Factors Influencing Margin Clearance and the Number of Stages of Mohs Micrographic Surgery in Basal Cell Carcinoma: A Retrospective Chart Review.

How patient and tumor factors influence clearance margins and the number of Mohs Micrographic Surgery (MMS) stages when treating basal cell carcinoma (BCC) remains widely uncharacterized. It is important to elucidate these relationships, as surgical outcomes may be compared nationally between colleagues. Our objective is to evaluate the relationships between defect size and patient demographics, as well as between BCC subtypes and the number of MMS stages. Our second objective is to compare practice patterns and characteristics of patients requiring MMS at academic centers and private practices. A retrospective chart review was performed using data collected at academic centers (2015-2018) and private practices (2011-2018) of BCC patients older than 18 years old who underwent MMS. In total, 7651 patients with BCC requiring MMS were identified. Academic center adjusted analyses demonstrated clearance margins 0.1 mm higher for every year's increase in age (p < 0.0001) and 0.25 increase in MMS stages for high-risk BCC (p < 0.0001). Private practice adjusted analyses demonstrated clearance margins 0.04 mm higher for every year's increase in age (p < 0.0001). Clearance margins correlate with older age, and additional MMS stages correlate with high-risk BCC, suggesting the role patient and tumor factors may play in predicting tumor clearance and MMS stages.

Chronic Low Back Pain in Adults: Evaluation and Management.

Chronic low back pain, defined as lumbar pain persisting for 12 weeks or more, occurs in about 13% of U.S. adults. Patients with chronic low back pain should have a history and physical examination to identify red flags that may indicate serious conditions that warrant immediate intervention or yellow flags (i.e., psychological, environmental, and social factors) that indicate risk of disability. The examination should include an evaluation for radicular symptoms. Routine imaging is not recommended but is indicated when red flags are present, there is a neuromuscular deficit, or if pain does not resolve with conservative therapy. Patients should avoid bed rest. Nonpharmacologic treatment is first-line management and may include therapies with varying evidence of support, such as counseling, exercise therapy, spinal manipulation, massage, heat, dry needling, acupuncture, transcutaneous electrical nerve stimulation, and physical therapy. Pharmacologic interventions are second-line treatment. Nonsteroidal anti-inflammatory drugs are the initial medication of choice; duloxetine may also be beneficial. Evidence is inconclusive to recommend the use of benzodiazepines, muscle relaxants, antidepressants, corticosteroids, insomnia agents, anticonvulsants, cannabis, acetaminophen, or long-term opioids. Epidural corticosteroid injections are not recommended except for short-term symptom relief in patients with radicular pain. Most patients with chronic low back pain will not require surgery; evaluation for surgery may be considered in those with persistent functional disabilities and pain from progressive spinal stenosis, worsening spondylolisthesis, or herniated disk. Physicians should consider prevention of chronic low back pain when patients present with acute back pain. Screening tools are available to predict the progression from acute to chronic low back pain, and targeted treatment strategies are beneficial for preventing progression.

Evaluation and management of benign tumors of the eye and eyelid.

Benign tumors of the eye and eyelid are common in children and adults, and they rarely undergo malignant transformation. Their workup and management have evolved over the years with increasing advancements in surgical and laser therapies. This contribution focuses on describing the following benign eye and eyelid tumors and their diagnostic and treatment approaches: congenital and acquired melanocytic nevi; nevus of Ota (Hori nevus); conjunctival papilloma; seborrheic keratosis; epidermoid cyst; dermoid cyst; milium; xanthelasma; hemangioma (cherry angioma and pyogenic granuloma); neurofibroma; neurilemmoma (schwannoma); and fibroepithelial polyp. Surgical removal is the primary treatment approach for many of these benign tumors. With advancements in laser technologies, there are now several laser types that can be used in the treatment of these benign eye and eyelid tumors. Other treatment modalities include cryosurgery, electrosurgery, and topical or intralesional medications. We hope this review will provide a reference to dermatologists and ophthalmologists in their approach to evaluation and management of benign eye and eyelid tumors.

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Modified Fitzpatrick Scale-Skin Color and Reactivity.

