Evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients.

BACKGROUND: Co-morbidities may induce local and systemic tumor progression of renal cell carcinoma (RCC); however, the prognostic impact of co-morbidities has not yet been well characterized. PATIENTS AND METHODS: RCC patients (n = 2206) surgically treated at three academic institutions in the US and Europe were included in the analysis. Presence of diabetes mellitus, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, coronary heart disease, and hypothyroidism were investigated for their association with clinicopathological features and cancer-specific survival. RESULTS: Hypertension was associated with less advanced T stages (p = 0.025), a lower risk of lymph-node (p = 0.026) and distant metastases (p = 0.001), and improved cancer specific survival in univariable analysis (HR 0.81 95% CI 0.69-0.96, p = 0.013). However, hypertension was not an independent prognostic factor after adjustment for TNM stages, grading, and ECOG performance status (HR 0.95, 95% CI 0.80-1.12; p = 0.530). A correlation between the use of concomitant anti-hypertensive medications and improved survival outcome was not identified. All other investigated co-morbidities did not show significant associations with clinicopathological features or cancer-specific survival. CONCLUSION: Although the investigated co-morbidities are capable or inducing pathophysiological changes that are predisposing factors for tumor progression, none is an independent prognostic factor in patients with RCC.

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma.

BACKGROUND: Melanoma-associated antigen-A (MAGE-A) and programmed-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We assessed survival outcomes in patients with MAGE-A and PD-L1 expression. METHODS: MAGE-A and PD-L1 expression on neoplastic cells was analyzed using tissue microarrays from patients with UC. We compared differential expression between disease stage and grade. MAGE-A and PD-L1 co-expression was subcategorized. Fisher's exact test was done for categorical variables followed by univariable and multivariable analysis of recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: Co-expression of MAGE+/PD-L1+ was higher in advanced disease; however, only MAGE+/PD-L1- was associated with shorter RFS [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.19-2.99; p = .006]. MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1; 95% CI 5.96-49.4; p ≤ .001). MAGE-A expression was more prevalent with high-grade (p = .015), and higher-stage ≥ pT2 (p = .001) disease. The 5-year RFS was 44% for MAGE+ versus 58% for MAGE- patients. On multivariable analysis, MAGE+ was also associated with shorter RFS (HR 1.55; 95% CI 1.05-2.30; p = .03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12; 95% CI 1.12-8.68; p = .03). CONCLUSION: MAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+ provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors.

Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many protein-coding genes are known to be expressed in RPE and are important for its development and maintenance, virtually nothing is known about the in vivo roles of non-coding transcripts. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and a few were implicated to play role in RPE based on studies in cell lines. Here, through RPE-specific conditional mutagenesis of Dicer1 or Dgcr8 in mice, the importance of miRNAs for RPE differentiation was uncovered. miRNAs were found to be dispensable for maintaining RPE fate and survival, and yet they are essential for the acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly, miRNAs of the RPE are required for maturation of adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The alterations in the miRNA and mRNA profiles in the Dicer1-deficient RPE point to a key role of miR-204 in regulation of the RPE differentiation program in vivo and uncover the importance of additional novel RPE miRNAs. This study reveals the combined regulatory activity of miRNAs that is required for RPE differentiation and for the development of the adjacent neuroretina.

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons.

Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli.

Use of a Simulated Model to Teach Male Adult Circumcision in Sub-Saharan Africa.

Male adult circumcision (MC) has been shown to reduce the risk of HIV transmission in men by 50-60 %. An upscaling in the training of providers to perform circumcision is necessary to meet demand since MC is a key component of essential surgery in the context of universal health coverage. We piloted a low-cost, high-fidelity model for training adult circumcision. Multi-centre, multinational data were collected on 74 trainees and clinicians (trainers) in sub-Saharan Africa. Both trainers and trainees gave excellent feedback for the model (content and face validity). The simulated model enables a safe and realistic simulation experience to perform MC. The model is quick to set up and easily transportable to multiple teaching sites.

The contemporary role of ablative treatment approaches in the management of renal cell carcinoma (RCC): focus on radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and cryoablation.

