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.     

The importance of rating scales in measuring patient-reported outcomes

ABSTRACT: BACKGROUND: A critical component that influences the measurement properties of a patient-reportedoutcome (PRO) instrument is the rating scale. Yet, there is a lack of general consensusregarding optimal rating scale format, including aspects of question structure, the number andthe labels of response categories. This study aims to explore the characteristics of ratingscales that function well and those that do not, and thereby develop guidelines forformulating rating scales. METHODS: Seventeen existing PROs designed to measure vision-related quality of life dimensions weremailed for self-administration, in sets of 10, to patients who were on a waiting list for cataractextraction. These PROs included questions with ratings of difficulty, frequency, severity, and global ratings. Using Rasch analysis, performance of rating scales were assessed byexamining hierarchical ordering (indicating categories are distinct from each other and followa logical transition from lower to higher value), evenness (indicating relative utilization ofcategories), and range (indicating coverage of the attribute by the rating scale). RESULTS: The rating scales with complicated question format, a large number of response categories, orunlabelled categories, tended to be dysfunctional. Rating scales with five or fewer responsecategories tended to be functional. Most of the rating scales measuring difficulty performedwell. The rating scales measuring frequency and severity demonstrated hierarchical orderingbut the categories lacked even utilization. CONCLUSION: Developers of PRO instruments should use a simple question format, fewer (four to five) andlabelled response categories.     

Synergistic therapeutic potential of dexamethasone and L-arginine in lipopolysaccharide-induced septic shock

BACKGROUND: Dexamethasone (DEX) is demonstrated to have anti-inflammatory properties and known to induce hemodynamic improvement in sepsis and septic shock. L-arginine (L-arg), a semi-essential amino acid, depending on its metabolic pathway, becomes very essential in stress situations such as heatstroke, burns, sepsis, trauma, and wound healing. The aim of this study was to evaluate the synergistic therapeutic effect of DEX and L-arg in rescuing the mice from experimental septic shock induced by bacterial lipopolysaccharide (LPS). The experiments were designed to delineate the molecular mechanisms responsible for the increased therapeutic benefit of the combination therapy (CT) in LPS-induced septic shock. METHODS: Acute endotoxemia was induced in Swiss male mice by i.p. injection of LPS (18 mg kg(-1)) at 0 h. LPS-treated mice were divided into four groups. The first group (DEX group) received DEX (2 mg kg(-1)) i.p. at +2 h of LPS. The second group (L-arg group) received L-arg i.p. at a dose of 120 mg/kg at +6 h of LPS injection. The third group (CT group) received DEX (2 mg kg(-1)) at +2 h LPS followed by L-arg at +6 h of LPS injection. The fourth group received saline in place of L-arg or DEX (LPS group). A sham group was also included, where normal mice received saline in place of LPS or L-arg or DEX. At +6 h, mice from sham group, LPS group, and DEX group were sacrificed at +24 h. Mice from sham group, DEX group, L-arg group, and CT group were sacrificed to examine various parameters associated with LPS endotoxemia. RESULTS: The CT with DEX followed by L-arg significantly increased the survival of mice injected with a lethal dose of LPS. Monotherapy with either DEX or L-arg given at the same dose and time did not increase the survival of the mice injected with LPS. DEX administration could significantly reduce the levels of serum TNF-alpha, IL-1beta, IFN-gamma, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and nitrite. DEX also down-regulated the expression of liver-inducible nitric oxide synthase (iNOS), and up-regulated the levels of serum anti-inflammatory cytokines like TGF-beta1 and IL-4, hepatic and splenic arginase, in LPS-injected mice. The enhanced therapeutic effect of CT correlated with reduced pathological symptoms, decreased Th1 cytokines, increased TGF-beta1 and arginase levels compared to the mice administered with either of the monotherapies. The CT group had significantly increased expression of hepatic Hsp 70 and reduced septic shock associated histopathology, in lung and liver, compared to the mice treated with either DEX or L-arg. CONCLUSIONS: The therapeutic combination therapy with DEX and L-arg, at the appropriate dose, time, and sequence of administration, changed the cytokine profile, in favor of reducing the inflammatory response. The significantly enhanced survival observed in the CT group was accompanied by an increased hepatic Hsp 70, hepatic arginase, splenic arginase, and decreased organ injury. This novel concept of combined therapy could form the basis of an effective therapeutic approach in the treatment of sepsis and septic shock.     

