Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration.

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways.

Mother-Daughter Ventricular Endoscopy: A Technical Note and 2-Dimensional Video.

BACKGROUND AND IMPORTANCE: While navigating the ventricles with a rigid endoscope provides excellent visualization and the ability to use endoscopic instruments for complex surgery, these endoscopes are often too large to navigate tight areas. We present a surgical video showing the technique of mother-daughter endoscopy, which consists of the introduction of a flexible 1-mm fiberoptic endoscope through the channel of a large rigid endoscope to allow visualization across small spaces or channels, in this case, the cerebral aqueduct. This combination of superior visualization and handling of rigid endoscopes and flexibility and small size of fiberoptic endoscopes enhances safety and broadens possibilities in ventricular surgery. CLINICAL PRESENTATION: A 64-year-old woman with prior endoscopic aqueductoplasty for triventricular hydrocephalus and a failed endoscopic third ventriculostomy presented with focal restenosis of the aqueduct. A repeat endoscopic aqueductoplasty with stent placement were performed. Mother-daughter endoscopy was used to explore the occluded aqueduct for improved safety before fenestration and to ensure proper stent placement after fenestration. CONCLUSION: Mother-daughter endoscopy can add safety to complex or high-risk endoscopic procedures, particularly those with tight spaces that the large mother endoscope cannot visualize.

Systematic review of the CUP trials characteristics and perspectives for next-generation studies.

BACKGROUND: Research on therapeutic strategies for patients with unknown primary cancer (CUP) has been underwhelming. This paper summarized and evaluated the CUP therapeutic research over the previous five years. Based on this evaluation, recommendations for clinical trial designs are made to improve the impact of CUP research on patients. METHODS: Published and ongoing research were evaluated. PubMed was searched from January 1, 2015, to November 1, 2021. The start date of 2015 was chosen to identify research published after ESMO issued new diagnostic and therapeutic guidelines. The US National Library of Medicine indexed ongoing clinical trials. FINDINGS: Of the 244 CUP studies indexed in PubMed, 11.9% were prospective studies, and 4.9% were clinical trials. The review protocol deemed 65 publications eligible for full-text review. Eleven studies evaluating therapeutic regimens were retained. The two prospective studies and non-randomized trials showed promising outcomes for site-specific treatments. Randomized clinical trials were less promising; however, the trials had recruitment challenges resulting in biased accrual and the inability to keep pace with advancing diagnostics and therapeutics. Most of the 35 ongoing studies were phase II single-arm trials assessing immune checkpoint inhibitors (ICI) or site-specific therapies among CUP patients with suspected favorable prognoses. CONCLUSION: Our evaluation suggests two prospective clinical trial designs that addressed recent study design and recruitment challenges. A visionary approach uses a multi-arm, multistage randomized trial to address rapid advancements in diagnosis and therapy. A pragmatic approach utilizes a single-arm trial with historical controls to overcome comparison group and recruitment challenges.

Is pudendal nerve entrapment a potential cause for weak ejaculation?

Ejaculatory dysfunction is one of the most common complaints of patients with sexual disorders. While it encompasses several ejaculatory disorders, weak ejaculation is seldom described in the literature. Since the pudendal nerve is the main nerve of ejaculation, we aim to hypothesize that pudendal nerve entrapment could be a cause of weak ejaculation, and that pudendal nerve release could contribute to the improvement of the ejaculatory stream. We presented two cases suffering from a weak ejaculatory stream and sensation of incomplete semen emptying, accompanied with clinical features of pudendal nerve entrapment. Both cases improved after pudendal nerve block and then laparoscopic transperitoneal pudendal release, with a sustained amelioration of the ejaculatory stream after 3 weeks of surgery. Pudendal canal entrapment is therefore a potentially curable cause for weak ejaculation.

Bladder instillation for urinary tract infection prevention in neurogenic bladder patients practicing clean intermittent catheterization: A systematic review.