INTRODUCTION: Currently, most of renal tumors are small, low grade, with a slow growth rate, a low metastatic potential, and with up to 30 % of these tumors being benign on the final pathology. Moreover, they are often diagnosed in elderly patients with preexisting medical comorbidities in whom the underlying medical conditions may pose a greater risk of death than the small renal mass. Concerns regarding overdiagnosis and overtreatment of patients with indolent small renal tumors have led to an increasing interest in minimally invasive, ablative as an alternative to extirpative interventions for selected patients. OBJECTIVE: To provide an overview about the state of the art in radiofrequency ablation (RFA), high-intensity focused ultrasound, and cryoablation in the clinical management of renal cell carcinoma. METHODS: A PubMed wide the literature search of was conducted. RESULTS: International consensus panels recommend ablative techniques in patients who are unfit for surgery, who are not considered candidates for or elect against elective surveillance, and who have small renal masses. The most often used techniques are cryoablation and RFA. These ablative techniques offer potentially curative outcomes while conferring several advantages over extirpative surgery, including improved patient procedural tolerance, faster recovery, preservation of renal function, and reduction in the risk of intraoperative and postsurgical complications. While it is likely that outcomes associated with ablative modalities will improve with further advances in technology, their application will expand to more elective indications as longer-term efficacy data become available. CONCLUSION: Ablative techniques pose a valid treatment option in selected patients.

Management of Lymph Node-positive Penile Cancer: A Systematic Review.

CONTEXT: Lymph node (LN) involvement in penile cancer is associated with poor survival. Early diagnosis and management significantly impact survival, with multimodal treatment approaches often considered in advanced disease. OBJECTIVE: To assess the clinical effectiveness of treatment options available for the management of inguinal and pelvic lymphadenopathy in men with penile cancer. EVIDENCE ACQUISITION: EMBASE, MEDLINE, the Cochrane Database of Systematic Reviews, and other databases were searched from 1990 to July 2022. Randomised controlled trials (RCTs), nonrandomised comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: We identified 107 studies, involving 9582 patients from two RCTs, 28 NRCSs, and 77 CSs. The quality of evidence is considered poor. Surgery is the mainstay of LN disease management, with early inguinal LN dissection (ILND) associated with better outcomes. Videoendoscopic ILND may offer comparable survival outcomes to open ILND with lower wound-related morbidity. Ipsilateral pelvic LN dissection (PLND) in N2-3 cases improves overall survival in comparison to no pelvic surgery. Neoadjuvant chemotherapy in N2-3 disease showed a pathological complete response rate of 13% and an objective response rate of 51%. Adjuvant radiotherapy may benefit pN2-3 but not pN1 disease. Adjuvant chemoradiotherapy may provide a small survival benefit in N3 disease. Adjuvant radiotherapy and chemotherapy improve outcomes after PLND for pelvic LN metastases. CONCLUSIONS: Early LND improves survival in nodal disease in penile cancer. Multimodal treatments may provide additional benefit in pN2-3 cases; however, data are limited. Therefore, individualised management of patients with nodal disease should be discussed in a multidisciplinary team setting. PATIENT SUMMARY: Spread of penile cancer to the lymph nodes is best managed with surgery, which improves survival and has curative potential. Supplementary treatment, including the use of chemotherapy and/or radiotherapy, may further improve survival in advanced disease. Patients with penile cancer with lymph node involvement should be treated by a multidisciplinary team.

Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell carcinoma.

