Publications by authors named "Börje Ljungberg"

202 Publications

Incidence trends in lung and bladder cancers in the Nordic Countries before and after the smoking epidemic.

Eur J Cancer Prev 2021 Jun 1. Epub 2021 Jun 1.

Biomedical Center, Faculty of Medicine, Charles University in Pilsen, Pilsen, Czech Republic Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland Department of surgical and perioperative sciences, Urology and andrology, Umeå University, Umeå, Sweden Division of Urologic Oncology, Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network and University of Toronto, Toronto, Ontario, Canada Department of Urology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Cigarette smoking epidemic, which started before the World War II, completely changed the cancer landscape. Reliable incidence data spanning the stepwise spreading epidemic are rare, but the Nordic cancer registries are unique sources in being able to catch the pre-epidemic situation in the female population where smoking became more prevalent after the War. For Swedish men, smoking prevalence has decease early and cancer rates may herald postsmoking rates. We used data from the NORDCAN database, constructed by the cancer registries of Denmark, Finland, Norway and Sweden, for the analysis of incidence changes in lung and bladder cancers from year 1943 (Denmark), from 1953 (Finland and Norway) and from 1960 (Sweden) until year 2016. The analyses revealed four novel observation relevant to the smoking epidemic. (1) The incidence of lung cancer in Norwegian women in the 1950s, when the smoking prevalence was very low, was 1.8/100 000 (world standard rate), which is at the level of lowest global female rates known to-date; (2) the earliest lung-to-bladder incidence ratio among Norwegian women was 0.64, probably benchmarking the incidence rates prior to the smoking epidemic; (3) bladder cancer incidence for Finnish women diagnosed in the 1950s was 1.2/100 000 which is at the level of the lowest rates currently known and (4) Swedish men with the lowest smoking prevalence in Europe, showed an epochal crossing of lung and bladder cancer incidence rates before year 2015. The data suggest that the approaching of the incidence rates for lung and bladder cancer can be expected in the course of the abating smoking epidemic.
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http://dx.doi.org/10.1097/CEJ.0000000000000694DOI Listing
June 2021

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care.

Eur Urol 2021 May 29. Epub 2021 May 29.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups. PATIENT SUMMARY: New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.042DOI Listing
May 2021

Incidence trends in bladder and lung cancers between Denmark, Finland and Sweden may implicate oral tobacco (snuff/snus) as a possible risk factor.

BMC Cancer 2021 May 25;21(1):604. Epub 2021 May 25.

Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

Background: The dominant risk factor for urinary bladder cancer has been cigarette smoking, but, as smoking prevalence is decreasing in many populations, other risk factors may become uncovered. Such new risk factors could be responsible for halting the declining incidence of bladder cancer. We hypothesize that snuff use by Swedish men may increase the rate for bladder cancer, as snuff contains carcinogenic nitrosamines.

Methods: We carried out an ecological study by comparing incidence trends in lung and bladder cancers between Danish, Finnish and Swedish men in order to test if the Swedish bladder cancer rate deviates from the Danish and Finnish ones. We used the NORDCAN database for cancer data from 1960 through 2016 to test the hypothesis.

Results: In the three countries, the incidence of lung cancer started to decrease after a peak incidence, and this was later followed by declining incidence in bladder cancer in Denmark from 1990 to 2016 by 14.3%, in Finland by 8.3% but not in Sweden (the decline of 1.4% was not significant). The difference in trends can be partly explained by the increasing incidence in Swedish men aged 70 or more years. Sweden differs from the two other countries by low male smoking prevalence but increasing use of snuff recorded by various surveys.

Conclusion: The stable bladder cancer trend for Swedish men was opposite to the declining trends in Denmark, Finland and globally. We suggest that this unusual finding may be related to the increasing use of snuff by Swedish men. Average users of snuff are exposed to at least 3 times higher levels of carcinogenic tobacco-specific nitrosamines than a smoker of one daily pack of cigarettes.
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http://dx.doi.org/10.1186/s12885-021-08371-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152093PMC
May 2021

Radical Nephrectomy: The Widening Gap Between Evolution of Technique and Evidence.

Eur Urol 2021 May 13. Epub 2021 May 13.

Department of Urology, The Royal Free London NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2021.04.038DOI Listing
May 2021

Pattern, timing and predictors of recurrence after surgical resection of chromophobe renal cell carcinoma.

World J Urol 2021 Apr 13. Epub 2021 Apr 13.

Division of Surgery and Interventional Science, University College London, London, UK.

