Variation in the management of cT1 renal cancer by surgical hospital volume: A nationwide study.

Objectives: To analyse variation in clinical management of cT1 renal cell carcinoma (RCC) in the Netherlands related to surgical hospital volume (HV). Materials and methods: Patients diagnosed with cT1 RCC during 2014-2020 were identified in the Netherlands Cancer Registry. Patient and tumour characteristics were retrieved. Hospitals performing kidney cancer surgery were categorised by annual HV as low (HV < 25), medium (HV = 25-49) and high (HV > 50). Trends over time in nephron-sparing strategies for cT1a and cT1b were evaluated. Patient, tumour and treatment characteristics of (partial) nephrectomies were compared by HV. Variation in applied treatment was studied by HV. Results: Between 2014 and 2020, 10 964 patients were diagnosed with cT1 RCC. Over time, a clear increase in nephron-sparing management was observed. The majority of cT1a underwent a partial nephrectomy (PN), although less PNs were applied over time (from 48% in 2014 to 41% in 2020). Active surveillance (AS) was increasingly applied (from 18% to 32%). For cT1a, 85% received nephron-sparing management in all HV categories, either with AS, PN or focal therapy (FT). For T1b, radical nephrectomy (RN) remained the most common treatment (from 57% to 50%). Patients in high-volume hospitals underwent more often PN (35%) for T1b compared with medium HV (28%) and low HV (19%). Conclusion: HV is related to variation in the management of cT1 RCC in the Netherlands. The EAU guidelines have recommended PN as preferred treatment for cT1 RCC. In most patients with cT1a, nephron-sparing management was applied in all HV categories, although differences in applied strategy were found and PN was more frequently used in high HV. For T1b, high HV was associated with less appliance of RN, whereas PN was increasingly used. Therefore, closer guideline adherence was found in high-volume hospitals.

Therapeutic ultrasound: The future of epilepsy surgery?

Epilepsy is one of the leading neurological diseases in both adults and children and in spite of advancement in medical treatment, 20 to 30% of patients remain refractory to current medical treatment. Medically intractable epilepsy has a real impact on a patient's quality of life, neurologic morbidity and even mortality. Actual therapy options are an increase in drug dosage, radiosurgery, resective surgery and non-resective neuromodulatory treatments (deep brain stimulation, vagus nerve stimulation). Resective, thermoablative or neuromodulatory surgery in the treatment of epilepsy are invasive procedures, sometimes requiring long stay-in for the patients, risks of permanent neurological deficit, general anesthesia and other potential surgery-related complications such as a hemorrhage or an infection. Radiosurgical approaches can trigger radiation necrosis, brain oedema and transient worsening of epilepsy. With technology-driven developments and pursuit of minimally invasive neurosurgery, transcranial MR-guided focused ultrasound has become a valuable treatment for neurological diseases. In this critical review, we aim to give the reader a better understanding of current advancement for ultrasound in the treatment of epilepsy. By outlining the current understanding gained from both preclinical and clinical studies, this article explores the different mechanisms and potential applications (thermoablation, blood brain barrier disruption for drug delivery, neuromodulation and cortical stimulation) of high and low intensity ultrasound and compares the various possibilities available to patients with intractable epilepsy. Technical limitations of therapeutic ultrasound for epilepsy surgery are also detailed and discussed.

[Medulloblastoma : management of a usually pediatric tumour in a young adult]. / Médulloblastome : prise en charge d'une tumeur habituellement pédiatrique chez un jeune adulte.

Medulloblastoma is a cerebellar grade IV tumour according to the WHO classification, mainly seen in children under the age of 15. This cancer can nevertheless occur in adults. We report the case of a 22-year-old patient with a medulloblastoma disseminated in the spine. The patient had a type 1 Arnold-Chiari malformation causing hydrocephalus treated by ventriculoperitoneal shunt. The current condition began with perineal and lower limb hypoesthesia, ataxic gait, erectile dysfunction and urinary incontinence. Subsequently, a predominant paraparesis of the right lower limb appeared. The patient was treated according to the PNET HR+5 protocol combining two courses of conventional chemotherapy followed by two courses of high-dose chemotherapy with autograft recovery. Given the excellent response, a proton therapy was then delivered to the whole cerebrospinal axis with boosts to the primary tumour sites. The case of this young adult patient shows on the one hand an atypical presentation, and on the other hand underlines, in the absence of a specific therapeutic strategy established for adults, the importance of collaboration between the adult and pediatric oncology departments, with management integrating innovations such as proton therapy and molecular typing.