BACKGROUND: The short arm of chromosome 3 (3p) harbors the von Hippel-Lindau (VHL) tumor suppressor gene, and the long arm of chromosome 14 (14q) harbors the hypoxia-inducible factor 1α (HIF-1α) gene. The objective of this study was to evaluate the significance of 3p loss (loss VHL gene) and 14q loss (loss HIF-1α gene) in clear cell renal cell carcinoma (ccRCC). METHODS: In total, 288 ccRCC tumors underwent a prospective cytogenetic analysis for alterations in chromosomes 3p and 14q. Tumors were assigned to 1 of 4 possible chromosomal alterations: VHL +3p/+14q (VHL wild type [VHL-WT]), VHL +3p/-14q (VHL-WT plus HIF2α [WT/H2]), -3p/+14q (HIF1α and HIF2α [H1H2]), and -3p/-14q (HIF2α [H2]). RESULTS: Among patients who had loss of 3p, tumors with -3p/-14q (H2) alterations were larger (P = .002), had higher grade (P = .002) and stage (P = .001), and more often were metastatic (P = .029) than tumors that retained 14q (H1H2). All patients who had tumors with -3p/-14q (H2) had worse cancer-specific survival (P = .014), and patients who had localized disease (P = .012) and primary T1 (pT1) tumors (P = .008) had worse recurrence-free survival. In patients who had pT1 tumors, combined 3p/14q loss was an independent predictor of recurrence-free survival (hazard ratio, 11.19; 95% confidence interval, 1.91-65.63) and cancer-specific survival (hazard ratio, 15.93; 95% confidence interval, 3.09-82.16). The current investigation was limited by its retrospective design, single-center experience, and a lack of confirmatory protein analyses. CONCLUSIONS: Loss of chromosome 3p (the VHL gene) was associated with improved survival in patients with ccRCC, whereas loss of chromosome 14q (the HIF-1α gene) was associated with worse outcomes. The results of the current study support the hypothesis that HIF-1α functions as an important tumor suppressor gene in ccRCC.

Prognostic impact of preoperative neutrophil-to-lymphocyte ratio in localized nonclear cell renal cell carcinoma.

PURPOSE: The preoperative neutrophil-to-lymphocyte ratio was proposed as a prognostic factor for localized clear cell renal cell carcinoma. We evaluated its role in nonclear cell renal cell carcinoma. MATERIALS AND METHODS: We queried 2 prospective kidney cancer databases. Patients who underwent full resection of localized (T1-3 N0/+ M0) nonclear cell renal cell carcinoma by radical or partial nephrectomy were included in analysis. Associations of the continuously coded neutrophil-to-lymphocyte ratio with disease-free survival were assessed with univariable and multivariable Cox regression models. Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Our final cohort included 281 patients. The 5-year disease-free survival rate was 88.1%. The neutrophil-to-lymphocyte ratio was significantly associated with disease-free survival. With each 1.0 increase in the ratio the risk of recurrence increased by 15% (HR 1.15, p=0.028). On multivariable analysis TNM group (HR 2.84, p=0.025), Fuhrman grade (HR 3.40, p<0.001) and the neutrophil-to-lymphocyte ratio (HR 1.17, p=0.022) were independently associated with disease-free survival. Adding the neutrophil-to-lymphocyte ratio improved the accuracy of a base model to predict disease-free survival from 78.8% to 80.8%. CONCLUSIONS: The neutrophil-to-lymphocyte ratio is an independent prognostic factor for disease-free survival after surgery with curative intent for localized nonclear cell renal cell carcinoma. It significantly increases the accuracy of established prognostic factors. The neutrophil-to-lymphocyte ratio may provide a meaningful adjunct for patient counseling and clinical trial design.

Systematic Review and Meta-analysis of Minimally Invasive Procedures for Surgical Inguinal Nodal Staging in Penile Carcinoma.