Purpose: Currently there are no specific guidelines for the post-operative follow-up of chromophobe renal cell carcinoma (chRCC). We aimed to evaluate the pattern, location and timing of recurrence after surgery for non-metastatic chRCC and establish predictors of recurrence and cancer-specific death.

Methods: Retrospective analysis of consecutive surgically treated non-metastatic chRCC cases from the Royal Free London NHS Foundation Trust (UK, 2015-2019) and the international collaborative database RECUR (15 institutes, 2006-2011). Kaplan-Meier curves were plotted. The association between variables of interest and outcomes were analysed using univariate and multivariate Cox proportional hazards regression models with shared frailty for data source.

Results: 295 patients were identified. Median follow-up was 58 months. The five and ten-year recurrence-free survival rates were 94.3% and 89.2%. Seventeen patients (5.7%) developed recurrent disease, 13 (76.5%) with distant metastases. 54% of metastatic disease diagnoses involved a single organ, most commonly the bone. Early recurrence (< 24 months) was observed in 8 cases, all staged ≥ pT2b. 30 deaths occurred, of which 11 were attributed to chRCC. Sarcomatoid differentiation was rare (n = 4) but associated with recurrence and cancer-specific death on univariate analysis. On multivariate analysis, UICC/AJCC T-stage ≥ pT2b, presence of coagulative necrosis, and positive surgical margins were predictors of recurrence and cancer-specific death.

Conclusion: Recurrence and death after surgically resected chRCC are rare. For completely excised lesions ≤ pT2a without coagulative necrosis or sarcomatoid features, prognosis is excellent. These patients should be reassured and follow-up intensity curtailed.
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http://dx.doi.org/10.1007/s00345-021-03683-9DOI Listing
April 2021

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

Cancer Epidemiol Biomarkers Prev 2021 Jun 13;30(6):1270-1274. Epub 2021 Apr 13.

International Agency for Research on Cancer (IARC-WHO), Lyon, France.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.

Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively).

Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.

Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1726DOI Listing
June 2021

A psychometric evaluation of the Functional assessment of cancer therapy-kidney symptom index (FKSI-19) among renal cell carcinoma patients suggesting an alternative two-factor structure.

Qual Life Res 2021 Apr 12. Epub 2021 Apr 12.

Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.

Purpose: To psychometrically evaluate the hypothesized four-factor structure of the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) health-related quality of life (HRQoL) instrument in a sample of surgically treated renal cell carcinoma (RCC) patients and examine if an alternative factor structure with good psychometric properties may be derived from the available items.

Methods: The model fit of the hypothesized four-factor structure was examined using confirmatory factor analysis on cohort data from 1731 individuals included in the National Swedish Kidney Cancer Register who had undergone surgery for RCC during the three years 2016-2018 and answered the FKSI-19 instrument within 6-12 months after surgery. Exploratory factor analysis was applied to the same dataset to derive a possible alternative factor solution.

Results: The four-factor structure did not reach the thresholds for good model fit using the normed χ-value or the Comparative Fit Index, although the Standardized Root Mean Square Residual and Root Mean Square Error of Approximation measures indicated good and acceptable model fits, respectively. An alternative 14-item trimmed FKSI version (FKSI-14) with a two-factor structure derived from the available FKSI-19 items was found to measure the same aspects of HRQoL as the full FKSI-19 instrument.

Conclusion: The present study is the first to use psychometric methods for examining the factor structure of the FKSI-19 instrument. The hypothesized four-factor structure of FKSI-19 provided a barely acceptable model fit. The two-factor FKSI-14 structure may be used as an alternative or complement to the four-factor structure when interpreting the FKSI-19 instrument.
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http://dx.doi.org/10.1007/s11136-021-02839-9DOI Listing
April 2021

Patient-reported outcome measures of abdominal wall morbidity after flank incision for open partial nephrectomy.

BJU Int 2021 Apr 7. Epub 2021 Apr 7.

Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.

Objective: To compare patient-reported outcome measures in patients with and without abdominal wall complications after open partial nephrectomy (OPN) via flank incision.

Patients And Methods: Patient-reported outcome measures were collected in 2017 from all patients operated on with OPN via flank incision between 2004 and 2016 in Västerbotten County, Sweden. Patients were mailed the ventral hernia pain questionnaire (VHPQ) and an abdominal wall asymmetry (AWA) questionnaire to evaluate postoperative AWA, attributed to bulge or incisional hernia. Demographic and follow-up data were retrieved from patient records.