BACKGROUND: There is growing interest in the development of a skin classification system that captures the world's diverse population. The Fitzpatrick skin classification scale is used both clinically and in research settings to determine an individual's skin color. With the high global burden of skin sensitivity (atopic dermatitis, keloid formation, etc), there is a need for a skin classification system that takes into consideration an individual's reaction to environmental insults and injuries. Our proposal builds on the existing Fitzpatrick skin classification scale by asking two additional questions of patients: do patients have sensitive skin; do patients have a history of hypertrophic scarring or keloids. By separating patients into 2 categories (sensitive vs non-sensitive skin), we create a system that can help dermatologists decide on which treatments to offer patients based on their skin classification. Dermatologists can better predict patient outcomes for dermatologic or cosmetic procedures by knowing how they react to environmental insults/injury. Santiago S, Brown R, Shao K, et al. Modified fitzpatrick scale- skin color and reactivity. J Drugs Dermatol. 2023;22(7):641-646. doi:10.36849/JDD.6859.  .

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

PURPOSE: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. PATIENTS AND METHODS: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. RESULTS: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. CONCLUSIONS: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Non-Adherence Tree Analysis (NATA)-An adherence improvement framework: A COVID-19 case study.

Poor medication adherence is a global phenomenon that has received a significant amount of research attention yet remains largely unsolved. Medication non-adherence can blur drug efficacy results in clinical trials, lead to substantial financial losses, increase the risk of relapse and hospitalisation, or lead to death. The most common methods of measuring adherence are post-treatment measures; that is, adherence is usually measured after the treatment has begun. What the authors are proposing in this multidisciplinary study is a new technique for predicting the factors that are likely to cause non-adherence before or during medication treatment, illustrated in the context of potential non-adherence to COVID-19 antiviral medication. Fault Tree Analysis (FTA), allows system analysts to determine how combinations of simple faults of a system can propagate to cause a total system failure. Monte Carlo simulation is a mathematical algorithm that depends heavily on repeated random sampling to predict the behaviour of a system. In this study, the authors propose a new technique called Non-Adherence Tree Analysis (NATA), based on the FTA and Monte Carlo simulation techniques, to improve adherence. Firstly, the non-adherence factors of a medication treatment lifecycle are translated into what is referred to as a Non-Adherence Tree (NAT). Secondly, the NAT is coded into a format that is translated into the GoldSim software for performing dynamic system modelling and analysis using Monte Carlo. Finally, the GoldSim model is simulated and analysed to predict the behaviour of the NAT. NATA is dynamic and able to learn from emerging datasets to improve the accuracy of future predictions. It produces a framework for improving adherence by analysing social and non-social adherence barriers. Novel terminologies and mathematical expressions have been developed and applied to real-world scenarios. The results of the application of NATA using data from six previous studies in relation to antiviral medication demonstrate a predictive model which suggests that the biggest factor that could contribute to non-adherence to a COVID-19 antiviral treatment is a therapy-related factor (the side effects of the medication). This is closely followed by a condition-related factor (asymptomatic nature of the disease) then patient-related factors (forgetfulness and other causes). From the results, it appears that side effects, asymptomatic factors and forgetfulness contribute 32.44%, 22.67% and 18.22% respectively to discontinuation of medication treatment of COVID-19 antiviral medication treatment. With this information, clinicians can implement relevant interventions and measures and allocate resources appropriately to minimise non-adherence.

Plasma and Urine Metabolite Profiles Impacted by Increased Dietary Navy Bean Intake in Colorectal Cancer Survivors: A Randomized-Controlled Trial.

Navy beans contain bioactive phytochemicals with colon cancer prevention properties as demonstrated in carcinogen-induced animal models. Human studies support that dietary navy bean intake modulates metabolism by the gut microbiome. This study investigated the effect of navy bean ingestion on plasma and urine metabolite profiles of overweight and obese colorectal cancer survivors. Twenty participants completed a single-blinded, randomized-controlled dietary intervention with precooked navy beans (35 g bean powder/day) or control (0 g/day) for 4 weeks. Plasma and urine were collected at baseline, 2 weeks, and 4 weeks following consumption. Nontargeted metabolomics was applied to study meals and snacks, navy beans, plasma, and urine. Increased navy bean consumption was hypothesized to (i) delineate dietary biomarkers and (ii) promote metabolic shifts relevant for cancer protection in the plasma and urine metabolome. At 4 weeks, 16 plasma and 16 urine metabolites were significantly different in the navy bean intervention group compared with placebo control (P < 0.05). Increased plasma 2,3-dihydroxy-2-methylbutyrate (1.34-fold), S-methylcysteine (1.92-fold), and pipecolate (3.89-fold), and urine S-adenosylhomocysteine (2.09-fold) and cysteine (1.60-fold) represent metabolites with cancer-protective actions following navy bean consumption. Diet-derived metabolites were detected in plasma or urine and confirmed for presence in the navy bean intervention meals and snacks. These included 3-(4-hydroxyphenyl)propionate, betaine, pipecolate, S-methylcysteine, choline, eicosapentaenoate (20:5n3), benzoate, S-adenosylhomocysteine, N-delta-acetylornithine, cysteine, 3-(4-hydroxyphenyl)lactate, gentisate, hippurate, 4-hydroxyhippurate, and salicylate. The navy bean dietary intervention for 4 weeks showed changes to pathways of metabolic importance to colorectal cancer prevention and merit continued attention for dietary modulation in future high-risk cohort investigations. PREVENTION RELEVANCE: This clinical study suggests that increased consumption of navy beans would deliver bioactive metabolites to individuals at high risk for colorectal cancer recurrence and produce metabolic shifts in plasma and urine profiles.

