Topography of mutational signatures in non-small cell lung cancer: emerging concepts, clinical applications, and limitations.

The genome of a cell is continuously battered by a plethora of exogenous and endogenous processes that can lead to damaged DNA. Repair mechanisms correct this damage most of the time, but failure to do so leaves mutations. Mutations do not occur in random manner, but rather typically follow a more or less specific pattern due to known or imputed mutational processes. Mutational signature analysis is the process by which the predominant mutational process can be inferred for a cancer and can be used in several contexts to study both the genesis of cancer and its response to therapy. Recent pan-cancer genomic efforts such as "The Cancer Genome Atlas" have identified numerous mutational signatures that can be categorized into single base substitutions, doublet base substitutions, or small insertions/deletions. Understanding these mutational signatures as they occur in non-small lung cancer could improve efforts at prevention, predict treatment response to personalized treatments, and guide the development of therapies targeting tumor evolution. For non-small cell lung cancer, several mutational signatures have been identified that correlate with exposures such as tobacco smoking and radon and can also reflect endogenous processes such as aging, APOBEC activity, and loss of mismatch repair. Herein, we provide an overview of the current knowledge of mutational signatures in non-small lung cancer.

Estimated mortality with early empirical antibiotic coverage of methicillin-resistant Staphylococcus aureus in hospitalized patients with bacterial infections: a systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis to estimate the effect of early active empirical antibiotics for MRSA on mortality, both in patients admitted with MRSA infections and in patients admitted with common infectious syndromes, for whom the causative pathogen may not have been MRSA. METHODS: A systematic literature search was conducted using Embase, MEDLINE, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from the earliest entry through to 26 April 2022. We included studies of patients hospitalized with culture-proven MRSA infections that compared mortality rates depending on whether patients received active empirical antibiotics. The primary outcome was the adjusted OR for mortality with early active empirical antibiotics. After performing random-effects meta-analysis, we estimated the absolute risk reduction in mortality with initial empirical MRSA coverage for common infectious syndromes based on the prevalence of MRSA and baseline mortality rate for each syndrome, as reported in the medical literature. RESULTS: Of an initial 2136 unique manuscripts, 37 studies (11 661 participants) met our inclusion criteria. Fifteen studies (6066 participants) reported adjusted OR of mortality. The pooled adjusted OR for mortality was 0.64 (95% CI, 0.48-0.84), favouring active empirical antibiotics. The estimated absolute mortality benefit was 0% for patients with pneumonia, 0.1% (95% CI, 0.04-0.2) for non-critically ill patients with soft tissue infections, 0.04% (95% CI, 0.01-0.05) for non-critically ill patients with urinary tract infections, 0.6% (95% CI, 0.2-1.0) for patients with septic shock, and 1.0% (95% CI, 0.3-1.4) for patients with catheter-related infections admitted to ICUs. CONCLUSIONS: For the three most common infections in the hospital, the absolute benefit on mortality of empirical antibiotics against MRSA is 0.1% or less. Meaningful benefit of empirical antimicrobials against MRSA is limited to patients with approximately 30% mortality and 10% prevalence of MRSA. Avoiding empirical antibiotics against MRSA for low-risk infections would substantially reduce the use of anti-MRSA therapy.

A bridge too far? Distance to waivered physicians and utilization of buprenorphine treatment for opioid use disorder in West Virginia Medicaid.

Background: Travel distance to medication treatment for opioid use disorder (OUD) is a challenge for many patients, but little is known about how distance is associated with medication treatment utilization. This study examines the association between distance to the nearest physician waivered to prescribe buprenorphine and patient-level buprenorphine treatment among West Virginia Medicaid expansion enrollees with diagnosed OUD. Methods: We conducted a cross-sectional spatial analysis with 2016 Medicaid claims data, separately examining individuals living in metropolitan and non-metropolitan areas. We calculated the driving distance from the centroid of patients' residential ZIP codes to the street address of the nearest waivered physician derived from the 2015 Drug Enforcement Administration listing. Regression models examined the association between distance and initiation and duration of buprenorphine (among those initiating). Results: We focused on 8,008 individuals with OUD in 2016. The nearest waivered prescriber in metropolitan areas was an average of 7.13 miles away from patients' residential ZIP codes and 14.54 miles in non-metropolitan areas. The providers they actually visited were a mean of 33.63 miles away in metro areas and 46.36 in non-metropolitan areas. In multivariable analyses, compared to those living <10 miles from a waivered physician, living >20 miles from a waivered physician was associated with -32.13 fewer days of treatment (95% CI: -57.86, -6.40) in metro areas and -16.70 fewer days in non-metro areas (95% CI: -32.32, -1.08). Conclusions: Longer travel distance to buprenorphine treatment is associated with a shorter duration of care that is likely to be clinically meaningful.

Dosimetric Correlate of Cardiac-Specific Survival Among Patients Undergoing Coronary Artery Stenting After Thoracic Radiotherapy for Cancer.

