Association of a novel 27-gene immuno-oncology assay with efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapies represent a major advance in treating a variety of advanced-stage malignancies. Nevertheless, only a subset of patients benefit, even when selected based on approved biomarkers such as PD-L1 and tumor mutational burden. New biomarkers are needed to maximize the therapeutic ratio of these therapies. METHODS: In this retrospective cohort, we assessed a 27-gene RT-qPCR immuno-oncology (IO) gene expression assay of the tumor immune microenvironment and determined its association with the efficacy of ICI therapy in 67 advanced-stage NSCLC patients. The 27-gene IO test score (IO score), programmed cell death ligand 1 immunohistochemistry tumor proportion score (PD-L1 TPS), and tumor mutational burden (TMB) were analyzed as continuous variables for response and as binary variables for one-year progression free survival. The threshold for the IO score was prospectively set based upon a previously described training cohort. Prognostic implications of the IO score were evaluated in a separate cohort of 104 advanced-stage NSCLC patients from The Cancer Genome Atlas (TCGA) who received non-ICI therapy. RESULTS: The IO score was significantly different between responders or non-responders (p = 0.007) and associated with progression-free survival (p = 0.001). Bivariate analysis established that the IO score was independent of PD-L1 TPS and TMB in identifying patients benefiting from ICI therapy. In a separate cohort of late-stage NSCLC patients from TCGA, the IO score was not prognostic of outcome from non-ICI-treated patients. CONCLUSIONS: This study is the first application of this 27-gene IO RT-qPCR assay in a clinical cohort with outcome data. IO scores were significantly associated with response to ICI therapy and prolonged progression-free survival. Together, these data suggest the IO score should be further studied to define its role in informing clinical decision-making for ICI treatment in NSCLC.

Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients.

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug's efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

Usefulness of patient-reported outcomes to assess the effectiveness of topical hormonal therapy for gynecologic symptoms after antihormonal treatment for breast cancer.

The aim of this retrospective study was to assess the efficacy of topical hormonal therapy (THT) to relieve vaginal symptoms resulting from antihormonal therapy in women with hormone receptor-positive breast cancer. A total of 74 breast cancer patients who received THT for vaginal complaints were retrospectively identified and statistically matched with 74 control breast cancer patients with vaginal complaints with no documented use of THT. Symptom scores were recorded from the center's proprietary patient-reported outcomes database, Patient Care Monitor (ConcertoHealthAI, Boston). A baseline score was noted at the initiation of antihormonal therapy and was followed at 6 and 12 months. The median differences between baseline, 6-month, and 12-month scores were analyzed. Repeated measures analysis of variance assessed the impact of topical hormonal replacement. There was no statistically significant difference in score change between the two groups at 6 and 12 months. In the active THT group, there were no statistically significant differences in vaginal complaints or sexual problems over time: {F (2, 146) = 0.99, P = 0.369; and F (2, 146) = 1.56, P = 0.217}, respectively. In this study, the use of topical hormonal replacement was not effective in alleviating vaginal symptoms.

Unusual recurrent metastasizing benign breast papilloma: a case report.

BACKGROUND: Papillary breast lesions may be benign, atypical, and malignant lesions. Pathological and clinical differentiation of breast papillomas can be a challenge. Unlike malignant lesions, benign breast papillomas are not classically associated with lymph node and distant metastasis. We report a unique case of a recurrent, benign breast papilloma presenting as an aggressive malignant tumor. CASE PRESENTATION: Our patient was a 56-year-old postmenopausal African American woman who was followed in the breast clinic with a long history of multiple breast papillomas. She underwent multiple resections over the course of 7-9 years. After being lost to follow-up for 2 years, she once again presented with a slowly enlarging left breast mass. Subsequent imaging revealed a predominantly cystic mass in the left breast, as well as a suspicious hypermetabolic internal mammary node and a hypermetabolic nodule in the pretracheal space. Biopsy of the internal mammary node demonstrated papillary neoplasm with benign morphology and immunostains positive for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/Neu. Due to the clinical picture concerning for malignancy, the patient was then started on endocrine therapy with palbociclib and letrozole before surgery. She then underwent simple mastectomy and sentinel lymph node dissection with negative nodes and pathology once again revealing benign papillary neoplasm. She underwent adjuvant chest wall radiation for 6 weeks and received letrozole following completion of her radiation therapy. She was without evidence of disease 30 months after surgery. CONCLUSIONS: We present an unusual case of multiple recurrent peripheral papillomas with entirely benign histologic features exhibiting malignant behavior over a protracted period of many years, with an invasion of pectoralis musculature and possibly internal mammary and mediastinal nodes. Her treatment course included multiple surgeries (ultimately mastectomy), radiation therapy, and endocrine therapy.