Results: A total of 198 patients were eligible for the study, and 146 questionnaires were returned (74%). Forty-five patients (31%) reported postoperative AWA and 27 (18%) reported ongoing pain. Three patients who reported AWA had a known incisional hernia. Pain and abdominal wall stiffness were more common in patients with AWA than in those without (P < 0.01 and P < 0.01, respectively). Of the 45 patients with AWA, 25 (56%) reported this as being negative cosmetically and 16 (36%) as negative regarding activities. Patients that reported AWA were younger and had a higher body mass index at surgery (P = 0.03 and 0.04, respectively).

Conclusion: Abdominal wall asymmetry is a common sequel of flank incision for OPN and is associated with a higher incidence of chronic pain and abdominal stiffness compared to absence of postoperative AWA. Some patients reported that the effect on daily activities and the cosmetic effect caused by AWA had a negative impact on their quality of life.
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http://dx.doi.org/10.1111/bju.15420DOI Listing
April 2021

Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?

BJU Int 2021 Apr 1. Epub 2021 Apr 1.

UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR).

Subjects: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM).

Results: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14-1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73-3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03-2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3-4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3-8.5; P < 0.001). Kaplan-Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study.

Conclusion: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed.
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http://dx.doi.org/10.1111/bju.15415DOI Listing
April 2021

Increased risk for renal cell carcinoma in end stage renal disease - a population-based case-control study.

Scand J Urol 2021 Jun 26;55(3):209-214. Epub 2021 Mar 26.

Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Purpose: End-stage renal disease (ESRD) is a known risk factor for the development of renal cell carcinoma (RCC). This case-control study was performed to assess the risk in a nationwide cohort and evaluate tumor characteristics and survival in the ESRD-RCC population.

Methods: In this study, 9,299 patients with RCC identified in the National Swedish Kidney Cancer Register from 2005 until 2014 and 93,895 matched controls were linked to the Swedish Renal Registry and the National Patient Register. ESRD was defined as chronic kidney disease stage 5, kidney transplantation or kidney dialysis 0-40 years before the diagnosis of RCC.

Results: A total of 117 patients with ESRD and subsequent RCC were identified and compared with 9,087 patients with RCC. There was a 4.5-times increased risk for RCC among ESRD patients (95% CI = 3.6-5.6;  < 0.001) compared to matched controls. Longer time with ESRD increased the risk of RCC (ESRD > 9 years, OR = 10.2, 95% CI = 7.0-14.8). The ESRD-RCC patients were younger ( = 0.002), had smaller tumors ( < 0.001) and had lower tumor stage ( = 0.045). The incidence of papillary and chromophobe RCC was higher and clear cell RCC lower among the ESRD patients ( < 0.001). The 5-year overall survival was 50% in ESRD-RCC patients and 63% in RCC-only patients ( < 0.05).

Conclusion: More than 9 years with ESRD increased the risk of developing RCC 10-times compared to individuals without ESRD and the tumors showed a different histopathological pattern. Despite a less advanced tumor stage at diagnosis, the overall survival in ESRD-RCC patients was lower compared to patients with RCC-only.
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http://dx.doi.org/10.1080/21681805.2021.1900387DOI Listing
June 2021

Outcome after resection of occult and non-occult lymph node metastases at the time of nephrectomy.

World J Urol 2021 Feb 25. Epub 2021 Feb 25.

Department of Urology, Renal Cancer Unit, Royal Free Hospital, London, UK.

Purpose: There is sparse evidence on outcomes of resected occult LN metastases at the time of nephrectomy (synchronous disease). We sought to analyse a large international cohort of patients and to identify clinico-pathological predictors of long-term survival.

Materials And Methods: We collected data of consecutive patients who underwent nephrectomy and LND for T cN0-1pN1 and cM0-1 RCC at 7 referral centres between 1988 and 2019. Patients were stratified into four clinico-pathological groups: (1) cN0cM0-pN1, (2) cN1cM0-pN1(limited, 1-3 positive nodes), (3) cN1cM0-pN1(extensive, > 3 positive nodes), and (4) cM1-pN1. Overall survival (OS) was estimated using the Kaplan-Meier method, and associations with all-cause mortality (ACM) were evaluated using Cox models with multiple imputations.

Results: Of the 4370 patients with LND, 292 patients with pN1 disease were analysed. Median follow-up was 62 months, during which 171 patients died. Median OS was 21 months (95% CI 17-30 months) and the 5-year OS rate was 24% (95% CI 18-31%). Patients with cN0cM0-pN1 disease had a median OS of 57 months and a 5-year OS rate of 43%. 5-year OS (median OS) decreased to 29% (33 months) in cN1cM0-pN1(limited) and to 23% (23 months) in cN1cM0-pN1(extensive) patients. Those with cM1-pN1 disease had the worst prognosis, with a 5-year OS rate of 13% (9 months). On multivariable analysis, age (p = 0.034), tumour size (p = 0.02), grade (p = 0.02) and clinico-pathological group (p < 0.05) were significant predictors of ACM.

