery (4.89 ± 3.47 cm vs 1.36 ± 0.43 cm; P < 0.02). Disease was stable in 67% of 21 patients with evaluable tumours ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5 ± 20.0 months. A total of 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these, one had additional metastatic disease, one harboured another tumour of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumour diameter. Values of a novel symptom score were positively correlated with tumour size (Rs = 0.46, P < 0.0001) and together with a positive biochemistry a linear size predictor (P < 0.01). Results support standardised clinical assessment and measurement of tumour size and metanephrines in VHL patients with non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualised intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.

Cumulative surgical morbidity in patients with multiple cerebellar and medullary hemangioblastomas.

OBJECTIVE: Patients affected with von Hippel-Lindau disease often develop multiple hemangioblastomas in the cerebellum and spinal cord. Timing of surgical intervention is difficult and depends largely on the anticipated surgical morbidity. However, data regarding surgical outcome after multiple cerebellar and medullary surgeries are scarce. Our objective was to evaluate cumulative surgical morbidity in patients operated on multiple cerebellar and medullary hemangioblastomas and to deduce recommendations for treatment. METHODS: We performed a retrospective analysis for a consecutive cohort of von Hippel-Lindau patients with surgical treatment of at least two cerebellar and/or medullary hemangioblastomas. Pre- and postoperative functional grades were reviewed in patients' files and compared by Modified Ranking Scale (cerebellar surgeries) or by Modified McCormick Score (medullary surgeries). RESULTS: Thirty-six patients were surgically treated for at least two cerebellar hemangioblastomas (12 patients), at least two medullary hemangioblastomas (19 patients) or at least two hemangioblastomas in both locations (5 patients). Fourthy-eight cerebellar and 80 medullary procedures were performed in total. On average, multiple cerebellar surgeries caused no clinical deterioration, whereas multiple medullary surgeries led to a slight cumulative deterioration of postoperative functional grades. The severity of this deterioration did not correlate to the number of performed medullary surgeries. CONCLUSION: Resection of multiple cerebellar hemangioblastomas is not associated with cumulative morbidity. Although there is a certain cumulative surgical morbidity caused by medullary surgeries, its extent does not increase with the number of performed surgeries. Microsurgical removal of asymptomatic tumors with radiographic progression can also be considered for patients with multiple tumors and previous surgeries.