The Prognostic Value of Human Papillomavirus Status in Penile Cancer: Outcomes From a Norwegian Cohort Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) can develop from human papillomavirus (HPV) infection. This study investigates if the prognostic value of the TNM stage groups or the components tumor stage (pT), grade of differentiation (Grade), lymphovascular invasion (LVI), and nodular stage (pN) depend on HPV status. Also, whether the value of tumor parameters (pT, Grade, and LVI) for predicting node-positive disease depends on HPV status was investigated. PATIENTS AND METHODS: Stored tumor tissue from 226 patients treated for PSCC in Western Norway between 1973 and 2023 was investigated for HPV DNA. Histopathological variables were reevaluated according to the current TNM classification. Disease course was registered from hospital records. Inclusion of an interaction term between HPV and TNM stage groups in Cox regression enabled analysis of whether cancer-specific survival (CSS) of the stage groups depended on HPV status. This was also done separately for pT, Grade, LVI, and pN. Logistic regression with interaction terms between HPV and the tumor parameters were used to investigate if their predictive value depended on HPV status. RESULTS: HPV DNA was detected in 43% of the tumors. Stratified by HPV status, there was no significant interaction term in the Cox regression between HPV status and TNM stage groups (P = .74). Similar results were found for pT (P = .94), Grade (P = .08), LVI (P = .91) and pN (P = .77). Moreover, there were no significant interaction terms in the logistic regression between HPV status and the tumor parameters pT, Grade, and LVI (all P > .2). CONCLUSIONS: This study found that prognosis of the TNM stage groups and the components pT, Grade, LVI, and pN were not modified by HPV in PSCC. The value of pT, Grade, and LVI for predicting lymph node-positive disease was not affected by HPV status.

Long-term follow-up of IgA nephropathy: clinicopathological features and predictors of outcomes.

Background: The establishment of the Oxford classification and newly developed prediction models have improved the prognostic information for immunoglobulin A nephropathy (IgAN). Considering new treatment options, optimizing prognostic information and improving existing prediction models are favorable. Methods: We used random forest survival analysis to select possible predictors of end-stage kidney disease among 37 candidate variables in a cohort of 232 patients with biopsy-proven IgAN retrieved from the Norwegian Kidney Biopsy Registry. The predictive value of variables with relative importance >5% was assessed using concordance statistics and the Akaike information criterion. Pearson's correlation coefficient was used to identify correlations between the selected variables. Results: The median follow-up period was 13.7 years. An isolated analysis of histological variables identified six variables with relative importance >5%: T %, segmental glomerular sclerosis without characteristics associated with other subtypes (not otherwise specified, NOS), normal glomeruli, global sclerotic glomeruli, segmental adherence and perihilar glomerular sclerosis. When histopathological and clinical variables were combined, estimated glomerular filtration rate (eGFR), proteinuria and serum albumin were added to the list. T % showed a better prognostic value than tubular atrophy/interstitial fibrosis (T) lesions with C-indices at 0.74 and 0.67 and was highly correlated with eGFR. Analysis of the subtypes of segmental glomerulosclerosis (S) lesions revealed that NOS and perihilar glomerular sclerosis were associated with adverse outcomes. Conclusions: Reporting T lesions as a continuous variable, normal glomeruli and subtypes of S lesions could provide clinicians with additional prognostic information and contribute to the improved performance of the Oxford classification and prognostic tools.

Penile Cancers Attributed to Human Papillomavirus Are Associated with Improved Survival for Node-positive Patients. Findings from a Norwegian Cohort Study Spanning 50 Years.