Conclusion: Depending on clinico-pathological group, grade and tumour size, 5-year survival of patients with LN metastases varies from 13 to 43%. Patients with resected occult lymph node involvement (cN0/pN1 cM0) have the best prognosis with a considerable chance of long-term survival.
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http://dx.doi.org/10.1007/s00345-021-03633-5DOI Listing
February 2021

Validation of data quality in the National Swedish Kidney Cancer Register.

Scand J Urol 2021 Apr 18;55(2):142-148. Epub 2021 Feb 18.

Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

Introduction: The National Swedish Kidney Cancer Register (NSKCR) was launched in 2005. It is used for health care quality improvement and research. The aim of this study was to validate the register's data quality by assessing the timeliness, completeness, comparability and validity of the register.

Material And Methods: To assess timeliness we evaluated the number of days between date of diagnosis and date of reporting the patient to the NSKCR. For completeness, we used data on number of cancer cases reported to the NSKCR compared to cases reported to the Swedish Cancer Register. Comparability was evaluated by reviewing coding routines and comparing data collected in the NSKCR to national and international guidelines. Validity was assessed by reabstraction of data from medical charts from 431 randomly selected patients diagnosed in 2007, 2010, 2013 and 2016.

Results: Timeliness has improved since the register started. In 2016, 76.9% and 96.5% of the patients were reported within 6 and 12 months respectively. Completeness was high, with a 99.5% coverage between 2008 and 2017. Registration forms and manuals were updated according to national and European guidelines. Improvements have been made continuously to decrease the risk of reporting mistakes and misunderstandings. Validity was high where a majority of the variables demonstrated an exact agreement >90% and few missing values.

Conclusion: Overall, the data quality of the NSKCR is high. Completeness, comparability and validity is high. Timeliness can be further improved, which will make it easier to follow changes and improve the care and research of RCC patients.
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http://dx.doi.org/10.1080/21681805.2021.1885485DOI Listing
April 2021

A tactile resonance sensor for prostate cancer detection - evaluation on human prostate tissue.

Biomed Phys Eng Express 2021 Feb 15. Epub 2021 Feb 15.

Umeå Universitet Medicinska fakulteten, Medical Bioscience, Pathology, Umea, 90185, SWEDEN.

Prostate cancer surgery risks erectile problems and incontinence for the patient. An instrument for guiding surgeons to avoid nerve bundle damage and ensure complete cancer removal is desirable. We present a tactile resonance sensor made of PZT ceramics, mounted in a 3D motorized translation stage for scanning and measuring tissue stiffness for detecting cancer in human prostate. The sensor may be used during surgery for guidance, scanning the prostate surface for the presence of cancer, indicating migration of cancer cells into surrounding tissue. Ten fresh prostates, obtained from patients undergoing prostate cancer surgery, were cut into 0.5 cm thick slices. Each slice was measured for tissue stiffness at about 25 different sites and compared to histology for validation cancer prediction by stiffness. The statistical analysis was based on a total of 148 sites with non-cancer and 40 sites with cancer. Using a generalized linear mixed model (GLMM), the stiffness data predicted cancer with an area under the curve of 0.74, after correcting for overfitting using bootstrap validation. Mean prostate stiffness on the logarithmic scale (p = 0.015) and standardized Z-scores (p = 0.025) were both significant predictors of cancer. This study concludes that stiffness measured by the tactile resonance sensor is a significant predictor of prostate cancer with potential for future development towards a clinical instrument for surgical guidance.
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http://dx.doi.org/10.1088/2057-1976/abe681DOI Listing
February 2021

Novel Liquid Biomarkers and Innovative Imaging for Kidney Cancer Diagnosis: What Can Be Implemented in Our Practice Today? A Systematic Review of the Literature.

Eur Urol Oncol 2021 Feb 3;4(1):22-41. Epub 2021 Jan 3.

European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group; Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Context: The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need.

Objective: To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis.

Evidence Acquisition: A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool.

Evidence Synthesis: Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation.

Conclusions: Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making.

Patient Summary: We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.
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http://dx.doi.org/10.1016/j.euo.2020.12.011DOI Listing
February 2021

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma.