Modulation of plasma and urine metabolome in colorectal cancer survivors consuming rice bran.

Rice bran has bioactive phytochemicals with cancer protective actions that involve metabolism by the host and the gut microbiome. Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and the increased incidence is largely attributed to poor dietary patterns, including low daily fiber intake. A dietary intervention trial was performed to investigate the impact of rice bran consumption on the plasma and urine metabolome of CRC survivors. Nineteen CRC survivors participated in a randomized-controlled trial that included consumption of heat-stabilized rice bran (30 g/day) or a control diet without rice bran for 4 weeks. A fasting plasma and first void of the morning urine sample were analyzed by non-targeted metabolomics using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After 4 weeks of either rice bran or control diets, 12 plasma and 16 urine metabolites were significantly different between the groups (p≤0.05). Rice bran intake increased relative abundance of plasma mannose (1.373-fold) and beta-citrylglutamate (BCG) (1.593-fold), as well as increased urine N-formylphenylalanine (2.191-fold) and dehydroisoandrosterone sulfate (DHEA-S) (4.488-fold). Diet affected metabolites, such as benzoate, mannose, eicosapentaenoate (20:5n3) (EPA), and N-formylphenylalanine have been previously reported for cancer protection and were identified from the rice bran food metabolome. Nutritional metabolome changes following increased consumption of whole grains such as rice bran warrants continued investigation for colon cancer control and prevention attributes as dietary biomarkers for positive effects are needed to reduce high risk for colorectal cancer recurrence.

Maximising the global health impact of future HIV cure-related interventions through advance planning.

Thinking about public health impact should inform HIV curative investigations. Should an effective HIV cure or sustained viral remission intervention emerge from ongoing investigations, implementation strategies aimed at ensuring global access will be needed if these approaches are to be impactful, and planning accordingly makes sense now. Specifically, we discuss three key access barriers to future cure-related interventions: high cost of the strategy; non-financial challenges to procurement, distribution and point-of-care delivery; and non-adherence and the need for long-term monitoring. As we argue, plans and decision-making for overcoming each of these barriers will need to be developed in advance. An evaluation of remaining barriers and likely global impact of the leading strategies under investigation should inform decisions on which strategy might receive funding priority. Among the strategies being investigated, implementation barriers for latency-reversing agents, immunotherapy and combination antiretroviral therapy (ART) may be overcome on a global scale with some effort. Overcoming implementation barriers for medically complex and high-risk interventions, such as stem cell and, to some degree, gene therapy, may be less feasible.

Re-excision rates after breast conserving surgery following the 2014 SSO-ASTRO guidelines.

BACKGROUND: In 2014, SSO-ASTRO published guidelines which recommended "no ink on tumor" as adequate margins for patients undergoing breast conservation for invasive breast cancer. In 2016, new SSO-ASTRO-ASCO guidelines recommended 2 mm margins for DCIS. We evaluated whether these guidelines affected re-excision rates at our institution. METHODS: Patients treated with breast conservation surgery from January 1, 2010-March 1, 2016 were identified. Re-excision rates, tumor characteristics, and presence of residual disease were recorded. The 2016 guidelines were retrospectively applied to the same cohort and expected re-excision rates calculated. RESULTS: Re-excision rates did not significantly decline before and after 2014 guideline adoption (11.9% before, 10.9% after; p = 0.65) or when the 2016 guidelines were retrospectively applied (8.4%; p = 0.10). CONCLUSIONS: The 2014 and 2016 guidelines had minimal impact on our re-excision rates, as most re-excisions were done for DCIS and 2016 guidelines supported our prior institutional practices of 2 mm margins for these patients.