CONTEXT: There are several procedures for surgical nodal staging in clinically node-negative (cN0) penile carcinoma. OBJECTIVE: To evaluate the diagnostic accuracy, perioperative outcomes, and complications of minimally invasive surgical procedures for nodal staging in penile carcinoma. EVIDENCE ACQUISITION: A systematic review of the Medline, Embase, and Cochrane controlled trials databases and ClinicalTrials.gov was conducted. Published and ongoing studies reporting on the management of cN0 penile cancer were included without any design restriction. Outcomes included the false negative (FN) rate, the number of nodes removed, surgical time, and postoperative complications. EVIDENCE SYNTHESIS: Forty-one studies were eligible for inclusion. Four studies comparing robot-assisted (RA-VEIL) and video-endoscopic inguinal lymphadenectomy (VEIL) to open inguinal lymph node dissection (ILND) were suitable for meta-analysis. A descriptive synthesis was performed for single-arm studies on modified open ILND, dynamic sentinel node biopsy (DSNB) with and without preoperative inguinal ultrasound (US), and fine-needle aspiration cytology (FNAC). DSNB with US + FNAC had lower FN rates (3.5-22% vs 0-42.9%) and complication rates (Clavien Dindo grade I-II: 1.1-20% vs 2.9-11.9%; grade III-V: 0-6.8% vs 0-9.4%) in comparison to DSNB alone. Favourable results were observed for VEIL/RA-VEIL over open ILND in terms of major complications (2-10.6% vs 6.9-40.6%; odds ratio [OR] 0.18; p < 0.01). Overall, VEIL/RA-VEIL had lower wound-related complication rates (OR 0.14; p < 0.01), including wound infections (OR 0.229; p < 0.01) and skin necrosis (OR 0.16; p < 0.01). The incidence of lymphatic complications varied between 20.6% and 49%. CONCLUSIONS: Of all the surgical staging options, DSNB with inguinal US + FNAC had the lowest complication rates and high diagnostic accuracy, especially when performed in high-volume centres. If DSNB is not available, favourable results were also found for VEIL/RA-VEIL over open ILND. Lymphatic-related complications were comparable across open and video-endoscopic ILND. PATIENT SUMMARY: We reviewed studies on different surgical approaches for assessing lymph node involvement in cases with penile cancer. The results show that a technique called dynamic sentinel node biopsy with ultrasound guidance and fine-needle sampling has high diagnostic accuracy and low complication rates. For lymph node dissection in penile cancer cases, a minimally invasive approach may offer favourable postoperative outcomes.

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival.

BACKGROUND: Tobacco use is a leading cause of premature death, yet few studies have investigated the effect of tobacco exposure on the outcome of patients with renal cell carcinoma (RCC). The authors of this report retrospectively studied the impact of smoking on clinicopathologic factors, survival outcomes, and p53 expression status in a large cohort of patients with RCC. METHODS: Eight hundred-two patients (457 nonsmokers and 345 smokers) who had up to 232 months of follow-up were compared for differences in their clinicopathologic features and survival outcomes. Immunohistochemical differences in p53 expression were correlated with smoking status. RESULTS: Smokers presented more commonly with pulmonary comorbidities (P < .0001) and cardiac comorbidities (P = .014) and with a worse performance status (P = .031) than nonsmokers. Smoking was associated significantly with tumor multifocality (P = .022), higher pathologic tumor classification (P = .037), an increased risk of bulky lymph node metastases (P = .031), and the presence of distant metastases (P < .0001), especially lung metastases (P < .0001). Both overall survival (OS) (62.37 months vs 43.64 months; P = .001) and cancer-specific survival (CSS) (87.43 months vs 56.57 months; P = .005) were significantly worse in patients who smoked. The number of pack-years was retained as an independent predictor of CSS and OS in patients with nonmetastatic disease. Mean expression levels of p53 were significantly higher in current smokers compared with former smokers and nonsmokers (P = .012). CONCLUSIONS: In patients with RCC, a history of smoking was associated with worse pathologic features and survival outcomes and with an increased risk of having mutated p53. Further investigation of the genetic and molecular mechanisms associated with decreased CSS in patients with RCC who have a history of smoking is indicated.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS). METHODS: The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated. RESULTS: Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015). CONCLUSIONS: Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c-MYC inhibitors or agents that target the MAPK/ERK (mitogen-activated protein kinase) pathway.

The zebrafish dystrophic mutant softy maintains muscle fibre viability despite basement membrane rupture and muscle detachment.