Eur Urol 2021 Mar 24;79(3):339-342. Epub 2020 Dec 24.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk. PATIENT SUMMARY: New data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
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http://dx.doi.org/10.1016/j.eururo.2020.12.005DOI Listing
March 2021

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 Mar 17;30(3):507-512. Epub 2020 Dec 17.

School of Public Health, Imperial College London, London, United Kingdom.

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives.

Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure.

Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025.

Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population.

Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1438DOI Listing
March 2021

Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma.

J Transl Med 2020 11 13;18(1):435. Epub 2020 Nov 13.

Department of Medical Biosciences, Pathology, Umeå University, 901 87, Umeå, Sweden.

Background: Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables.

Methods: A novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression.

Results: The "triple classifier" which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (CIP) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis.

Conclusions: The triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.
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http://dx.doi.org/10.1186/s12967-020-02608-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666468PMC
November 2020

The Impact of Histological Subtype on the Incidence, Timing, and Patterns of Recurrence in Patients with Renal Cell Carcinoma After Surgery-Results from RECUR Consortium.

Eur Urol Oncol 2021 Jun 24;4(3):473-482. Epub 2020 Oct 24.

Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK; Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Current follow-up strategies for patients with renal cell carcinoma (RCC) after curative surgery rely mainly on risk models and the treatment delivered, regardless of the histological subtype.

Objective: To determine the impact of RCC histological subtype on recurrence and to examine the incidence, pattern, and timing of recurrences to improve follow-up recommendations.

Design, Setting, And Participants: This study included consecutive patients treated surgically with curative intention (ie, radical and partial nephrectomy) for nonmetastatic RCC (cT1-4, M0) between January 2006 and December 2011 across 15 centres from 10 countries, as part of the euRopEan association of urology renal cell carcinoma guidelines panel Collaborative multicenter consortium for the studies of follow-Up and recurrence patterns in Radically treated renal cell carcinoma patients (RECUR) database project.

Outcome Measurements And Statistical Analysis: The impact of histological subtype (ie, clear cell RCC [ccRCC], papillary RCC [pRCC], and chromophobe RCC [chRCC]) on recurrence-free survival (RFS) was assessed via univariate and multivariate analyses, adjusting for potential interactions with important variables (stage, grade, risk score, etc.) Patterns of recurrence for all histological subtypes were compared according to recurrence site and risk criteria.

Results And Limitations: Of the 3331 patients, 62.2% underwent radical nephrectomy and 37.8% partial nephrectomy. A total of 2565 patients (77.0%) had ccRCC, 535 (16.1%) had pRCC, and 231 (6.9%) had chRCC. The median postoperative follow-up period was 61.7 (interquartile range: 47-83) mo. Patients with ccRCC had significantly poorer 5-yr RFS than patients with pRCC and chRCC (78% vs 86% vs 91%, p = 0.001). The most common sites of recurrence for ccRCC were the lung and bone. Intermediate-/high-risk pRCC patients had an increased rate of lymphatic recurrence, both mediastinal and retroperitoneal, while recurrence in chRCC was rare (8.2%), associated with higher stage and positive margins, and predominantly in the liver and bone. Limitations include the retrospective nature of the study.

Conclusions: The main histological subtypes of RCC exhibit a distinct pattern and dynamics of recurrence. Results suggest that intermediate- to high-risk pRCC may benefit from cross-sectional abdominal imaging every 6 mo until 2 yr after surgery, while routine imaging might be abandoned for chRCC except for abdominal computed tomography in patients with advanced tumour stage or positive margins.

Patient Summary: In this analysis of a large database from 15 countries around Europe, we found that the main histological subtypes of renal cell carcinoma have a distinct pattern and dynamics of recurrence. Patients should be followed differently according to subtype and risk score.
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http://dx.doi.org/10.1016/j.euo.2020.09.005DOI Listing
June 2021

Targeted therapy for metastatic renal cell carcinoma.

Cochrane Database Syst Rev 2020 10 14;10:CD012796. Epub 2020 Oct 14.

Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.

Background: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.

Objectives: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.

Search Methods: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.

Selection Criteria: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.

Data Collection And Analysis: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.

Main Results: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants.

Authors' Conclusions: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.
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http://dx.doi.org/10.1002/14651858.CD012796.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094280PMC
October 2020

Survival advantage of upfront cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma compared with systemic and palliative treatments in a real-world setting.

Scand J Urol 2020 Dec 8;54(6):487-492. Epub 2020 Sep 8.

Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Recently, the CARMENA and SURTIME studies, suggested that upfront cytoreductive nephrectomy (CN) should be abandoned for patients with intermediate and high-risk metastatic renal cell carcinoma (mRCC). However, CN remains an indication in low-risk and when immediate systemic treatment is not required. The aim was to evaluate the long-term overall survival (OS) in patients with primary mRCC, based on the first line treatment.

Methods: There were 1483 patients with primary mRCC in the National Kidney Cancer Registry from 2005 to 2013. Data on primary treatment, TNM stage, RCC type, tumor size, patient age and sex were extracted. Survival time was calculated from time of diagnosis to time of death or until July 2019. Mann-Whitney U and Chi-square tests, the Kaplan-Meyer method and Cox regression analyses were used.

Results: Patients primary treated with CN had a significantly longer OS ( < .001) than patients primary treated with systemic therapy or palliation. In a Cox regression multivariate analysis, the hazard ratio for CN compared with no CN was 1.600, 95%Ci (1.492 - 1.691),  < .001. Also occurrence of lymph node metastases, T-stage, patients age and year of diagnosis, remained as independent predictors of OS.

Conclusion: Patients primary treated with CN survived significantly longer than patients primary treated with systemic therapy or palliation, in all age groups. CN was an important first-line treatment option in mRCC patients.
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http://dx.doi.org/10.1080/21681805.2020.1815833DOI Listing
December 2020

Menstrual Factors, Reproductive History, Hormone Use, and Urothelial Carcinoma Risk: A Prospective Study in the EPIC Cohort.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1654-1664. Epub 2020 May 28.

Hellenic Health Foundation, Kaisareias 13 & Alexandroupoleos, Athens, Greece.

Background: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk.

Methods: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non-muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models.

Results: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR = 0.48; 0.25-0.90; in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03-1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non-muscle-invasive urothelial carcinoma risk was observed.

Conclusions: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk.

Impact: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0184DOI Listing
August 2020

Significance of PI3K signalling pathway in clear cell renal cell carcinoma in relation to VHL and HIF status.

J Clin Pathol 2021 Apr 28;74(4):216-222. Epub 2020 May 28.

Department of Surgical and Preoperative Sciences, Urology and Andrology, Umeå Universitet, Umea, Västerbotten, Sweden.

Renal cell carcinoma (RCC) includes diverse tumour types characterised by various genetic abnormalities. The genetic changes, like mutations, deletions and epigenetic alterations, play a crucial role in the modification of signalling networks, tumour pathogenesis and prognosis. The most prevalent RCC type, clear cell RCC (ccRCC), is asymptomatic in the early stages and has a poorer prognosis compared with the papillary and the chromophobe types RCCs. Generally, ccRCC is refractory to chemotherapy and radiation therapy. Loss of von Hippel-Lindau (VHL) gene and upregulation of hypoxia-inducible factors (HIF), the signature of most sporadic ccRCC, promote multiple growth factors. Hence, VHL/HIF and a variety of pathways, including phosphatase and TEnsin homolog on chromosome 10/phosphatidylinositol-3-kinase (PI3K)/AKT, are closely connected and contribute to the ontogeny of ccRCC. In the recent decade, multiple targeting agents have been developed based on blocking major signalling pathways directly or indirectly involved in ccRCC tumour progression, metastasis, angiogenesis and survival. However, most of these drugs have limitations; either metastatic ccRCC develops resistance to these agents, or despite blocking receptors, tumour cells use alternate signalling pathways. This review compiles the state of knowledge about the PI3K/AKT signalling pathway confined to ccRCC and its cross-talks with VHL/HIF pathway.
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http://dx.doi.org/10.1136/jclinpath-2020-206693DOI Listing
April 2021

The renal cell cancer database Sweden (RCCBaSe) - a new register-based resource for renal cell carcinoma research.

Scand J Urol 2020 Jun 21;54(3):235-240. Epub 2020 May 21.

Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

In 2005, the National Swedish Kidney Cancer Register (NSKCR) was set up to collect data on newly diagnosed patients with renal cell carcinoma (RCC). In 2015, the NSKCR was linked to a number of national healthcare and demographic registers to construct the Renal Cell Cancer Database Sweden (RCCBaSe). The aim was to facilitate research on trends in incidence, effects of treatment and survival, with detailed data on tumour characteristics, treatment, pharmaceutical prescriptions, socioeconomic factors and comorbidity. All patients registered in the NSKCR between 2005 and 2014 were included. For each case, ten controls and first-degree relatives for cases and controls were identified. The RCCBaSe was created linking all cases, controls and first-degree relatives to a number of national registers with information on co-morbidity, socioeconomic factors and pharmaceutical prescriptions. Between 2005 and 2014, a total of 9,416 patients with RCC were reported to the NSKCR. 94,159 controls and a total cohort of 575,007 individuals including cases, controls and first-degree relatives were identified. Linkage to the Swedish cancer register resulted in 106,772 matches. When linked to the National patient register, 432,677 out-patient and 471,359 in-patient matches were generated. When linked to the Swedish renal registry 1,778 matches were generated. Linkage to the Prescribed drug register resulted in 448,084 matches and linkage to the The Longitudinal integration database for health insurance and labour market studies database resulted in 450,017 matches. By linking the NSKCR to several Swedish national databases, a unique database for RCC research has been created.
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http://dx.doi.org/10.1080/21681805.2020.1766561DOI Listing
June 2020

