Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer

BackgroundSTK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.MethodsForty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.ResultsIn the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype.ConclusionsOur retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.     

Impact of ceftazidime restriction on gram-negative bacterial resistance in an intensive care unit

The present study included three periods: (1) a 12-month prerestriction and control period in 2001; (2) a 12-month restriction period with reduced ceftazidime prescribing in favor of piperacillin-tazobactam (2002); (3) and a 24 month postrestriction period (2003–2004). Note that, for results, P represents the difference between 2002 and 2001; P′, the difference between 2003 and 2001; and P″, the difference between 2004 and 2001. No changes in hygiene practices were observed during these three periods. The purpose of this study was to assess the effect of reducing ceftazidime use in an intensive care unit (ICU) upon Gram-negative bacterial resistance, particularly as regards Pseudomonas aeruginosa. During the three periods of the study, patients were similar concerning age, Simplified Acute Physiology Score (SAPSII), the site of nosocomial infection, and the requirements for mechanical ventilation (75% in 2001, 76% in 2002, 74% in 2003, and 85% in 2004). The most commonly isolated pathogens were P. aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. The use of ceftazidime decreased significantly from 12.6% in 2001 to 9% in 2002, to 3% in 2003 (P′ = 0.0009), and 2.6% in 2004 (P″ = 0.0001) in favor of piperacillin-tazobactam (0% 2001 to 3.7% in 2003; P′ = 0.002; and 5% in 2004; P″ = 0.0001). Simultaneously, we observed a significant decrease in isolates of P. aeruginosa resistant to piperacillin-tazobactam (P = 0.03; P′ = 0.004; P″ = 0.009), and those resistant to imipenem in 2003 (P′ = 0.008). We also noted a significant decrease in A. baumannii isolates resistant to ceftazidime (P′ = 0.01; P″ = 0.0004) and those resistant to imipenem in both 2002 and 2004 (P = 0.03; P″ = 0.04), and a considerable decrease in isolates of Klebsiella pneumoniae producing expanded spectrum betalactamase (ESBL) in 2003 and 2004 (P′ = 0.04; P″ = 6.10⁻⁵). In contrast, we noted an increase in penicillinase-producing isolates of K. pneumoniae, from 6% in 2001 to 16% in 2002 (p = 0.01), 20% in 2003 (P′ = 0.001), and 32% in 2004 (P″ = 10⁻⁶). We concluded that restriction of ceftazidime use was demonstrated to be efficient in reducing antimicrobial resistance, especially to K. pneumoniae ESBL.     

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the P13K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.     

Childhood Overweight/Obesity and Pediatric Asthma: The Role of Parental Perception of Child Weight Status

Childhood obesity and asthma are on the rise in the U.S. Clinical and epidemiological data suggest a link between the two, in which overweight and obese children are at higher risk for asthma. Prevention of childhood obesity is preferred over treatment, however, in order to be receptive to messages, parents must perceive that their child is overweight. Many parents do not accurately assess their child’s weight status. Herein, the relation between parental perceptions of child weight status, observed body mass index (BMI) percentiles, and a measure of child feeding practices were explored in the context of asthma, food allergy, or both. Out of the children with asthma or food allergy that were classified as overweight/obese by BMI percentiles, 93% were not perceived as overweight/obese by the parent. Mean scores for concern about child weight were higher in children with both asthma and food allergy than either condition alone, yet there were no significant differences among the groups in terms of pressure to eat and restrictive feeding practices. In summary, parents of children with asthma or food allergy were less likely to recognize their child’s overweight/obese status and their feeding practices did not differ from those without asthma and food allergy.     

A bulking agent may lead to adrenal insufficiency crisis: a case report

Adrenal insufficiency is a life-threatening disorder which must be treated with glucocorticoid replacement and needs permanent dose adjustment during patient's different somatic situations. Insufficient glucocorticoid doses result in adrenal crisis and must be treated with intravenous hydrocortisone. The patient was known with Adrenal insufficiency and was treated optimally with fludrocortisone and prednisolone since seven years with no history of adrenal crisis. The patient was admitted with abdominal pain, weakness, fatigue and nausea developed 3-4 days after taking psyllium, a bulking agent, prescribed by a surgeon to diagnose anal fissure. Detailed medical history, physical examinations, laboratory and imaging examinations did not approve any other cause of adrenal crisis. Psyllium may interfere with gastrointestinal absorption of prednisolone and/or fludrocortisone and trigger acute adrenal crisis in patients with adrenal insufficiency.     