Prescription of Pharmacotherapy and the Incidence of Stroke in Patients With Symptoms of Peripheral Artery Disease.

Background and Purpose- Current guidelines recommend prescription of a number of medications to prevent cardiovascular events in patients with peripheral artery disease (PAD). The impact that these medications have on the incidence of stroke in PAD patients has not been thoroughly investigated. This study aimed to investigate the association of prescription of antihypertensive drugs, antiplatelet medications, and statins, as well as cardiovascular disease risk factors, with stroke incidence in patients with symptoms of PAD. Methods- A database search was completed to identify studies reporting the incidence of stroke and prescription of antihypertensive drugs, antiplatelet medications, and statins in patients with PAD symptoms. A random-effects model was used to meta-analyze the incidence of stroke in patients with symptoms of PAD and in subgroups with intermittent claudication and critical limb ischemia. Metaregression was performed to explore the association between the incidence of stroke and the prescription of medications and the presence of cardiovascular disease risk factors. Results- Twelve studies including 67 915 patients with symptoms of PAD were included. A meta-analysis of data from 7 studies demonstrated an incidence of stroke of 1.31 per 100 patient-years. Patients with critical limb ischemia experienced stroke 2.3× more frequently than those with intermittent claudication (95% CI, 1.58-3.36; P<0.01). The reported prescription of antihypertensive agents varied between 10% and 71%, antiplatelet drugs between 49% and 90%, and statins between 11% and 79% in different studies. Metaregression suggested an association between a lower incidence of stroke and the prescription of antiplatelet drugs ( R2=0.81, P<0.01), and statins ( R2=0.85, P<0.01), but not antihypertensives medications. A prior history of cerebrovascular events was associated with a higher incidence of stroke ( R2=0.58, P<0.05). Conclusions- This review supports previous research which suggests the need for more effective means of ensuring more widespread prescription of preventative medications in patients with PAD.

Lack of disparities in screening for associated anomalies in children with anorectal malformations.

INTRODUCTION: Patients with anorectal malformations (ARM) often have associated congenital anomalies and should undergo several screening exams in the first year of life. We hypothesized that racial and socioeconomic disparities exist in the screening processes for these patients. METHODS: After IRB approval, a retrospective review of patients with ARM born between 2005 and 2016 was performed at a quaternary care children's hospital. Demographics including gender, race, insurance, and zip code were collected. Zip code was used as a surrogate for median income. Chart review was performed to identify anomaly type and whether Vertebral defects, Anorectal malformations, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities screening was performed within 1 y of age. Descriptive statistics and chi square analyses were performed. RESULTS: One hundred patients (59% male, 68% low malformation) were identified. African American and Caucasian subjects represented 41% and 40% of the population, respectively. Overall, 68 of 100 patients had at least one screening test for each of the Vertebral defects, Anorectal malformations, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities associations. Although some minor differences were noted (more African Americans received skeletal survey than Caucasians, 80.5% versus 60%, P = 0.00335), no pattern of systematic bias in the receipt or timing of screening was evident based on race, insurance, or income. CONCLUSIONS: There do not appear to be racial or socioeconomic disparities in screening for associated anomalies in patients with ARM. However, overall gaps in screening still exist, and work must be carried out to appropriately screen all patients for associated anomalies.

A Versatile Strategy for Characterization and Imaging of Drip Flow Microbial Biofilms.

The inherent architectural and chemical complexities of microbial biofilms mask our understanding of how these communities form, survive, propagate, and influence their surrounding environment. Here we describe a simple and versatile workflow for the cultivation and characterization of model flow-cell-based microbial ecosystems. A customized low-shear drip flow reactor was designed and employed to cultivate single and coculture flow-cell biofilms at the air-liquid interface of several metal surfaces. Pseudomonas putida F1 and Shewanella oneidensis MR-1 were selected as model organisms for this study. The utility and versatility of this platform was demonstrated via the application of several chemical and morphological imaging techniques-including matrix-assisted laser desorption/ionization mass spectrometry imaging, secondary ion mass spectrometry imaging, and scanning electron microscopy-and through the examination of model systems grown on iron substrates of varying compositions. Implementation of these techniques in combination with tandem mass spectrometry and a two-step imaging principal component analysis strategy resulted in the identification and characterization of 23 lipids and 3 oligosaccharides in P. putida F1 biofilms, the discovery of interaction-specific analytes, and the observation of several variations in cell and substrate morphology present during microbially influenced corrosion. The presented workflow is well-suited for examination of both single and multispecies drip flow biofilms and offers a platform for fundamental inquiries into biofilm formation, microbe-microbe interactions, and microbially influenced corrosion.