Johan F. Langenhuijsen

Cryosurgery for Prostate Cancer: an Update on Clinical Results of Modern Cryotechnology

CONTEXT Cryosurgery is an evolving treatment for localized prostate cancer in European centers. Modern cryotechnology is associated with a low complication rate, but its definitive role in the spectrum of different treatment modalities remains to be determined. OBJECTIVE The primary objective of this review is to analyze the oncological results and complication rates of modern cryosurgery for prostate cancer. Secondarily, the impact of patient selection and the criteria for treatment success are discussed. EVIDENCE ACQUISITION A structured literature review was performed by an online Pubmed search for data of primary and salvage cryosurgery of the prostate. Papers with relevant information on clinical outcome and complication rates were selected. EVIDENCE SYNTHESIS The introduction of gas-based third-generation cryotechnology has significantly decreased side effects with similar oncological results compared to older techniques. The occurrence of severe complications like rectourethral fistulas (<1%) has almost been eradicated, but the rates of erectile dysfunction remain high (90%). With salvage cryosurgery more side effects can be expected with an average incontinence rate of 8% and fistulas up to 3.4%. Nevertheless, this minimal invasive treatment remains an option for radiorecurrent prostate cancer. Focal cryosurgery is considered experimental, but is an interesting new development in cryosurgery. The intermediate-term biochemical disease free survival rates of 60%-90% are comparable to the results of other treatment modalities. However, the current data of cryosurgery in literature are of low-level evidence which should be discussed when counselling patients. CONCLUSIONS Modern cryosurgery is reliable and results are promising with minimal morbidity. Focal cryosurgery in selected patients aims to reduce side effects, but is currently experimental treatment. Randomized trials comparing the outcomes of the different treatment modalities and long-term follow-up data are needed to define the ultimate role of cryosurgery in the treatment of localized prostate cancer.

Randomized controlled trial comparing hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy

Background Laparoscopic donor nephrectomy (LDN) has become the gold standard for live-donor nephrectomy, as it results in a short convalescence time and increased quality of life. However, intraoperative safety has been debated, as severe complications occur incidentally. Hand-assisted retroperitoneoscopic donor nephrectomy (HARP) is an alternative approach, combining the safety of hand-guided surgery with the benefits of endoscopic techniques and retroperitoneal access. We assessed the best approach to optimize donors’ quality of life and safety. Methods In two tertiary referral centers, donors undergoing left-sided nephrectomy were randomly assigned to HARP or LDN. Primary endpoint was physical function, one of the dimensions of the Short Form-36 questionnaire on quality of life, at 1 month postoperatively. Secondary endpoints included intraoperative events and operation times. Follow-up was 1 year. Results In total, 190 donors were randomized. Physical function at 1 month follow-up did not significantly differ between groups (estimated difference, 1.79; 95% confidence interval, −4.1 to 7.68; P=0.55). HARP resulted in significantly shorter skin-to-skin time (mean, 159 vs. 188 min; P<0.001), shorter warm ischemia time (2 vs. 5 min; P<0.001) and a lower intraoperative event rate (5% vs. 11%, P=0.117). Length of stay (both 3 days; P=0.135) and postoperative complication rate (8% vs. 8%; P=1.00) were not significantly different. Potential graft-related complications did not significantly differ (6% vs. 13%; P=0.137). Conclusions Compared with LDN, left-sided HARP leads to similar quality of life, shorter operating time, and warm ischemia time. Therefore, we recommend HARP as a valuable alternative to the laparoscopic approach for left-sided donor nephrectomy.