The skeletal muscle basement membrane fulfils several crucial functions during development and in the mature myotome and defects in its composition underlie certain forms of muscular dystrophy. A major component of this extracellular structure is the laminin polymer, which assembles into a resilient meshwork that protects the sarcolemma during contraction. Here we describe a zebrafish mutant, softy, which displays severe embryonic muscle degeneration as a result of initial basement membrane failure. The softy phenotype is caused by a mutation in the lamb2 gene, identifying laminin beta2 as an essential component of this basement membrane. Uniquely, softy homozygotes are able to recover and survive to adulthood despite the loss of myofibre adhesion. We identify the formation of ectopic, stable basement membrane attachments as a novel means by which detached fibres are able to maintain viability. This demonstration of a muscular dystrophy model possessing innate fibre viability following muscle detachment suggests basement membrane augmentation as a therapeutic strategy to inhibit myofibre loss.

Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation.

PURPOSE: While microvascular invasion is an accepted risk factor in various cancers, its prognostic role in renal cell carcinoma is still unclear. Therefore, a large multicenter study examining the experience of 5 international institutions was performed to evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival. MATERIALS AND METHODS: A total of 2,596 patients (475 with microvascular invasion and 2,121 without microvascular invasion) having up to 212 (median 22.4) months of followup were compared for differences in clinicopathological features, occurrence of metastases and cancer specific survival. RESULTS: Patients with microvascular invasion presented with higher age (p = 0.001) and a worse Eastern Cooperative Oncology Group performance status (p <0.0001). Microvascular invasion was associated with larger tumor diameter (p <0.0001), higher Fuhrman grade (p <0.0001), more advanced pT stage (p <0.0001), and the presence of lymph node and distant metastases (p <0.0001). In particular, in nonmetastatic cases worse survival was associated with microvascular invasion (p <0.0001, HR 2.38). Univariate analysis demonstrated a strong correlation between microvascular invasion and cancer specific survival (p <0.0001). However, after controlling for gender, Eastern Cooperative Oncology Group performance status, Fuhrman grade and TNM stage statistical significance was lost. Of interest, low stage tumors with microvascular invasion were strongly correlated with the occurrence of metastases (p <0.0001). CONCLUSIONS: Microvascular invasion occurs in nearly 1 of 5 patients with renal cell carcinoma, is tightly correlated with adverse clinicopathological features and is an independent predictor of metastatic spread including in those presenting with low stage tumors.

Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma.

UNLABELLED: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long-term survival is poor and the durable responses to systemic therapy are infrequent. Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion. OBJECTIVES: To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design. Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy. PATIENTS AND METHODS: A single-centre database was reviewed to identify all patients with sRCC. Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome. RESULTS: Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.5-30), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation. The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis. A total of 85 patients (81.7%) died during the follow-up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.7-8.9). In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome. A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool. CONCLUSIONS: Both patients with localized and metastatic sRCC have very poor survival outcomes. Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis. A prognostic model, if validated, could aid in patient counselling and/or clinical trial design.

A deeper analysis of the spacing effect after "deep" encoding.

The most common encoding strategies used by participants in word list studies include rehearsal and using the story mnemonic. Previous studies have suggested that with a rote-rehearsal strategy, mixed lists lead people to borrow rehearsal time from massed items and to give it to spaced items. Using rehearse-aloud methodologies, we demonstrated in Experiment 1 that the borrowing effect does not occur in the story mnemonic. However, the rates of rehearsal of individual items provided a good prediction of their subsequent recall rates, with spaced items being rehearsed more often in both mixed and pure lists. In experiment 2, we demonstrated that creating "story links" between items enhanced recall, but it did not affect the magnitude of the spacing effect. These results suggest that a massed-item deficit in encoding may underlie the spacing effect in the story mnemonic.

What Is the Most Effective Management of the Primary Tumor in Men with Invasive Penile Cancer: A Systematic Review of the Available Treatment Options and Their Outcomes.