OBJECTIVES: To retrospectively evaluate outcomes among cancer survivors previously treated with thoracic radiotherapy (RT) who later underwent percutaneous coronary intervention (PCI). METHODS: From 1998 to 2012, 76 patients first received curative RT (>30 Gy, except for Hodgkin lymphoma patients) involving the heart and lungs followed by PCI. Heart and lung-specific dosimetric parameters were correlated with overall survival (OS) and cardiac-specific survival by Cox variate methods. RESULTS: The mean interval between cancer diagnosis and PCI was 3.7 years (range, 0.1 to 12.6 y). Median follow-up since cancer diagnosis was 5.5 years. At analysis, 46 patients (61%) were alive, 5 (7%) died of cardiac causes, and 9 (12%) of cancer. Higher maximum RT heart dose was related to poorer OS since PCI (P=0.009). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P=0.005) and higher mean heart dose (P<0.001) were related to poorer OS since cancer diagnosis. ß-Blockers, higher mean heart dose (hazard ratio [HR]=1.49, P<0.001), and percentage of targeted volume or organ receiving ≥40 Gy for heart doses (HR=1.32, P<0.001) were associated with poorer non-cancer-specific survival since cancer diagnosis. Diabetes (HR=3.84, P=0.008) and increased percentage of targeted volume or organ receiving ≥45 Gy (HR=1.01 per additional 100 cm irradiated, P=0.01) for the heart decreased major adverse cardiac event-free survival. CONCLUSIONS: Prior heart and lung-directed RT had volume-dependent and dose-dependent adverse effects on long-term cardiac outcomes for patients subsequently treated with PCI. RT planning that minimizes heart and lung irradiation doses should be encouraged.

Genome-based Mutational Analysis by Next Generation Sequencing in Patients with Malignant Pleural and Peritoneal Mesothelioma.

BACKGROUND/AIM: Malignant mesothelioma is a rare malignancy with limited therapeutic options. Exome-based next-generation sequencing (NGS) techniques may direct the future of molecular targeting and improve systemic therapies for patients with mesothelioma. MATERIALS AND METHODS: Eleven patients with NGS testing were selected, with a total of 236 somatic cancer-related mutations analyzed. Descriptive and Kaplan-Meier statistics were applied. RESULTS: The median age was 65 years (range=27-73 years); 4 (36%) patients were females. Seven (64%) and four patients (36%) had pleural and peritoneal mesothelioma, respectively. Detectable mutations were found in 86% of the pleural and 50% of the peritoneal mesothelioma patients (overall, 73% of patients). The families of BAP1 (36%), CDKNA2A/B (27%) and NF2 (27%) represented the most frequently mutated genes. The median overall survival for all patients was 20.8 months, with 1- and 2-year survival rates of 91% and 40%, respectively. CONCLUSION: Genomic alterations as potential therapeutic targets were found by NGS. These findings will help in the development of new screening tools and targeting therapies, and in turn impact the standard-of-care and potentially lengthen disease control and survival periods in the future.

The Impact of Healthcare Access on Knowledge and Willingness for HIV Testing in Chinese Female Entertainment Workers.

Chinese female entertainment workers are at high risk for HIV. We assessed the impact of healthcare access on HIV knowledge, condom use, and their willingness to receive HIV testing. We surveyed 257 entertainment workers in a cross-sectional study. Demographic, knowledge, and behavioral risk factors were examined. Of 257 women, 107 (42.1%) reported inconsistent condom use. Only 9% had prior HIV testing. Their HIV knowledge was generally poor. Having access to healthcare, being able to obtain condoms, and managers providing health information were associated with consistent condom use (all P < 0.01). Having access to healthcare was related to previous HIV testing (P < 0.01). Our study showed that having a doctor and access to healthcare had positive effects on HIV knowledge and likelihood of condom use and previous HIV testing. Chinese medical providers can play a significant role in encouraging HIV testing and outreach in migrant women employed at entertainment venues.

Doxepin for Radiation Therapy-Induced Mucositis Pain in the Treatment of Oral Cancers.

Radiotherapy (RT), an integral part of the oncologic treatment for patients with head and neck cancer, can cause adverse side effects such as oral mucositis (OM). Pain from OM can impact a patient's quality of life and interrupt RT treatment schedules, which decreases the probability for achieving cancer cure. Conventionally, RT-induced OM pain is treated with analgesics and/or mouthwash rinses. Doxepin, a traditional tricyclic antidepressant with analgesic and anesthetic properties when applied topically to the mucosa, has been shown to lower OM pain in multiple single-arm trials (Epstein et al.) and more recently, in a placebo-controlled crossover study (Leenstra and Miller et al.). Currently, a placebo-controlled study (Sio and Miller et al.) using doxepin for esophagitis pain caused by RT to the thorax is underway. Doxepin will also be further compared with magic mouthwash and a placebo solution in a three-arm trial (Miller and Sio et al.) with head and neck cancer patients with OM pain caused by RT. Doxepin may represent a new standard for treating RT-induced OM pain in the future.

Patient age is related to decision-making, treatment selection, and perceived quality of life in breast cancer survivors.

BACKGROUND: Patients with breast cancer must choose among a variety of treatment options when first diagnosed. Patient age, independent of extent of disease, is also related to quality of life. This study examined the impact of patient age on treatment selected, factors influencing this selection, and perceived quality of life. METHODS: A 62-question survey evaluating breast cancer treatment and quality of life was mailed to breast cancer survivors. Responses were stratified by age (<50, 50-65, >65 years) and extent of disease. RESULTS: Of the 1,131 surveys mailed, 402 were included for analysis. There were 104, 179, and 119 women aged <50, 50-65, and >65 years, respectively. The median patient age was 58 years, and the average interval from diagnosis to survey participation was 31.5 months. CONCLUSIONS: Young women were more likely to have undergone aggressive therapies and had better physical functioning than old women. Old patients reported good quality of life and body image. Clinicians should consider patient age when discussing breast cancer treatment options.