OBJECTIVE: To assess the efficacy and safety of different modalities of bladder instillation in patients with neurogenic bladder practicing intermittent catheterization. METHODS: A systematic review of the literature were conducted using two databases: Medline via PubMed and Scopus. Articles evaluating bladder instillation in patients with neurogenic bladder, who are practicing intermittent catheterization, were collected and assessed for the efficacy and safety of the studied agent by two different reviewers. RESULTS: Among the 1896 studies, eight involving 346 patients with neurogenic bladder, were included in this systematic review according to the PRISMA protocols. Gentamicin, Hyaluronic acid, and Lactobacillus rhamnosus was found to decrease the incidence of urinary tract infections, the former reduced multidrug-resistant organisms. Kanamycin-colistin, showed a drop in the mean incidence of bacteriuria in males only. Trisdine, the only studied antiseptic, significantly reduced bacteriuria. Neomycin, however, showed no efficacy in term of bacteriuria. Regarding safety, when evaluated, no major adverse events were reported with any of the studied modalities. CONCLUSION: Bladder instillations of either antibiotics, antiseptics, hyaluronic acid, or Lactobacillus rhamnosus GG are efficient and safe in patients having neurogenic bladder, with recurrent urinary tract infections and practicing clean intermittent catheterization, with gentamicin being the most recommended product among the different studied agents.

Perceptions of the COVID-19 vaccine among patients with cancer: a single-institution survey.

Aims: This paper reports the results of a survey assessing the acceptance of the COVID-19 vaccine among patients with cancer. Patients and methods: In total, 111 adult patients with cancer from a single institution were asked to complete a questionnaire designed to assess their knowledge about the vaccine, their readiness to be vaccinated and the determinants of their decision. Results: 61.3% of the patients considered themselves more vulnerable to COVID-19 than the general population. Television, radio and newspapers were the major sources of information about the vaccine. A total of 55% of the patients were ready to be vaccinated and 14.4% refused the vaccine. The main reason for refusal was incompatibility with patients' disease or treatment. Conclusion: Most of the patients in this institutional sample accepted the COVID-19 vaccine. Better communication of information with patients is needed to decrease vaccine hesitancy.

Lay abstract Major cancer societies consider vaccinating patients with cancer against COVID-19 a priority. The investigators conducted a survey assessing perceptions of the vaccine among patients with cancer. A total of 111 patients were asked to complete a questionnaire evaluating their knowledge about the vaccine, their readiness to be vaccinated and the determinants of their decision. Most (61.3%) patients considered themselves more susceptible to COVID-19 than the general population. Television, radio and newspapers were the major sources of information about the vaccine. The majority of patients (55%) were ready to be vaccinated and 14.4% refused the vaccine. The main reason for refusal was incompatibility with patients' disease or treatment. Better communication with patients is needed to decrease vaccine hesitancy.

Checkpoint inhibitors in BCG-unresponsive nonmuscle invasive bladder cancer: can they help spare the bladder?

Intravesical BCG therapy has been for years, the standard of care in nonmuscle-invasive bladder cancer. But upon recurrence/relapse, radical cystectomy is imposed, due to the paucity of other therapeutic options. Immunotherapy has been revolutionizing cancer treatment, and its indications continue to broaden. It has been approved for the treatment of advanced urothelial cancer of the bladder, mainly as a second-line therapy. Its activity is being studied in nonmuscle-invasive bladder cancer that is not responsive to BCG; we herein report the trials investigating these checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab) in this particular setting.

Lay abstract Administration of BCG vaccine inside the bladder has, for a long time, been the treatment of bladder cancer that has not invaded the layers of this organ, or at least has not arrived at the muscle of the bladder. However, when this cancer recurs or has not responded to this type of treatment, radical cystectomy (i.e., complete removal of the bladder) is imposed. While the latter is associated with significant decrease in quality of life, and when immunotherapy (therapy that relies on immune white blood cells combatting tumor cells) has shown promising results in metastatic bladder cancer, trials are ongoing to prove the potential benefits of this novel therapy in confined, but not responsive to BCG, bladder cancer. In this article, we report these studies, highlighting the most important ones that are, if not already, leading to approval of immunotherapy in this setting.

