Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Molecular testing with next-generation sequencing appears to identify biofilm on penile prostheses better than traditional cultures: The new gold standard?

INTRODUCTION: Traditional culture is the current standard-of-care to determine therapeutic antibiotics for patients suffering from penile prostheses (PP) infections. However, approximately 50% of PPs removed for infection are culture negative. Next-generation sequencing (NGS) compares DNA sequences to reference sequences with known microbial taxonomies to identify isolates and report relative abundances. We aim to compare the ability for standard culture and NGS techniques to identify microorganisms and biofilm composition on PPs. MATERIALS AND METHODS: Ninety-one PPs explanted for mechanical malfunction were included in this study. Devices removed for infection or erosion were excluded. During revision surgery, two specimens were collected and sent for culture testing at institutional laboratory and for NGS testing (MicroGenDx, Lubbock, TX, USA). Species' relative abundances, sample diversity and richness, and compositional differences among samples were analyzed. RESULTS: NGS had a higher rate of microbial detection (n = 72, 79.1%) compared to culture results (n = 3, 3.3%). Some of the bacteria identified using both methods were known prosthetic infectious pathogens, with NGS producing more isolates (mean: 11) than culture (mean: 1). Escherichia coli was the most abundant and most frequently occurring bacteria detected on NGS. Coagulase-negative Staphylococci were the most common bacteria detected on traditional culture. CONCLUSIONS: NGS appears to be beneficial in its thorough analysis of PP biofilm composition when compared to culture methods. We hope that further research will be able to demonstrate a clinical benefit of NGS in characterizing distinct microbiomes and biofilms of infected PP, which can aid in tailoring antimicrobial therapy and improving patient outcomes.

Darolutamide: An Evidenced-Based Review of Its Efficacy and Safety in the Treatment of Prostate Cancer.

Men treated with androgen deprivation therapy for rising PSA after failed local therapy will often develop castrate resistance, and the appearance of metastases predicts a poor prognosis. Thus, researchers have long sought to prolong the onset of metastasis in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Until 2018, patients in this group had no FDA-approved treatment options. They were typically managed with androgen-deprivation therapy (ADT) to maintain castrate systemic testosterone levels and given approved therapies for metastatic CRPC once metastases appeared. However, third-generation androgen receptor inhibitors (ARIs) have dramatically changed the treatment paradigm, having shown the ability to extend metastasis-free survival (MFS) significantly over ADT alone in Phase 3 trials. The newest of these, darolutamide, prolonged MFS 22 months over placebo while also improving a host of secondary and exploratory endpoints such as overall survival (OS), prostate-specific antigen (PSA) progression and time to pain progression, chemotherapy initiation, and symptomatic skeletal events. Among third-generation ARIs, darolutamide is unique in that it incorporates two pharmacologically active diastereomers and has demonstrated resistance to all known androgen receptor (AR) mutations. Additionally, patients taking darolutamide appear to experience comparatively few central nervous system-related adverse events (AEs) such as fatigue and falls, and no increases in seizures have been reported in the drug's clinical or preclinical development. Various authors attribute the low incidence of CNS-related AEs to darolutamide's minimal penetration of the blood-brain barrier (BBB). Other side effects ranging from hot flashes to hypothyroidism also occurred at rates similar to those of the placebo arm in Phase 3. As ADT in itself raises cardiovascular risk, the cardiovascular safety of third-generation antiandrogens as a category warrants continued scrutiny. In total, however, published data suggest that darolutamide provides a reasonable option for patients with nonmetastatic CRPC. Ongoing research will determine darolutamide's potential role in additional disease states such as localized and castration-sensitive PCa.

Assessment of high-grade prostate cancer risk using prostate cancer biomarkers.

INTRODUCTION: To identify patients at risk of high-grade prostate cancer using prostate cancer biomarkers. MATERIALS AND METHODS: A total of 601 men were screened for prostate cancer in 2012, 2015, and 2016 using prostate cancer biomarkers: prostate health index (phi), 4KScore, and SelectMDx. The first two are blood tests that incorporate several PSA isoforms; SelectMDx measures mRNA levels of homeobox C6 and distal-less homeobox 1 in post-digital rectal examination urine samples. The performance of each biomarker was evaluated using cut off values based on published literature. Gleason Grade Group (GG) ≥ 2 is considered as high-grade prostate cancer. RESULTS: For patients with PSA < 1.5 ng/mL, none were at risk for GG ≥ 2 cancer based on SelectMDx > 0%, whereas 17.1% were at intermediate to high risk of finding GG ≥ 2 cancer with 4KScore ≥ 7.5%, and 3.5% were at risk of finding any prostate cancer with phi ≥ 36 at biopsy. For cut offs revised for finding men at high risk for GG ≥ 2 cancer at biopsy, only one patient with PSA < 1.5 ng/mL would be at risk with 4KScore ≥ 20% and none with phi ≥ 52.7. For patients with PSA 1.5 to 3.99 ng/mL, 2%, 8%, and 1% were at high risk for finding GG ≥ 2 cancer at biopsy based on phi, 4KScore, and SelectMDx, respectively. CONCLUSIONS: Men with PSA < 1.5 ng/mL are at very low risk of finding high-grade prostate cancer at biopsy. However, some men with PSA between 1.5 to 3.99 ng/mL may be at intermediate to high risk for high-grade prostate cancer. Thus, primary care physicians could run biomarkers test and refer those with positive biomarker results to a specialist for further evaluation.