Mortality among chemical workers at Texas City plant: 1940–2001

Objectives  To evaluate the mortality experience of workers at a major chemical manufacturing site and to examine brain and liver cancers excesses reported at this site in previous studies. Methods  This study included 9,730 employees at the Texas City location who worked between 1940 and 2001. Standardized mortality ratios and confidence intervals were calculated. Results  There was less than expected deaths due to all cause mortality and no increase in all cancer mortality. Brain tumor mortality, which did exceed expected rates in past years, was at expected levels in recent years. Liver cancer mortality was greater than expected. Conclusion  Brain tumor mortality was either due to chance in the early years or the cause of the brain tumors has been eliminated. Mortality due to liver cancer is higher than expected but only among men hired before 1950. Eugenio Salazar is deceased.     

Vascular mechanisms underlying the hypotensive effect of Rumex acetosa

Context: Rumex acetosa L. (Polygonaceae) is well known in traditional medicine for its therapeutic efficacy as an antihypertensive.

Objective: The study investigates antihypertensive potential of crude methanol extract (Ra.Cr) and fractions of Rumex acetosa in normotensive and hypertensive rat models and probes the underlying vascular mechanisms.

Materials and methods: Ra.Cr and its fractions were tested in vivo on normotensive and hypertensive Sprague-Dawley rats under anaesthesia for blood pressure lowering effect. In vitro experiments on rat and Oryctolagus cuniculus rabbit aortae were employed to probe the underlying vasorelaxant mechanism.

Results: In normotensive rats under anaesthesia, Ra.Cr caused fall in MAP (40?mmHg) at 50?mg/kg with % fall of 27.88?±?4.55. Among the fractions tested, aqueous fraction was more potent at the dose of 50?mg/kg with % fall of 45.63?±?2.84. In hypertensive rats under similar conditions, extract and fractions showed antihypertensive effect at same doses while aqueous fraction being more potent, exhibited 68.53?±?4.45% fall in MAP (70?mmHg). In isolated rat aortic rings precontracted with phenylephrine (PE), Ra.Cr and fractions induced endothelium-dependent vasorelaxation, which was partially blocked in presence of l-NAME, indomethacin and atropine. In isolated rabbit aortic rings pre-contracted with PE and K⁺-(80?mM), Ra.Cr induced vasorelaxation and shifted Ca²⁺ concentration–response curves to the right and suppressed PE peak formation, similar to verapamil, in Ca²⁺-free medium.

Discussion and conclusions: The data indicate that l-NAME and atropine-sensitive endothelial-derived NO and COX enzyme inhibitors and Ca²⁺ entry blocking-mediated vasodilator effect of the extract explain its antihypertensive potential.     

Reporting quality in systematic reviews of in vitro studies: a systematic review

Background: Systematic reviews (SRs) and/or meta-analyses of in vitro research have an important role in establishing the foundation for clinical studies. In this study, we aimed to evaluate the reporting quality of SRs of in vitro studies using the PRISMA checklist.

Method: Four databases were searched including PubMed, Virtual Health Library (VHL), Web of Science (ISI) and Scopus. The search was limited from 2006 to 2016 to include all SRs and/or meta-analyses (MAs) of pure in vitro studies. The evaluation of reporting quality was done using the PRISMA checklist.

Results: Out of 7702 search results, 65 SRs were included and evaluated with the PRISMA checklist. Overall, the mean overall quality score of reported items of the PRISMA checklist was 68%. We have noticed an increasing pattern in the numbers of published SRs of in vitro studies over the last 10 years. In contrast, the reporting quality was not significantly improved over the same period (p?=?.363). There was a positive but not significant correlation between the overall quality score and the journal impact factor of the included studies.

Conclusions: The adherence of SRs of in vitro studies to the PRISMA guidelines was poor. Therefore, we believe that using reporting guidelines and journals paying attention to this fact will improve the quality of SRs of in vitro studies.