Correlation Between In Vivo 18F-FDG PET and Immunohistochemical Markers of Glucose Uptake and Metabolism in Pheochromocytoma and Paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) can be localized by 18F-FDG PET. The uptake is particularly high in tumors with an underlying succinate dehydrogenase (SDH) mutation. SDHx-related PPGLs are characterized by compromised oxidative phosphorylation and a pseudohypoxic response, which mediates an increase in aerobic glycolysis, also known as the Warburg effect. The aim of this study was to explore the hypothesis that increased uptake of 18F-FDG in SDHx-related PPGLs is reflective of increased glycolytic activity and is correlated with expression of different proteins involved in glucose uptake and metabolism through the glycolytic pathway. Methods: Twenty-seven PPGLs collected from patients with hereditary mutations in SDHB (n = 2), SDHD (n = 3), RET (n = 5), neurofibromatosis 1 (n = 1), and myc-associated factor X (n = 1) and sporadic patients (n = 15) were investigated. Preoperative 18F-FDG PET/CT studies were analyzed; mean and maximum standardized uptake values (SUVs) in manually drawn regions of interest were calculated. The expression of proteins involved in glucose uptake (glucose transporters types 1 and 3 [GLUT-1 and -3, respectively]), phosphorylation (hexokinases 1, 2, and 3 [HK-1, -2, and -3, respectively]), glycolysis (monocarboxylate transporter type 4 [MCT-4]), and angiogenesis (vascular endothelial growth factor [VEGF], CD34) were examined in paraffin-embedded tumor tissues using immunohistochemical staining with peroxidase-catalyzed polymerization of diaminobenzidine as a read-out. The expression was correlated with corresponding SUVs. Results: Both maximum and mean SUVs for SDHx-related tumors were significantly higher than those for sporadic and other hereditary tumors (P < 0.01). The expression of HK-2 and HK-3 was significantly higher in SDHx-related PPGLs than in sporadic PPGLs (P = 0.022 and 0.025, respectively). The expression of HK-2 and VEGF was significantly higher in SDHx-related PPGLs than in other hereditary PPGLs (P = 0.039 and 0.008, respectively). No statistical differences in the expression were observed for GLUT-1, GLUT-3, and MCT-4. The percentage anti-CD 34 staining and mean vessel perimeter were significantly higher in SDHx-related PPGLs than in sporadic tumors (P = 0.050 and 0.010, respectively). Mean SUVs significantly correlated with the expression of HK-2 (P = 0.027), HK-3 (P = 0.013), VEGF (P = 0.049), and MCT-4 (P = 0.020). Conclusion: The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased 18F-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters.

Neoadjuvant androgen deprivation for prostate volume reduction: The optimal duration in prostate cancer radiotherapy

OBJECTIVES For locally advanced prostate cancer, the results of radiotherapy are improved by combination with androgen deprivation therapy. Volume reduction achieved with neoadjuvant hormonal treatment can facilitate dose escalation without increasing the toxicity. The optimal duration of hormonal treatment, however, is unknown. The endpoint of this study is the optimal duration of androgen deprivation for prostate volume reduction in a cohort of patients scheduled for external beam radiotherapy. PATIENTS AND METHODS Twenty patients scheduled for external beam radiotherapy with cT2-3No/xMo prostate cancer were treated with a luteinizing hormone releasing hormone agonist (busereline) and nonsteroidal anti-androgen (nilutamide) for 9 months consecutively. Repeated CT scan examination was performed 3-monthly to measure prostate volumes until the start of radiation therapy. The analysis of volume reduction was performed with the Wilcoxon signed ranks test. RESULTS The baseline median prostate volume for the cohort of patients was 82 cc (95% CI: 61-104 cc) with a median volume reduction of 31% (95% CI: 26%-35%) (P < 0.0001) after 3 months of androgen deprivation. Between 3 and 6 months, a median volume reduction of 9% (95% CI: 4%-14%) (P < 0.0001) was observed. The effect was more pronounced in large prostates (>60 cc) than in small prostates (≤60 cc). In the total cohort of patients no significant volume reduction occurred between 6 and 9 months of maximal androgen blockade (MAB). CONCLUSIONS In this study, we have shown that the most significant prostate volume reduction is achieved after 3 months of MAB with a maximum reduction after 6 months. Therefore, the optimal duration of neoadjuvant androgen deprivation to reduce prostate volume before prostate cancer radiotherapy is 6 months. In small prostates 3 months of hormonal treatment may be enough for maximal volume reduction.

