Male sex and pretreatment weight loss are associated with poor outcome in patients with advanced non-small cell lung cancer treated with immunotherapy: a retrospective study.

The influence of sex and body mass index (BMI) on the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a retrospective study to evaluate the relationship between sex, BMI, pretreatment weight loss (PWL), and clinical outcomes in 399 stage IV NSCLC patients treated with ICIs using data abstracted from medical records. Multivariable Cox proportional hazards models were used to assess the impact on overall survival and progression-free survival. Females were significantly more likely to experience immune-related adverse events and had a significantly lower risk of death compared to males in our patient cohort. In stratified analyses, the latter was limited to those receiving first-line monotherapy. BMI was overall not significantly associated with outcome. However, underweight patients had a significantly higher risk of both progression and death compared to normal weight patients in the first-line monotherapy group. When stratified by sex, underweight males had a significantly higher risk of progression and death compared to normal weight males. This was not observed among females. Those with PWL had overall significantly worse outcomes compared to those without. In stratified analyses, PWL was associated with significantly worse OS in both females and males. Stratified by treatment, the worse outcome was limited to those receiving ICI monotherapy. In summary, utilizing real-world data, this study suggests that male sex, being underweight, and PWL negatively impact ICI efficacy in NSCLC patients. Therapeutic approaches to improve ICI outcomes in underweight patients and those with PWL should be investigated.

Granulomatous Myositis Associated With Acetylcholine Receptor Antibodies Without Clinical Myasthenia.

ABSTRACT: Myasthenia gravis associated with concurrent inflammatory myopathy is a rare but well-described syndrome, most often seen in patients with thymoma. We present a case of biopsy-proven granulomatous myositis associated with positive acetylcholine receptor binding, blocking, and modulating and antistriated antibodies, without clear clinical symptoms of myasthenia gravis and in the absence of thymoma. In addition, we include rarely reported neuromuscular ultrasound findings of granulomatous myositis in a patient without sarcoidosis. Inflammatory myopathy may precede development of myasthenia gravis in myasthenia gravis associated with concurrent inflammatory myopathy, and it is important to remain vigilant for symptoms suggestive of myasthenia gravis, especially in the presence of positive myasthenia-associated antibodies.

Association Between Metabolic Syndrome and Endometrial Cancer Survival in a SEER-Medicare Linked Database.

BACKGROUND: Metabolic syndrome has previously been linked to increased risk of endometrial cancer. This study examines the association between metabolic syndrome and cancer-specific survival (CSS) in early stage and locoregionally advanced endometrial cancer. METHODS: The SEER-Medicare linked database was used to identify a cohort of patients with endometrial cancer between 1992 and 2011 who underwent hysterectomy. Patients with incomplete stage or grade information were excluded. Patients were stratified into early stage (stage I to II) or locoregionally advanced (stage III to IVa) disease. Metabolic syndrome status was determined through Medicare claims 1 year before diagnosis. The relationship between metabolic syndrome and CSS was evaluated using univariable and multivariable Cox proportional hazards regression analyses. RESULTS: A total of 10,090 patients with endometrial cancer were identified. The mean age was 75 and the majority (91.5%) were white. At diagnosis, 86.6% of patients were early stage and 13.4% were locoregionally advanced. Sixteen percent of patients had metabolic syndrome. On stage stratified multivariable analysis, race, income quartile, year of diagnosis, histopathology, and adjuvant treatment were associated with CSS in early stage disease. Presence of metabolic syndrome was associated with worse CSS in early stage disease (hazard ratio=1.28, 95% confidence interval: 1.09-1.53); this difference did not exist for locoregionally advanced disease (hazard ratio=1.18, 95% confidence interval: 0.93-1.49). CONCLUSIONS: In elderly early stage endometrial cancer patients, metabolic syndrome is associated with worse CSS. Control of metabolic syndrome through lifestyle and pharmacologic therapies may improve cancer prognosis in this population.

Pharmacoresistance with newer anti-epileptic drugs in mesial temporal lobe epilepsy with hippocampal sclerosis.

This study aims to evaluate the overall prognosis, prognostic factors, and efficacy of treatment in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who have access to third generation anti-epileptic drugs but not to epilepsy surgery. Eighty-five MTLE-HS patients were retrospectively placed into a seizure-free (seizure-free for >1year) or drug-resistant group, and the two groups were compared on the basis of age, sex, age at onset of seizures, duration of epilepsy, side of lesion, handedness, EEG findings, history of CNS infection, history of febrile convulsions, history of head trauma, history of cognitive impairment, family history of seizures, number of current anti-epileptic drugs (AEDs), total number of AED trials, and presence of individual AEDs. Only 24.7% of MTLE-HS patients had achieved seizure freedom for >1 year. Poor prognosis and drug-resistance were associated with younger age at onset of seizures (p=0.002), longer duration of epilepsy (p=0.018), greater number of current AEDs (p<0.001), and greater total number of AED trials (p<0.001). In addition, regimens with newer AEDs had no greater efficacy than regimens with older AEDs. Most medically managed MTLE-HS patients do not achieve seizure freedom despite multiple AED trials, and treatment with third generation AEDs should not preclude evaluation for epilepsy surgery.

BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity.

The AP-1 factor basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ Th17, Th9, and follicular Th cell development. However, its precise role in Th2 differentiation and function remains unclear, and the requirement for BATF in nonallergic settings of type-2 immunity has not been explored. In this article, we show that, in response to parasitic helminths, Batf-/- mice are unable to generate follicular Th and Th2 cells. As a consequence, they fail to establish productive type-2 immunity during primary and secondary infection. Batf-/- CD4+ T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of IL-4 and IL-13. In contrast to Th17 and Th9 cell subsets in which BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity site (RHS)6 and RHS7 of the locus control region relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf-/- CD4+ T cells do not obtain permissive epigenetic modifications within the Th2 locus, which were linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity and begin to elucidate a novel mechanism by which it regulates type-2 cytokine production through its modification of the Th2 locus control region.

Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes.

Systemic sclerosis (SSc) is a fibrotic and autoimmune disease characterized clinically by skin and internal organ fibrosis and vascular damage, and serologically by the presence of circulating autoantibodies. Although etiopathogenesis is not yet well understood, the results of numerous genetic association studies support genetic contributions as an important factor to SSc. In this paper, the major genes of SSc are reviewed. The most recent genome-wide association studies (GWAS) are taken into account along with robust candidate gene studies. The literature search was performed on genetic association studies of SSc in PubMed between January 2000 and March 2014 while eligible studies generally had over 600 total participants with replication. A few genetic association studies with related functional changes in SSc patients were also included. A total of forty seven genes or specific genetic regions were reported to be associated with SSc, although some are controversial. These genes include HLA genes, STAT4, CD247, TBX21, PTPN22, TNFSF4, IL23R, IL2RA, IL-21, SCHIP1/IL12A, CD226, BANK1, C8orf13-BLK, PLD4, TLR-2, NLRP1, ATG5, IRF5, IRF8, TNFAIP3, IRAK1, NFKB1, TNIP1, FAS, MIF, HGF, OPN, IL-6, CXCL8, CCR6, CTGF, ITGAM, CAV1, MECP2, SOX5, JAZF1, DNASEIL3, XRCC1, XRCC4, PXK, CSK, GRB10, NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1. These genes encode proteins mainly involved in immune regulation and inflammation, and some of them function in transcription, kinase activity, DNA cleavage and repair. The discovery of various SSc-associated genes is important in understanding the genetics of SSc and potential pathogenesis that contribute to the development of this disease.