Renal Tumor Invasion Depth and Diameter are the Two Most Accurate Anatomical Features Regarding the Choice of Radical Versus Partial Nephrectomy

Background and Aims: To evaluate simple tumor characteristics (renal tumor diameter and parenchymal invasion depth) compared with more complex classifications, that is, Renal Tumor Invasion Index (RTII) and Preoperative Aspects and Dimensions Used for an Anatomical classification, in predicting the type of nephrectomy (radical vs partial) performed. Material and Methods: A total of 915 patients who had undergone either partial nephrectomy (n=388, 42%) or radical nephrectomy (n=527, 58%) were identified from the Helsinki University Hospital kidney tumor database between 1 January 2006 and 31 December 2014. Tumor maximum diameter and depth of invasion into the parenchyma were estimated from computed tomography or magnetic resonance imaging images and compared with Preoperative Aspects and Dimensions Used for an Anatomical and Renal Tumor Invasion Index. Logistic regression and receiver operating curves were used to compare the parameters at predicting the type of nephrectomy. Results and conclusion: All the anatomical variables of receiver operating curve/area under the curve analyses were significant predictors for the type of nephrectomy. Parenchymal invasion (area under the curve 0.91; 95% confidence interval, 0.89-0.93), RTII (area under the curve 0.91; 95% confidence interval, 0.89-0.93), and diameter (area under the curve 0.91; 95% confidence interval, 0.89-0.93) performed significantly better than Preoperative Aspects and Dimensions Used for an Anatomical classification (area under the curve 0.88; 95% confidence interval, 0.85-0.89). In multivariable analysis, invasion depth was the best predictor of nephrectomy type (percentage correct, 85.6%). Addition of one anatomic parameter into the model of non-anatomical cofactors improved the accuracy of the model significantly, but the addition of more parameters did not. Parenchymal invasion depth and tumor diameter are the most accurate anatomical features for predicting the nephrectomy type. All potential anatomical classification systems should be tested against these two simple characteristics.Peer reviewe

Aortofemoral surgery and sexual function

Objectives:To determine the incidence and pathophysiology of erectile dysfunction (ED) in patients with aortoiliac occlusive disease (AIOD) and the effects of aortofemoral surgery, including endarterectomy (E) and reconstruction (R), on erectile function (EF).Design:Evaluation of EF before and 3 months after surgery.Methods:31 out of 40 male patients scheduled for aortofemoral surgery were given multiple choice questionnaires and penile dynamic Colour Doppler Ultrasonography.Results:Of the 31 who agreed to enter the study five (16%) were found to be potent and 26 (84%) to suffer from ED. This was purely arteriogenic in 8% of the cases, purely venogenic in 23%, combined arteriogenic and venogenic in 53%, and neurogenic in 16%. Twenty patients returned for postoperative evaluation of EF, nine who had undergone E and 11 who had undergone R. Improvement of EF, in terms of increased penile arterial inflow, occurred in seven patients, six who had undergone E and one who had undergone R. EF remained unchanged in nine patients, three who had undergone E and six who had undergone R. Deterioration of EF occurred in four patients, all who had undergone R, and was attributable to decreased arterial inflow in two cases and to neurogenic surgical injury in the other two.Conclusions:The majority of patients with AIOD suffers from ED. Reduced penile arterial inflow and cavernovenous leakage are equally important in the pathophysiology of ED in patients with AIOD, suggesting that atherosclerosis may also compromise the penile veno-occlusive mechanism. Endarterectomy seems more likely than reconstruction to improve or maintain EF

Precision systems medicine in urological Tumors – Molecular profiling and functional testing

Background: Most precision cancer medicine efforts are based on the identification of oncogenic driver mutations by genome sequencing. We believe and have emerging evidence that this will miss therapeutic opportunities and additional technologies, such as cell-based functional testing should be included. Pioneering studies in leukemia indicate the value of ex-vivo drug testing to identify novel, clinically actionable therapeutic opportunities. Methods: Using conditional re-programming technology, we established patient-derived cells (PDCs) from castration-resistant prostate cancer (CRPC)3 and renal cell cancer (RCC) in order to pilot precision systems medicine in solid tumours. The PDCs were compared with primary tumour tissue by genomic profiling and then subjected to drug sensitivity profiling with >306 approved and investigational oncology drugs. Results: Here, we generated both benign and malignant PDCs from prostate tissue, including six benign PDCs that were androgen receptor (AR)-negative, basal/transit-amplifying phenotype, but could re-express AR in 3D-culture. The PDCs from a CRPC patient displayed multiple CNAs, some of which were shared with the parental tumor. The cancer-selective drug profile for these PDCs showed sensitivity to taxanes, navitoclax, bexarotene, tretinoin, oxaliplatin and mepacrine3. RCC displays extensive intra-tumour heterogeneity and clonal evolution. There is, however, very little information on how much this impacts drug sensitivities. Therefore, we generated several PDCs from each RCC patient across multiple tumour regions. We verified their clonal relationship with the uncultured tumour tissue by NGS and performed drug sensitivity profiling. The PDCs retained CNAs and driver mutations in e.g. VHL, PBRM1, PIK3C2A, KMD5C, TSC2 genes present in the original tumour tissue. Drug testing with 461 oncology drugs identified shared vulnerability among the multiple PDCs to pazopanib and temsirolimus that inhibit well-established renal cancer pathways EGFR/PDGFR/ FGFR and mTOR. Importantly, however, the individual PDC from different regions in one patient also showed distinct drug response profiles, confirming that genomic heterogeneity leads to variability in drug responses. Conclusions: Our aim is to generate molecular profiles and drug testing data using representative PDCs from each patient to help clinicians in treatment decision and to facilitate the early selection of the best drug candidates for clinical development. We believe this approach will help to personalize treatment, prioritize drugs for clinical testing, provide for intelligent selection of drug combinations and improve treatment outcomes.Non peer reviewe

Sexual dimorphism in the genetic influence on human childlessness

Previous research has found a genetic component of human reproduction and childlessness. Others have argued that the heritability of reproduction is counterintuitive due to a frequent misinterpretation that additive genetic variance in reproductive fitness should be close to zero. Yet it is plausible that different genetic loci operate in male and female fertility in the form of sexual dimorphism and that these genes are passed on to the next generation. This study examines the extent to which genetic factors influence childlessness and provides an empirical test of genetic sexual dimorphism. Data from the Swedish Twin Register (N=9942) is used to estimate a classical twin model, a genomic-relatedness-matrix restricted maximum likelihood (GREML) model on twins and estimates polygenic scores of age at first birth on childlessness. Results show that the variation in individual differences in childlessness is explained by genetic differences for 47% in the twin model and 59% for women and 56% for men using the GREML model. Using a polygenic score (PGS) of age at first birth (AFB), the odds of remaining childless are around 1.25 higher for individuals with 1 SD higher score on the AFB PGS, but only for women. We find that different sets of genes influence childlessness in men and in women. These findings provide insight into why people remain childless and give evidence of genetic sexual dimorphism