Prognostic role of neutrophil-to-lymphocyte ratio (NLR) in urological tumors: an umbrella review of evidence from systematic reviews and meta-analyses.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been studied as a biomarker for cancer prognosis, predicting survival in many tumors. The aim of this umbrella review was to combine the results from all systematic reviews and meta-analyses related to the prognostic role of the NLR in patients with urological tumors. METHODS: A PubMed, Scopus, Embase and Cochrane search was undergone from inception through September 2020 for systematic reviews and meta-analyses investigating the prognostic value of NLR in urological tumors, subdivided into prostate cancer, renal cell carcinoma, urothelial bladder and upper tract carcinomas PROSPERO (CRD42020216310). RESULTS: The results have shown, with a high level of evidence, that an elevated NLR predicts worse overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) in prostate cancer, worse OS, PFS and RFS in renal cell carcinoma, worse OS, PFS, RFS and cancer-specific survival (CSS) in muscle invasive bladder cancer, worse PFS and RFS in non-muscle invasive bladder cancer, and worse OS, PFS, RFS and CSS in urothelial upper tract carcinoma. CONCLUSION: NLR has a significant prognostic value in urological tumors and should be included in prognostic scores of these cancers.

Anti-neoplastic agents for patients on peritoneal dialysis: A systematic review.

BACKGROUND: There is no clear consensus on the administration of anti-neoplastic agents to patients on peritoneal dialysis. Dose adjustments to prevent serious adverse events are still not established. Thus, the aim of this study was to systematically review current evidence on the use of systemic oncology therapies in peritoneal dialysis. METHODS: A systematic review was conducted using PubMed, Scopus, and Cochrane. All relevant data was collected, including clinical and pharmacokinetic parameters, with comparison to subjects with normal renal function. RESULTS: Sixteen studies were included. All were case reports. Eighteen types of anti-cancer drugs were reviewed. Multiple adverse events and altered pharmacokinetics were reported. CONCLUSION: Data concerning the use of anti-neoplastic drugs in patients on peritoneal dialysis are still sparse. The elimination of anti-cancer agents seems often altered in such patients, resulting in serious adverse events. Based on the available evidence, we suggest the need for dose adjustment of each drug.

The use of mirabegron in neurogenic bladder: a systematic review.

PURPOSE: To evaluate the use of mirabegron in patients with neurogenic bladder. METHODS: A systematic review of the literature was conducted using four databases (Medline via PubMed, Scopus, Cochrane, and EMBASE). Articles evaluating mirabegron in neurogenic bladder patients were collected, and assessment of the drug's efficacy was reviewed according to clinical and urodynamic parameters. RESULTS: Seven studies were selected and a total of 302 patients with NB were evaluated, ranging from 15 to 66 patients per study. All of the patients had received antimuscarinics as a previous treatment modality. Mirabegron was used as a second-line treatment after antimuscarinics lacked efficacy or caused adverse effects. The duration of the treatments ranged from 4 to 12 weeks. Reported in two studies each, bladder compliance and maximal cystometric capacity were the most commonly improved urodynamic parameters. In the majority of the studies, positive outcomes were reported for clinical scores. Additionally, analysis of the IPSS subscores revealed an improvement of storage symptoms as opposed to voiding symptoms. In all of the studies, mirabegron was well tolerated. CONCLUSION: Mirabegron appears to be an effective treatment in the management of neurogenic bladder unresponsive to antimuscarinics, particularly in patients presenting with storage symptoms. There is still no evidence concerning the use of mirabegron as a first-line therapy for neurogenic bladder.