Le médulloblastome est une tumeur cérébelleuse de grade IV selon l'Organisation Mondiale de la Santé, principalement observée chez les enfants de moins de 15 ans. Ce cancer peut néanmoins survenir chez l'adulte. Nous rapportons le cas d'un patient de 22 ans présentant un médulloblastome disséminé au niveau du rachis. Le patient est porteur d'une malformation d'Arnold-Chiari de type 1 provoquant une hydrocéphalie traitée par dérivation ventriculo-péritonéale. L'affection actuelle a débuté par une hypoesthésie du périnée et des membres inférieurs, une démarche ataxique, un trouble érectile et des troubles vésico-sphinctériens. Par la suite est apparue une paraparésie prédominant au membre inférieur droit. Le patient a été traité selon le protocole pédiatrique PNET HR+5 combinant deux cures de chimiothérapie conventionnelle suivies de deux cures de chimiothérapie à haute dose avec rattrapage par autogreffe. Vu l'excellente réponse, une protonthérapie a été administrée sur l'axe cérébrospinal avec surdosages sur les sites primaires de la tumeur. Le cas de ce jeune adulte illustre, d'une part, une présentation atypique et d'autre part, souligne, en l'absence de stratégie thérapeutique spécifique établie pour l'adulte, l'importance de la collaboration entre les services d'Oncologie adulte et pédiatrique, la prise en charge intégrant les innovations telles que la protonthérapie et le typage moléculaire.

Cytoreductive nephrectomy in metastatic renal cell carcinoma: outcome of patients treated with a multidisciplinary, algorithm-driven approach.

PURPOSE: Metastatic renal cell carcinoma (mRCC) represents a significant and rising burden of disease, with rapidly evolving treatment modalities. The role of cytoreductive nephrectomy (CN) is controversial in this setting. As such, London Cancer has pursued a multidisciplinary team (MDT) approach when assessing suitability for surgery. METHODS: A retrospective analysis of treatment-naive synchronous mRCC patients, managed via a renal-specialist MDT, was conducted between January 2015 and December 2018. An MDT selection algorithm for CN-using the International Metastatic Renal Cell Carcinoma Database Consortium score (IMDC), performance status and metastatic disease burden-was developed. RESULTS: 87 treatment-naive synchronous mRCC patients received either CN (n = 18), Systemic therapy (ST) alone (n = 43) or Best supportive care (BSC) (n = 26). Progression free survival (PFS) and overall survival (OS) were assessed. 51% and 39% were IMDC intermediate and poor risk. Median PFS was 28.6 months and 4.5 months in the CN group and ST alone group, respectively, Hazard Ratio for death was 3.63 [(95% CI 1.68-7.83) p < 0.05]. OS remains immature for the CN group, but a median OS of 12.8 months was observed in the ST group and 5.0 months for BSC. 1-year OS rate for CN, ST and BSC groups was 77.8%, 55.8% and 23.10%, respectively. CONCLUSION: These findings describe outcomes of an unselected series of patients treated via an MDT-driven, protocolised treatment pathway. MDT pathway-based decision making may improve patient selection for CN. Further research is needed to evaluate the role of CN amongst a growing landscape of treatment strategies, including immune checkpoint inhibitors and combination therapies. Multi-disciplinary team, pathway-based treatment strategy may improve patient selection for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma.

Percutaneous Microwave Ablation of Histologically Proven T1 Renal Cell Carcinoma.