Context: The primary lesion in penile cancer is managed by surgery or radiation. Surgical options include penile-sparing surgery, amputative surgery, laser excision, and Moh's micrographic surgery. Radiation is applied as external beam radiotherapy (EBRT) and brachytherapy. The treatment aims to completely remove the primary lesion and preserve a sufficient functional penile stump. Objective: To assess whether the 5-yr recurrence-free rate and other outcomes, such as sexual function, quality of life, urination, and penile preserving length, vary between various treatment options. Evidence acquisition: The EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED), Google Scholar, and ClinicalTrials.gov were searched for publications from 1990 through May 2021. Randomized controlled trials, nonrandomized comparative studies (NRCSs), and case series (CSs) were included. Evidence synthesis: The systematic review included 88 studies, involving 9578 men from 16 NRCSs and 72 CSs. The cumulative mean 5-yr recurrence-free rates were 82.0% for penile-sparing surgery, 83.9% for amputative surgery, 78.6% for brachytherapy, 55.2% for EBRT, 69.4% for lasers, and 88.2% for Moh's micrographic surgery, as reported from CSs, and 76.7% for penile-sparing surgery and 93.3% for amputative surgery, as reported from NRCSs. Penile surgery affects sexual function, but amputative surgery causes more appearance concerns. After brachytherapy, 25% of patients reported sexual dysfunction. Both penile-sparing surgery and amputative surgery affect all aspects of psychosocial well-being. Conclusions: Despite the poor quality of evidence, data suggest that penile-sparing surgery is not inferior to amputative surgery in terms of recurrence rates in selected patients. Based on the available information, however, broadly applicable recommendations cannot be made; appropriate patient selection accounts for the relative success of all the available methods. Patient summary: We reviewed the evidence of various techniques to treat penile tumor and assessed their effectiveness in oncologic control and their functional outcomes. Penile-sparing as well as amputative surgery is an effective treatment option, but amputative surgery has a negative impact on sexual function. Penile-sparing surgery and radiotherapy are associated with a higher risk of local recurrence, but preserve sexual function and quality of life better. Laser and Moh's micrographic surgery could be used for smaller lesions.

Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation.

Mechanisms influencing the development of olfactory bulb glomeruli are poorly understood. While odor receptors (ORs) play an important role in olfactory sensory neuron (OSN) axon targeting/coalescence (Mombaerts et al., 1996; Wang et al., 1998; Feinstein and Mombaerts, 2004), recent work showed that G protein activation alone is sufficient to induce OSN axon coalescence (Imai et al., 2006; Chesler et al., 2007), suggesting an activity-dependent mechanism in glomerular development. Consistent with these data, OSN axon projections and convergence are perturbed in mice deficient for adenylyl cyclase III, which is downstream from the OR and catalyzes the conversion of ATP to cAMP. However, in cyclic nucleotide-gated (CNG) channel knock-out mice OSN axons are only transiently perturbed (Lin et al., 2000), suggesting that the CNG channel may not be the sole target of cAMP. This prompted us to investigate an alternative channel, the hyperpolarization-activated, cyclic nucleotide-gated cation channel (HCN), as a potential developmental target of cAMP in OSNs. Here, we demonstrate that HCN channels are developmentally precocious in OSNs and therefore are plausible candidates for affecting OSN axon development. Inhibition of HCN channels in dissociated OSNs significantly reduced neurite outgrowth. Moreover, in HCN1 knock-out mice the formation of glomeruli was delayed in parallel with perturbations of axon organization in the olfactory nerve. These data support the hypothesis that the outgrowth and coalescence of OSN axons is, at least in part, subject to activity-dependent mechanisms mediated via HCN channels.

Evaluation of exon-skipping strategies for Duchenne muscular dystrophy utilizing dystrophin-deficient zebrafish.

Duchenne muscular dystophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene. By utilizing antisense oligonucleotides, splicing of the dystrophin transcript can be altered so that exons harbouring a mutation are excluded from the mature mRNA. Although this approach has been shown to be effective to restore partially functional dystrophin protein, the level of dystrophin protein that is necessary to rescue a severe muscle pathology has not been addressed. As zebrafish dystrophin mutants (dmd) resemble the severe muscle pathology of human patients, we have utilized this model to evaluate exon skipping. Novel dmd mutations were identified to enable the design of phenotype rescue studies via morpholino administration. Correlation of induced exon-skipping efficiency and the level of phenotype rescue suggest that relatively robust levels of exon skipping are required to achieve significant therapeutic ameliorations and that pre-screening analysis of exon-skipping drugs in zebrafish may help to more accurately predict clinical trials for therapies of DMD.