BACKGROUND: Human papillomavirus (HPV) infection is a risk factor for the development of penile squamous cell carcinoma (PSCC). It remains inconclusive whether HPV-related PSCC has a different prognosis from non-HPV-related PSCC. OBJECTIVE: To investigate the relationship between HPV status and survival as well as temporal changes in the proportion of HPV-related PSCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort of 277 patients treated in Norway between 1973 and 2022 was investigated for HPV DNA in tumor tissue. Clinicopathological variables and disease course were registered. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves and Cox regression were used to investigate the determinants of cancer-specific survival (CSS). The chi-square test for trend in proportions enabled investigation of temporal changes in the HPV-related proportion of PSCC patients treated in Western Norway (n = 211). RESULTS AND LIMITATIONS: HPV DNA was detected in tumor tissue from 131 (47%) patients. Stratified by HPV status, 5-yr CSS did not differ between groups (p = 0.37). When investigating only node-positive patients, however, presence of HPV DNA was an independent predictor of better survival in multivariable Cox regression after adjustment for age, nodal stage, and adjuvant therapy (hazard ratio 0.54, 95% confidence interval: [0.30-0.99], p = 0.04). In cases from Western Norway, an increasing proportion of HPV-related cases over time was found (p = 0.01). The main limitation is the retrospective study design. CONCLUSIONS: HPV DNA in tumor tissue was associated with significantly better CSS for node-positive patients. The proportion of HPV DNA-positive PSCC has increased significantly in Western Norway over the past 50 yr. PATIENT SUMMARY: We investigated the impact of human papillomavirus (HPV) on the survival of penile cancer patients treated over a 50-yr period in Norway. We found that for patients with lymph node metastasis, survival was better for HPV-related cases. We also found that the proportion of cases due to HPV has increased in Western Norway.

Validation of two IgA nephropathy risk-prediction tools using a cohort with a long follow-up.

BACKGROUND: Recently, two immunoglobulin A (IgA) nephropathy-prediction tools were developed that combine clinical and histopathologic parameters. The International IgAN Prediction Tool predicts the risk for 50% declines in the estimated glomerular filtration rate or end-stage kidney disease up to 80 months after diagnosis. The IgA Nephropathy Clinical Decision Support System uses artificial neural networks to estimate the risk for end-stage kidney disease. We aimed to externally validate both prediction tools using a Norwegian cohort with a long-term follow-up. METHODS: We included 306 patients with biopsy-proven primary IgA nephropathy in this study. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford Classification. We used discrimination and calibration as principles for externally validating the prognostic models. RESULTS: The median patient follow-up was 17.1 years. A cumulative, dynamic, time-dependent receiver operating characteristic analysis showed area under the curve values ranging from 0.90 at 5 years to 0.83 at 20 years for the International IgAN Prediction Tool, while time-naive analysis showed an area under the curve value at 0.83 for the IgA Nephropathy Clinical Decision Support System. The International IgAN Prediction Tool was well calibrated, while the IgA Nephropathy Clinical Decision Support System tends to underestimate risk for patients at higher risk and overestimates risk in the lower risk categories. CONCLUSIONS: We have externally validated two prediction tools for IgA nephropathy. The International IgAN Prediction Tool performed well, while the IgA Nephropathy Clinical Decision Support System has some limitations.

A multiomics disease progression signature of low-risk ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Identification of ccRCC likely to progress, despite an apparent low risk at the time of surgery, represents a key clinical issue. From a cohort of adult ccRCC patients (n = 443), we selected low-risk tumors progressing within a 5-years average follow-up (progressors: P, n = 8) and non-progressing (NP) tumors (n = 16). Transcriptome sequencing, miRNA sequencing and proteomics were performed on tissues obtained at surgery. We identified 151 proteins, 1167 mRNAs and 63 miRNAs differentially expressed in P compared to NP low-risk tumors. Pathway analysis demonstrated overrepresentation of proteins related to "LXR/RXR and FXR/RXR Activation", "Acute Phase Response Signaling" in NP compared to P samples. Integrating mRNA, miRNA and proteomic data, we developed a 10-component classifier including two proteins, three genes and five miRNAs, effectively differentiating P and NP ccRCC and capturing underlying biological differences, potentially useful to identify "low-risk" patients requiring closer surveillance and treatment adjustments. Key results were validated by immunohistochemistry, qPCR and data from publicly available databases. Our work suggests that LXR, FXR and macrophage activation pathways could be critically involved in the inhibition of the progression of low-risk ccRCC. Furthermore, a 10-component classifier could support an early identification of apparently low-risk ccRCC patients.