OBJECTIVES: To assess the safety and efficacy of percutaneous microwave ablation (MWA) of histologically proven T1 renal cell carcinoma (RCC). METHODS: We analysed patients with a histologically proven RCC (≤ 7 cm) treated by MWA from April 2012-April 2018. Primary and secondary efficacy, local tumour recurrence (LTR), morbidity and mortality were reported. Efficacy was defined as no residual tumour enhancement on follow-up imaging 1 month after the first ablation (primary efficacy) and after re-ablation(s) for residual disease (secondary efficacy). Adverse events (AE) were registered by the Clavien-Dindo classification and the common terminology criteria for AE. Univariable and multivariable logistic regression analyses were performed to investigate a relation among pre-treatment factors incomplete ablation and complications. RESULTS: In 100 patients, a total of 108 RCCs (85 T1a and 23 T1b) were treated by MWA. Median size was 3.2 cm (IQR 2.4-4.0). Primary efficacy was 89% (95%CI 0.81-0.94) for T1a lesions and 52% (95%CI 0.31-0.73) for T1b lesions (p < 0.001). Fifteen lesions (7 T1a) were re-ablated for residual disease by MWA in one (n = 13) and two (n = 2, both T1b) sessions resulting in secondary efficacy rates of 99% (T1a) and 95% (T1b, p = 0.352). LTR occurred in four tumours (2 T1a, 2 T1b) after 10-60 months. Six (4%) AEs grade > 3-5 were observed (2 T1a, 4 T1b, p = 0.045). Multivariable analysis showed that mR.E.N.A.L. nephrometry was independently associated with incomplete ablation (p = 0.012). CONCLUSION: Microwave ablation is safe and effective for T1a and T1b RCC lesions with a significantly lower primary efficacy for T1b lesions.

Prediction of early (30-day) and late (30-90-day) mortality after radical cystectomy in a comprehensive cancer centre over two decades.

BACKGROUND: Radical cystectomy (RC) is associated with substantial postoperative mortality. In this study, we analyzed early (30-day; 30 M) and late (30-90-day; 30-90 M) mortality after RC in a Dutch tertiary referral center and determined factors associated with 30 M, 30-90 M and 90-day mortality (90 M). PATIENTS AND METHODS: We identified 823 patients who underwent RC for bladder cancer in the Netherlands Cancer Institute between 1997 and 2017. Predictive factors for mortality were analyzed to identify patients with a higher mortality risk. Multivariate logistic regression analysis was performed to examine the influence of patient, surgical and histopathological variables on 30 M, 30-90 M and 90 M. RESULTS: Thirty-day mortality was 1.9% and 90 M was 6.0%. Multivariable analysis showed that age (OR 1.08, 95% CI 1.01-1.1, p = 0.002) and ASA 3-4 (OR 3.57, 95% CI 1.25-10.16, p = 0.002) were significant predictors of 30 M while higher ASA score (OR 2.9, 95% CI 1.31-6.5, p = 0.009) and higher pathological T stage (OR 8.8, 95% CI 1.9-40.4, p = 0.005) were associated with 30-90 M. Risk of 90 M was increased in patients with ASA 3-4 (OR 2.4, 95% CI 1.2-4.9, p = 0.01), pT3-4 (OR 3.1, 95% CI 1.27-7.57, p = 0.01) and positive LNs (OR 2.5, 95% CI 1.25-4.98, p = 0.009). CONCLUSIONS: Patient-related factors predicted 30 M whereas both patient-related and cancer-related factors predicted 30-90 M. This suggests that patient mix, i.e. patient- vs. cancer-related factors for 30 M and 30-90 M, should be taken into account if mortality rates are to be compared between hospitals.

Cryoablation and immunotherapy: an overview of evidence on its synergy.