European Association of Urology Guidelines Office Rapid Reaction Group: An Organisation-wide Collaborative Effort to Adapt the European Association of Urology Guidelines Recommendations to the Coronavirus Disease 2019 Era.

Eur Urol 2020 Jul 27;78(1):21-28. Epub 2020 Apr 27.

Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

The coronavirus disease 2019 (COVID-19) pandemic is unlike anything seen before by modern science-based medicine. Health systems across the world are struggling to manage it. Added to this struggle are the effects of social confinement and isolation. This brings into question whether the latest guidelines are relevant in this crisis. We aim to support urologists in this difficult situation by providing tools that can facilitate decision making, and to minimise the impact and risks for both patients and health professionals delivering urological care, whenever possible. We hope that the revised recommendations will assist urologist surgeons across the globe to guide the management of urological conditions during the current COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.eururo.2020.04.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183974PMC
July 2020

Limitations of Available Studies Prevent Reliable Comparison Between Tumour Ablation and Partial Nephrectomy for Patients with Localised Renal Masses: A Systematic Review from the European Association of Urology Renal Cell Cancer Guideline Panel.

Eur Urol Oncol 2020 08 31;3(4):433-452. Epub 2020 Mar 31.

Department of Urology, University of Rennes, Rennes, France. Electronic address:

The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel performed a protocol-driven systematic review (SR) on thermal ablation (TA) compared with partial nephrectomy (PN) for T1N0M0 renal masses, in order to provide evidence to support its recommendations. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed, and only comparative studies published between 2000 and 2019 were included. Twenty-six nonrandomised comparative studies were included, recruiting a total of 167 80 patients. Risk of bias (RoB) assessment revealed high or uncertain RoB across all studies, with the vast majority being retrospective, observational studies with poorly matched controls and short follow-up. Limited data showed TA to be safe, but its long-term oncological effectiveness compared with PN remains uncertain. A quality assessment of pre-existing SRs (n=11) on the topic, using AMSTAR, revealed that all SRs had low confidence rating, with all but two SRs being rated critically low. In conclusion, the current data are inadequate to make any strong and clear conclusions regarding the clinical effectiveness of TA for treating T1N0M0 renal masses compared with PN. Therefore, TA may be cautiously considered an alternative to PN for T1N0M0 renal masses, but patients must be counselled carefully regarding the prevailing uncertainties. We recommend specific steps to improve the evidence base based on robust primary and secondary studies. PATIENT SUMMARY: In this report, we looked at the literature to determine the effectiveness of thermoablation (TA) in the treatment of small kidney tumours compared with surgical removal. We found that TA could cautiously be offered as an option due to many remaining uncertainties regarding its effectiveness.
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http://dx.doi.org/10.1016/j.euo.2020.02.001DOI Listing
August 2020

Topographic distribution of first landing sites of lymphatic metastases from patients with renal cancer.

Urol Oncol 2020 05 3;38(5):521-525. Epub 2020 Mar 3.

Netherlands Cancer Institute, Department of Urology, Amsterdam, the Netherlands; Royal Free Hospital, Department of Urology, Renal Cancer Unit, London, United Kingdom. Electronic address:

Introduction And Objective: Adjuvant studies with checkpoint inhibitors have attracted new interest in accurate pathological lymph node (LN) staging in renal cell carcinoma. Sentinel lymph node (SN) studies in cN0 patients revealed the pattern of lymphatic radiotracer drainage from renal tumors. The aim of this study was to describe the location of single- or oligometastatic LN and analyze if the topography of these first landing sites matches the drainage pattern observed in SN studies of renal tumors.

Materials And Methods: We collected data from 8 referral centers from 1990 to 2018 of all patients with pT1-4 cN0 or cN1 M0 renal cell carcinoma with pathologically confirmed single- or oligometastases in locoregional LN. The location of LN metastases, number, size of metastatic LN, and survival were analyzed using descriptive statistics with SPSS version 22 (IBM, Chicago, IL).