Utilizing the MEST score for prognostic staging in IgA nephropathy.

BACKGROUND: The Oxford classification/MEST score is an established histopathologic scoring system for patients with IgA nephropathy (IgAN). The objective of this study was to derive a prognostic model for IgAN based on the MEST score and histopathologic features. METHODS: A total of 306 patients with biopsy-proven primary IgAN were included. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford classification. The study endpoint was end-stage renal disease (ESRD). Patients were subclassified into three risk models based on histologic features (Model A), a composite score calculated from the adjusted hazard ratio values (Model B), and on quartiles (Model C). RESULTS: The mean follow-up time was 16.5 years (range 0.2-28.1). In total, 61 (20%) patients reached ESRD during the study period. Univariate analysis of M, E, S, T and C lesions demonstrated that all types were associated with an increased risk of ESRD; however, a multivariate analysis revealed that only S, T and C lesions were associated with poor outcomes. Statistical analysis of 15-year data demonstrated that Models A and B were as predictive as the MEST score, with an area-under-the-curve at 0.85. The Harrel c index values were 0.81 and 0.80 for the MEST score and Models A and B, respectively. In the present cohort, adding C lesions to the MEST score did not improve the models prognostic value. CONCLUSIONS: Patients can be divided into risk classes based on their MEST scores. Histopathologic data provide valuable prognostic information at the time of diagnosis. Model B was the most suitable for clinical practice because it was the most user-friendly.

AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in "low-risk" patients who were potentially eligible for adjuvant treatments or more intensive follow-up. METHODS: We assembled a cohort of ccRCC patients (n = 443) and identified all "low-risk" patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these "low-risk" patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas. RESULTS: Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E-7). CONCLUSION: AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as "low risk" at the time of surgery.

The levels of IL-6 and soluble IL-33R are increased in the renal vein during surgery for clear cell renal cell carcinoma.

PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.

Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).

PURPOSE: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. METHODS: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. RESULTS: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. CONCLUSIONS: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

The Biological Context of C-Reactive Protein as a Prognostic Marker in Renal Cell Carcinoma: Studies on the Acute Phase Cytokine Profile.

High serum levels of the acute phase protein C-reactive protein (CRP) are associated with an adverse prognosis in renal cancer. The acute phase reaction is cytokine-driven and includes a wide range of inflammatory mediators. This overall profile of the response depends on the inducing event and can also differ between patients. We investigated an extended acute phase cytokine profile for 97 renal cancer patients. Initial studies showed that the serum CRP levels had an expected prognostic association together with tumor size, stage, nuclear grading, and Leibovich score. Interleukin (IL)6 family cytokines, IL1 subfamily mediators, and tumor necrosis factor (TNF)α can all be drivers of the acute phase response. Initial studies suggested that serum IL33Rα (the soluble IL33 receptor α chain) levels were also associated with prognosis, although the impact of IL33Rα is dependent on the overall cytokine profile, including seven IL6 family members (IL6, IL6Rα, gp130, IL27, IL31, CNTF, and OSM), two IL1 subfamily members (IL1RA and IL33Rα), and TNFα. We identified a patient subset characterized by particularly high levels of IL6, IL33Rα, and TNFα alongside an adverse prognosis. Thus, the acute phase cytokine reaction differs between renal cancer patients, and differences in the acute phase cytokine profile are associated with prognosis.

Prognostic Factors in Anti-Neutrophil Cytoplasmic Antibody-Associated Glomerulonephritis with Severe Glomerular Sclerosis: A National Registry-Based Cohort Study.