Cancer cells can escape the immune system by different mechanisms. The evasion of cancer cells from immune surveillance is prevented by immune checkpoint inhibitors, allowing the patient's own immune system to attack their cancer. Immune checkpoint inhibitors have shown improvement in overall survival for melanoma, lung cancer and renal cell carcinoma in clinical trials. Unfortunately, not all patients respond to this therapy.In cancer management, percutaneous ablation techniques are well established for both cure and local control of many tumour types. Cryoablation of the tumour tissue results in cell destruction by freezing. Contrary to heat-based ablative modalities, cryoablation induces tumour cell death by osmosis and necrosis. It is hypothesised that with necrosis, the intracellular contents of the cancer cells stay intact allowing the immune system to induce an immune-specific reaction. This immune-specific reaction can, in theory, also affect cancer cells outside the ablated tissue, known as the abscopal effect. Unfortunately, this effect is rarely observed, but when cryoablation is combined with immunotherapy, the effect of both therapies may be enhanced. Although several preclinical studies demonstrated a synergistic effect between cryoablation and immunotherapy, prospective clinical trials are needed to prove this clinical benefit for patients. In this review, we will outline the current evidence for the combination of cryoablation with immunotherapy to treat cancer.

Interactive virtual 3D models of renal cancer patient anatomies alter partial nephrectomy surgical planning decisions and increase surgeon confidence compared to volume-rendered images.

PURPOSE: To determine whether the interactive visualisation of patient-specific virtual 3D models of the renal anatomy influences the pre-operative decision-making process of urological surgeons for complex renal cancer operations. METHODS: Five historic renal cancer patient pre-operative computed tomography (CT) datasets were retrospectively selected based on RENAL nephrectomy score and variety of anatomy. Interactive virtual 3D models were generated for each dataset using image segmentation software and were made available for online visualisation and manipulation. Consultant urologists were invited to participate in the survey which consisted of CT and volume-rendered images (VRI) for the control arm, and CT with segmentation overlay and the virtual 3D model for the intervention arm. A questionnaire regarding anatomical structures, surgical approach, and confidence was administered. RESULTS: Twenty-five participants were recruited (54% response rate), with 19/25 having > 5 years of renal surgery experience. The median anatomical clarity score increased from 3 for the control to 5 for the intervention arm. A change in planned surgical approach was reported in 19% of cases. Virtual 3D models increased surgeon confidence in the surgical decisions in 4/5 patient datasets. There was a statistically significant improvement in surgeon opinion of the potential utility for decision-making purposes of virtual 3D models as compared to VRI at the multidisciplinary team meeting, theatre planning, and intra-operative stages. CONCLUSION: The use of pre-operative interactive virtual 3D models for surgery planning influences surgical decision-making. Further studies are needed to investigate if the use of these models changes renal cancer surgery outcomes.

Potentially curable recurrent disease after surgically managed non-metastatic renal cell carcinoma in low-, intermediate- and high-risk patients.

PURPOSE: Guidelines recommend risk-adapted follow-up (FU) strategies after (partial) nephrectomy in non-metastatic renal cell carcinoma (RCC). Since current systemic therapy does not cure metastatic RCC, only timely detected recurrence accessible for local therapy is potentially curable. This study analyzed the rate and management of potentially curable recurrences per risk group. METHODS: This is a retrospective study including non-metastatic RCC patients who underwent (partial) nephrectomy from 2004 to 2011, with a minimum follow-up of 4 years. Risk stratification was by Leibovich score (clear cell subtype) and UICC/AJCC grading (other subtypes). Recurrence, time to recurrence, symptoms and detection method were documented. Isolated local recurrence, solitary- and oligometastases (≤3 lesions, single site) were considered potentially curable. RESULTS: Among 234 patients, followed during a median of 61.9 months, 68 patients (29.1 %) developed a recurrence of which 28 (41.2 %) were considered potentially curable. The 5-year risk of recurrence for low-, intermediate- and high-risk patients was 7.8, 26.3 and 59.1 % of which 71.4, 52.2 and 23.1 % were considered potentially curable, respectively. In high-risk patients, incurable recurrence was detected after a median of 7.9 (3.7-17.2) months versus 13.9 (6-41.3) months for potentially curable lesions. Only 13 of potentially curable lesions (46 %) received local therapy. CONCLUSION: FU protocols should be adapted to the recurrence pattern of potentially curable disease. Most of the benefit may be achieved in intermediate-risk and high-risk-patients free of recurrence 1 year after surgery. Despite frequent imaging, only 13 patients (5.6 % of all patients followed) were managed with local therapy of whom only 4 remained free of disease.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

[Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. / L'ischémie a un impact limité sur la fonction rénale après néphrectomie partielle sur rein unique chez les patients sans insuffisance rénale préopératoire.

OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5.

Follow-up after cystectomy: regularly scheduled, risk adjusted, or symptom guided? Patterns of recurrence, relapse presentation, and survival after cystectomy.

AIMS: To evaluate the efficacy of follow-up based on the patterns of recurrence, relapse presentation and survival after cystectomy, and to define a risk adjusted follow-up schedule. PATIENTS AND METHODS: The records of 343 patients with regular follow-up after cystectomy were reviewed for primary site of recurrence, accompanying symptoms, means of recurrence diagnosis, and clinicopathological factors. Based on Cox proportional hazard models, and the results of imaging studies low and high risk groups are identified and a risk adjusted follow-up protocol is proposed. RESULTS: The risk of a recurrence was related to increasing pT, tumour positive lymph nodes, tumour positive surgical margins, and pre-operative dilatation of the upper urinary tract, and low and high risk groups were defined consequently. 84% of all recurrences occurred within 2 years, with only one recurrence beyond 2 years in the low risk group. Although the minority of all patients (34%) is asymptomatic at time of recurrence, symptomatic recurrences were adversely associated with survival. CT-scans and chest X-rays accounted for 90% of the diagnostic tools to detect a recurrence in patients without symptoms. CONCLUSIONS: Asymptomatic patients may benefit from early treatment after disease recurrence. A risk adjusted follow-up strategy based on stage of disease and additional clinicopathological factors can dichotomise patients at high and low risk for recurrence. The small benefit in survival after early detection has to be confirmed in future studies, and weighed against the available treatment options of recurrences and their subsequent costs.

Predictive factors of chronic kidney disease stage V after partial nephrectomy in a solitary kidney: a multi-institutional study.

OBJECTIVE: Partial Nephrectomy (PN) in a solitary kidney is at risk of chronic kidney disease (CKD) stage V and/or haemodialysis (HD). Our objective was to determine predictive factors of CKD stage V in this population. MATERIAL & METHODS: Data from 300 patients were retrospectively collected from 16 tertiary centres. Clinical and operative parameters, tumor characteristics and renal function before surgery were analyzed. Patients with and without CKD stage V (defined as MDRD<1 5 ml/min) were compared using χ2 and Student-t tests for qualitative and quantitative variables, respectively. Predictive factors of CKD stage V were evaluated with a multivariable analysis using a Cox regression model. RESULTS: Median age and BMI were 63 years old and 26 kg/m², respectively. Most of the patients (65%) were male with an anatomic solitary kidney (88.3%). Median tumor size was 4 cm and 98% were malignant tumors. Median operative time, blood loss and clamping time were 180 min, 350 ml and 20 min respectively. Renal cooling was used in 19.3% and clamping of the pedicle was performed in 61.6%. Twenty five patients (8.5%) presented post operative CKD stage V at last follow-up and 18 underwent HD (6%) post-operatively because of acute renal insufficiency. There was no difference between CKD stage V and non CKD stage V patients concerning Charlson index, operative time (180 min vs 179 min, p = 0.39), blood loss (475 ml vs 350 ml, p = 0.51), use of renal cooling and type of clamping. Patients with CKD stage V were older (70 vs 63 years old, p = 0.005), had a lower baseline renal function (clearance MDRD 41 vs. 62 ml/min, p<0.0001) and an increased tumor size (p = 0.02). Complications occurred in 91 patients (30%) with 16% of minor (Clavien 1-2) and 14% of major (Clavien > 2) complications, respectively. In multivariable analysis, baseline MDRD, BMI, and the occurrence of a minor complication were independent predictive factors of post operative CKD stage V. CONCLUSION: PN in a solitary kidney is at risk of post-operative CKD stage V and HD. Pre-operative altered renal function and post operative complications are the main predictive factors of permanent CKD stage V.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. MATERIALS AND METHODS: This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. RESULTS: Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. CONCLUSIONS: Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.