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti–carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of 111In-labeled girentuximab. Methods: 111In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of 111In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single 111In-girentuximab injection and scintigraphy without any treatment. Distribution of 111In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Results: Treatment with sorafenib resulted in a marked decrease of 111In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, −38.4%; range, +9.1% to −79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Conclusion: Treatment with sorafenib resulted in a treatment duration–dependent significantly decreased uptake of 111In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

Impairment of cognitive functioning during Sunitinib or Sorafenib treatment in cancer patients: a cross sectional study

BackgroundImpairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI).MethodsThree groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing.ResultsNo significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks.ConclusionsOur data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and Executive Functioning. We propose that patients who are treated with VEGFR TKI are monitored and informed for possible signs or symptoms associated with cognitive impairment.Trial registrationClinicalTrials.gov Identifier: NCT01246843.

Hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy: HARP-trial

BackgroundTransplantation is the only treatment offering long-term benefit to patients with chronic kidney failure. Live donor nephrectomy is performed on healthy individuals who do not receive direct therapeutic benefit of the procedure themselves. In order to guarantee the donors safety, it is important to optimise the surgical approach. Recently we demonstrated the benefit of laparoscopic nephrectomy experienced by the donor. However, this method is characterised by higher in hospital costs, longer operating times and it requires a well-trained surgeon. The hand-assisted retroperitoneoscopic technique may be an alternative to a complete laparoscopic, transperitoneal approach. The peritoneum remains intact and the risk of visceral injuries is reduced. Hand-assistance results in a faster procedure and a significantly reduced operating time. The feasibility of this method has been demonstrated recently, but as to date there are no data available advocating the use of one technique above the other.Methods/designThe HARP-trial is a multi-centre randomised controlled, single-blind trial. The study compares the hand-assisted retroperitoneoscopic approach with standard laparoscopic donor nephrectomy. The objective is to determine the best approach for live donor nephrectomy to optimise donors safety and comfort while reducing donation related costs.DiscussionThis study will contribute to the evidence on any benefits of hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy.Trial RegistrationDutch Trial Register NTR1433

Low-pressure pneumoperitoneum during laparoscopic donor nephrectomy to optimize live donors' comfort.

Nowadays, laparoscopic donor nephrectomy (LDN) has become the gold standard to procure live donor kidneys. As the relationship between donor and recipient loosens, it becomes of even greater importance to optimize safety and comfort of the surgical procedure. Low‐pressure pneumoperitoneum has been shown to reduce pain scores after laparoscopic cholecystectomy. Live kidney donors may also benefit from the use of low pressure during LDN. To evaluate feasibility and efficacy to reduce post‐operative pain, we performed a randomized blinded study. Twenty donors were randomly assigned to standard (14 mmHg) or low (7 mmHg) pressure during LDN. One conversion from low to standard pressure was indicated by protocol due to lack of progression. Intention‐to‐treat analysis showed that low pressure resulted in a significantly longer skin‐to‐skin time (149 ± 86 vs. 111 ± 19 min), higher urine output during pneumoperitoneum (23 ± 35 vs. 11 ± 20 mL/h), lower cumulative overall pain score after 72 h (9.4 ± 3.2 vs. 13.5 ± 4.5), lower deep intra‐abdominal pain score (11 ± 3.3 vs. 7.5 ± 3.1), and a lower cumulative overall referred pain score (1.8 ± 1.9 vs. 4.2 ± 3). Donor serum creatinine levels, complications, and quality of life dimensions were not significantly different. Our data show that low‐pressure pneumoperitoneum during LDN is feasible and may contribute to increase live donors’ comfort during the early post‐operative phase.

Phase 2 Study of Lutetium 177-Labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Renal Cell Carcinoma.

UNLABELLED Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. PATIENT SUMMARY We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).

Current Status of Focal Cryoablation for Small Renal Masses.

Focal cryoablation is an established minimally invasive technique for the treatment of small renal masses. Because of the lack of robust evidence, it is indicated in selected patients who have relative contraindications to extirpative approaches. With appropriate selection of patients, cryoablation is safe and effective. Main advantages are low risk for complication, minimal invasiveness, and good functional outcomes; oncological outcomes require further studies. The role of the percutaneous approach has been expanding because of its ability to reduce pain and hospitalization, the possibility of performing the procedure under sedation, and the fact that it is potentially more cost effective.