BACKGROUND: Classification of patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) into histological classes is useful for predicting a patient's risk of progression to end-stage renal disease (ESRD). However, even in the worst prognostic group, the 5-year end-stage renal disease-free survival rate is as high as 50%. OBJECTIVES: To investigate those prognostic factors indicative of progression to ESRD in patients with ANCA-GN and sclerosing histology. METHODS: Patients from the Norwegian Kidney Biopsy Registry between 1991 and 2012 who had biopsy verified pauci-immune glomerulonephritis, positive ANCA serology, and sclerosing histology were included. Cases with ESRD during follow-up were identified via linkage with the Norwegian Renal Registry. Potential prognostic factors with relevant cut-offs were compared in patients with and without progression to ESRD during follow-up. RESULTS: Of 23 included patients, 10 progressed to ESRD. ESRD patients had a lower initial estimated glomerular filtration rate (eGFR; 21 versus 52 ml/min/1.73 m2) and a lower percentage of normal glomeruli (4% versus 15%). Five-year risks of ESRD with eGFR >15 versus ≤15 ml/min/1.73 m2 were 77% and 15%, with percentage normal glomeruli >10% versus ≤10%, 83% and 39%. CONCLUSIONS: eGFR and percentage of normal glomeruli are strong risk factors for ESRD in ANCA-GN with sclerosing histology.

Prognosis and Histological Classification in Elderly Patients with ANCA-Glomerulonephritis: A Registry-Based Cohort Study.

BACKGROUND: The value of a histologic classification scheme to classify patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) into focal, mixed, crescentic, and sclerotic types for predicting risk of end-stage renal disease (ESRD) is well documented. However, the prognostic value of histological classification specifically in elderly patients (≥70 years) with ANCA-GN has not previously been investigated. METHODS: Patients with biopsy-verified pauci-immune necrotizing glomerulonephritis were identified from the Norwegian Kidney Biopsy Registry between 1991 and 2012 and those ≥70 years of age at the time of diagnosis and having positive anti-neutrophil cytoplasmic antibody serology were included in this study. The incidence rate of ESRD and/or death was determined by linking the study cohort to the Norwegian Renal Registry and the Population Registry of Norway. The ESRD-free survival and patient survival were compared between the 4 histological types. RESULTS: Of the 81 patients included, 20 progressed to ESRD and 34 died. The 1-year and 5-year ESRD-free survival varied between histological groups (p = 0.003) as follows: focal, 97% and 97%, respectively; mixed, 70% and 57%; crescentic, 76% and 63%; and sclerotic, 49% and 49%. Patient survival did not differ significantly between groups (p = 0.30). CONCLUSION: Histological classification in elderly patients with ANCA-GN is useful for predicting ESRD but not survival.

Impact of Proteinase 3 versus Myeloperoxidase Positivity on Risk of End-Stage Renal Disease in ANCA-Associated Glomerulonephritis Stratified by Histological Classification: A Population-Based Cohort Study.

BACKGROUND: End-stage renal disease (ESRD) risk in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated glomerulonephritis (ANCA-GN) according to ANCA serotype and stratified by histological classification has not been previously investigated. METHODS: Patients from the Norwegian Kidney Biopsy Registry (NKBR) between 1991 and 2012 who had biopsy-verified pauci-immune glomerulonephritis and positive antineutrophil cytoplasmic antibody serology were included. Cases with ESRD during follow-up were identified in the Norwegian Renal Registry. ESRD-free survival with proteinase 3 (PR3) versus myeloperoxidase- (MPO-) ANCA positivity stratified into 4 histological classes was investigated. RESULTS: Three hundred fifty-eight patients, of whom 87 progressed to ESRD during follow-up, were included. Patients with PR3- as compared to MPO-ANCA were younger (58 versus 64 years, p = 0.001), had a higher percentage of males (62 versus 41%, p < 0.001), had a lower percentage with a sclerozing glomerulonephritis pattern (4 versus 16%, p < 0.001), and had a significantly higher cumulative ESRD-free survival (90 versus 80%, p = 0.007) at 1-year follow-up. No significant differences in cumulative ESRD-free survival with PR3- as compared to MPO-ANCA were observed by histological stratification. CONCLUSION: Advanced glomerular sclerosis is found more frequently in patients with MPO-ANCA, explaining the higher risk of ESRD. ANCA serotypes have no impact on prognosis of patients with similar histological findings.

Exploring sex-specific differences in the presentation and outcomes of ANCA-associated vasculitis: a nationwide registry-based cohort study.