Results: From 3,794 patients with histologically confirmed pN1, a total of 76 patients (2%) with single- or oligometastatic pN1 were identified, of whom 24 (31.6%) and 52 (68.4%) were cN0 and cN1, respectively. On the left side, LN metastases were predominantly located in the para-aortal (48.0%; 95% confidence interval [CI] 29.22-63.12%) and hilar (31.42%; 95% CI 17.4-49.4%) area. On the right side, metastases located in retrocaval (26.82%; 95% CI 14.7-43.2%), hilar (26.82%; 95% CI 14.7-43.2%), interaortocaval (26.82%; 95% CI 14.7-43.2%), and paracaval (17.07%; 95% CI 7.6-32.6%) LNs. These landing sites exactly matched the lymphatic drainage pattern of intratumorally injected radiotracer reported in SN studies for both sides.

Conclusions: Single- or oligometastatic LNs in renal cancer are mainly located in the hilar, retro-, para, and interaortocaval region on the right side and para-aortal region on the left side. These first landing sites match the drainage pattern reported in SN trials.
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http://dx.doi.org/10.1016/j.urolonc.2019.12.023DOI Listing
May 2020

An in-vitro assay using human spermatozoa to detect toxicity of biologically active substances.

Sci Rep 2019 10 10;9(1):14525. Epub 2019 Oct 10.

Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden.

Identifying the key toxic players within an in-vivo toxic syndrome is crucial to develop targeted therapies. Here, we established a novel method that characterizes the effect of single substances by means of an ex-vivo incubation set-up. We found that primary human spermatozoa elicit a distinct motile response on a (uremic) toxic milieu. Specifically, this approach describes the influence of a bulk toxic environment (uremia) as well as single substances (uremic toxins) by real-time analyzing motile cellular behavior. We established the human spermatozoa-based toxicity testing (HSTT) for detecting single substance-induced toxicity to be used as a screening tool to identify in-vivo toxins. Further, we propose an application of the HSTT as a method of clinical use to evaluate toxin-removing interventions (hemodialysis).
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http://dx.doi.org/10.1038/s41598-019-50929-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787250PMC
October 2019

Interactions between TGF-β type I receptor and hypoxia-inducible factor-α mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma.

Cell Cycle 2019 09 24;18(17):2141-2156. Epub 2019 Jul 24.

a Department of Medical Biosciences, Pathology , Umeå , Sweden.

To investigate the significance of expression of HIF-1α, HIF-2α, and SNAIL1 proteins; and TGF-β signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-α and TGF-β signaling pathway, including the TGF-β type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1α/2α, TGF-β signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1α and HIF-2α were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2α associated with poor cancer-specific survival, while HIF-1α and SNAIL1 did not associate with survival. Moreover, HIF-2α positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1α positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2α. Intriguingly, experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1α and HIF-2α, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1α and HIF-2α, through its kinase activity. Under hypoxic conditions, HIF-α proteins correlated with the activated TGF-β signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-β signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-α contributes to tumor progression.
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http://dx.doi.org/10.1080/15384101.2019.1642069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986558PMC
September 2019

Safe Use of Immune Checkpoint Inhibitors in the Multidisciplinary Management of Urological Cancer: The European Association of Urology Position in 2019.

Eur Urol 2019 Sep 21;76(3):368-380. Epub 2019 Jun 21.

Department of Urology, University Hospitals Leuven, Leuven, Belgium.

Immune checkpoint inhibitors (ICIs) are now used routinely to treat advanced or metastatic urothelial and renal cell carcinoma, among other cancers. Furthermore, multiple trials are currently exploring their role in adjuvant, neoadjuvant, and noninvasive (eg, high-grade non-muscle-invasive bladder cancer) settings. Consequently, urologists are increasingly confronted with patients who are on, have recently received, or will be treated with ICI therapy. The care of these patients is likely to be shared between urologists and medical oncologists, with additional occasional support of other medical specialties. Therefore, it is important that urologists have good knowledge of immune-related side effects. Here, we provide advice on prevention, early diagnosis, and clinical management of the most relevant toxicities to strengthen urologists' insight and, thus, role in the multidisciplinary management in the new immunotherapy era. PATIENT SUMMARY: Immune therapy is a common treatment for many patients with advanced cancer. We describe common side effects of this treatment, and advise how they are best prevented and managed.
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http://dx.doi.org/10.1016/j.eururo.2019.05.041DOI Listing
September 2019