PURPOSE: Sex-specific differences in the risk of end-stage renal disease (ESRD) in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) stratified by histological classification have not been previously investigated. METHODS: Patients with biopsy-verified pauci-immune necrotizing GN and positive ANCA serology in the Norwegian Kidney Biopsy Registry between 1991 and 2012 were included. Patients with ESRD during follow-up were identified from the Norwegian Renal Registry. ESRD-free survival stratified by histological classifications was investigated. RESULTS: We analyzed 358 patients, of whom 87 progressed to ESRD during follow-up. Overall ESRD-free survival at 1 and 5 years in the entire cohort was 81 and 71% in males versus 90 and 80% in females, respectively; 94 and 84% in males versus 98 and 98% in females with focal histology, respectively; 85 and 76% in males versus 89 and 77% in females with mixed histology, respectively; 72 and 58% in males versus 90 and 78% in females with crescentic histology, respectively; and 52 and 46% in males versus 60 and 38% in females with sclerotic histology, respectively. Males had an increased risk of ESRD (adjusted hazard ratio, 2.44 [1.56-3.82]; p < 0.001). CONCLUSION: Male sex is associated with increased risk of ESRD across all histological classes of ANCA-GN.

Tumour cell expression of interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and anti-angiogenic treatment is currently first line therapy for metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have a major influence on patient quality of life. The need for predictive biomarkers to select responders to receptor tyrosine kinase inhibitors upfront is urgent. We investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in mccRCC. Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumour tissue was stained by immunohistochemistry for selected markers related to angiogenesis [vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR2), platelet-derived growth factor receptor ß (PDGFRß), and heat shock protein 27 (HSP27)] and immune responses [Interleukin 6 receptor α (IL6Rα), interleukin-6 (IL6), and jagged1 (JAG1)]. The predictive potential of the candidate markers was assessed by correlations with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. Low tumour cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher's exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF-A and HSP27. Furthermore, low expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF-A, VEGFR2, and PDGFRß. Loss of tumour cell expression of IL6Rα in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.

National Norwegian Practice Patterns for Surgical Treatment of Kidney Cancer Tumors ≤7cm: Adherence to Changes in Guidelines May Improve Overall Survival.

BACKGROUND: Guidelines on surgical treatment for kidney cancer (KC) have changed over the last 10 yr. We present population-based data for patients with KC tumors ≤7cm from 2008 to 2013 to investigate whether surgical practice in Norway has changed according to guidelines. OBJECTIVE: To assess the predictors of treatment and survival after KC surgery. DESIGN, SETTING, AND PARTICIPANTS: We identified all surgically treated KC patients with tumors ≤7cm without metastasis diagnosed during 2008-2013 (2420 patients) from the Cancer Registry of Norway. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcomes were analyzed using joinpoint regression, multivariate logistic regression, Kaplan-Meier survival estimates, Cox regression, relative survival (RS), and competing-risk analyses. RESULTS AND LIMITATIONS: The mean follow-up was 5.2 yr. There was a 28% increase in the number of patients undergoing surgical treatment over the study period. Joinpoint regression revealed a significant annual increase in partial nephrectomy (PN) and a small reduction in radical nephrectomy (RN). PN increased from 43% to 66% for tumors ≤4cm and from 10% to 18% for tumors of 4.1-7cm. Minimally invasive (MI) RN increased from 53% to 72% and MI PN from 25% to 64%, of which 55% of procedures were performed with robotic assistance in 2013. The geographical distribution of treatment approaches differed significantly. Both PN and MI approaches were more frequent in high-volume hospitals. Cox regression analysis revealed that PN, age, and Fuhrman grade and stage were independent predictors of survival. There were no significant differences in cancer-specific survival (p=0.8). The 5-yr RS for T1a disease was higher after PN than after RN. CONCLUSIONS: The rate of PN for tumors ≤7cm increased in the 6-yr study period. MI approaches increased for both RN and PN. This treatment shift coincides with the new guideline recommendations in 2010. The possible better survival for patients undergoing PN compared to RN indicates the importance of following evidence-based guidelines. PATIENT SUMMARY: The use of partial nephrectomy and minimally invasive surgery for kidney cancer tumors increased in Norway from 2008 to 2013 according to population-based data, coinciding with guideline changes. The study illustrate that adherence to guidelines may improve patient outcomes.

Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.

Cancer in ANCA-Associated Glomerulonephritis: A Registry-Based Cohort Study.

BACKGROUND: Immunosuppressive therapy for antineutrophil cytoplasmic antibody-associated vasculitis has been associated with increased malignancy risk. OBJECTIVES: To quantify the cancer risk associated with contemporary cyclophosphamide-sparing protocols. METHODS: Patients from the Norwegian Kidney Biopsy Registry between 1988 and 2012 who had biopsy-verified pauci-immune glomerulonephritis and positive antineutrophil cytoplasmic antibody (ANCA) serology were included. Standardised incidence ratios (SIRs) were calculated to compare the study cohort with the general population. RESULTS: The study cohort included 419 patients. During 3010 person-years, cancer developed in 41 patients (9.79%); the expected number of cancer cases was 37.5 (8.95%). The cohort had SIRs as follows: 1.09, all cancer types (95% CI, 0.81 to 1.49); 0.96, all types except nonmelanoma skin cancer (95% CI, 0.69 to 1.34); 3.40, nonmelanoma skin cancer (95% CI, 1.62 to 7.14); 3.52, hematologic cancer (95% CI, 1.32 to 9.37); 2.12, posttransplant cancer (95% CI, 1.01 to 4.44); and 1.53, during the 1-5-year follow-up after diagnosis (95% CI, 1.01 to 2.32). CONCLUSIONS: Cancer risk did not increase significantly in this cohort with ANCA-associated glomerulonephritis. However, increased risk of nonmelanoma skin cancer, posttransplant cancer, and hematologic cancer indicates an association between immunosuppression and malignancy.

Prognostic Value of Histologic Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: A kidney biopsy is preferred for the diagnosis of ANCA-associated vasculitis with renal involvement. The aim of our study was to evaluate the prognostic value of a histopathologic classification scheme recently proposed by an international consortium of renal pathologists in a large Norwegian cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients diagnosed with ANCA-associated GN were included from the Norwegian Kidney Biopsy Registry 1991-2012. Renal morphology was classified as focal, mixed, crescentic, or sclerotic. Study end point was ESRD. Patients were followed from kidney biopsy to end of 2012. RESULTS: Two hundred fifty patients with ≥10 glomeruli in the biopsy were included in our study. During a median follow-up of 3.5 years (0.7-7.6), 60 cases of ESRD occurred. Ninety-six (38%) biopsies were classified as focal, 61 (24%) biopsies were classified as mixed, 71 (28%) biopsies were classified as crescentic, and 22 (9%) biopsies were classified as sclerotic; 1- and 5-year cumulative renal survival rates were 96% and 90%, respectively, for the focal class, 86% and 75%, respectively, for the mixed class, 81% and 69%, respectively, for the crescentic class, and 56% and 51%, respectively, for the sclerotic class. By multivariate Cox regression analyses, the sclerotic class had a significantly worse renal prognosis than the focal (hazard ratio, 9.65; 95% confidence interval, 2.38 to 39.16) or combined mixed/crescentic classes (hazard ratio, 3.27; 95% confidence interval, 1.41 to 7.61), but no significant differences in outcome were observed in the crescentic class compared with the mixed class (hazard ratio, 1.13; 95% confidence interval, 0.44 to 2.87) or the combined mixed/crescentic class compared with the focal class (hazard ratio, 1.93; 95% confidence interval, 0.61 to 6.12). Accuracy by receiver operator characteristic curve analysis was estimated to be 0.72 (95% confidence interval, 0.65 to 0.80). In 108 additional patients with three to nine glomeruli in the biopsy, the prognostic value of this classification scheme was unchanged. CONCLUSIONS: The histopathologic classification is a predictor of renal outcome of moderate quality. Merging the mixed and crescentic classes in the future could simplify the scheme.