Visual defects in Nepalese children with Down syndrome

Background: Down syndrome (DS) is a common chromosomal anomaly. People with this syndrome have recognisable physical characteristics and limited intellectual abilities. The aim of this study was to determine visual defects, especially refractive error and binocular anomalies, in a sample of Nepalese children with DS. Methods: Thirty‐six children with DS (19 boys and 17 girls) from the Kathmandu valley, aged from four months to 18 years, underwent detailed optometric examination. Cycloplegic refraction was performed on all subjects. Vision on presentation of all the children was assessed with preferential looking cards, the Kay picture cards, the Bailey‐Lovie logMAR chart or the Snellen chart. Binocular function was assessed with cover test, Hirschberg or Bruckner test. Results: Cycloplegic refraction of the children revealed that 80 per cent of the children had significant refractive error. Most of them had hyperopia (55 per cent), followed by astigmatism (44 per cent), myopia (25 per cent) and anisometropia (19 per cent). Only two (5.6 per cent) children were strabismic and both of them were alternating esotropes. Nystagmus was present in 10 (28 per cent). Other ocular findings were upward slanting palpebral fissures, blepharitis, congenital nasolacrimal duct obstruction, blepharoconjunctivitis, chalazion and lenticular opacities. Conclusion: Nepalese children with DS have a high prevalence of refractive error and nystagmus. Regular eye examinations are indicated for these children to enable early diagnosis and appropriate management of ocular disorders to improve their vision and quality of life.     

Heavy metal accumulation in medicinal plants collected from environmentally different sites

Objective To estimate the heavy metal content in soil and selected medicinal plants procured from environmentally different sites of the same city. Methods Soil and plant samples of Abutilon indicum, Calotropis procera, Euphorbia hirta, Peristrophe bycaliculata, and Tinospora cordifolia were collected from 3 environmentally different sites of the city： heavy traffic area （HTA）, industrial area （IA）, and residential area （RA）. Pb by inductively coupled plasma emission spectrometry and compared Cd, Cr, and Ni were estimated in soil and plant samples Results The level of heavy metal was higher in soil than in plant parts studied. Accumulation of heavy metals varied from plant to plant. Pb was the highest in Calotropis procera root from HTA site and the lowest in Peristrophe bycaliculata whole plant from IA site. It was also lower in residential area than in heavy traffic area. Conclusion The level of heavy metal content differed in the same medicinal plant collected from environmentally different sites of the same city. Thus, it reiterates our belief that every medicinal plant sample should be tested for contaminant load before processing it further for medication.     

Kala-azar-new developments in diagnosis and treatment

Kala-azar is an endemic, disease in many parts of India. Traditionally diagnosis of this disease was based on demonstrating the parasites in various tissues like bone marrow or splenic aspirates. However, lack of high sensitivity of these methods led to the use of various immunodiagnostic methods in the diagnosis of kala-azar. Antigen detection and polymerase chain reaction to detect parasitic DNA have been found to be useful in patients with an underlying immunosuppressive disease like AIDS. For treating kala-azar, pentavalent antimonial compounds are still the first-line agents. However, due to increasing resistance to this agent, many patients at present requie other drugs including amphotericin B and pentamidine. Toxic effects of these second-line agents have led to development of drug dellvery systems like liposomal amphotericin B, which has shown uniform efficacy in clinical trials. Combining stibogluconate with either paromomycin or interferon-γ has also been shown to be useful in many patients with drug-resistant kala-azar.     

Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria

Background: MRI is an established investigation in the evaluation of neonates with suspected hypoxic-ischaemic encephalopathy (HIE). However, its role as a predictor of neurodevelopmental outcome remains complex. Objective: To establish reproducible simplified MR criteria and evaluate their role in predicting neurodevelopmental outcome in term neonates with HIE. Materials and methods: Term neonates with suspected HIE had MRI at 7–10 days of age. MR scans were interpreted according to new simplified criteria by two radiologists blinded to the clinical course and outcome. The new simplified criteria allocated grade 1 to cases with no central and less than 10% peripheral change, grade 2 to those with less than 30% central and/or 10–30% peripheral area change, and grade 3 to those with more than 30% central or peripheral change. MRI changes were compared with clinical neurodevelopmental outcome evaluated prospectively at 1 year of age. Neurodevelopmental outcome was based upon the DQ score (revised Griffith's) and cerebral palsy on neurological assessment. Results: Of 20 subjects, all those showing severe (grade 3) MR changes (35%) died or had poor neurodevelopmental outcome. Subjects with a normal MR scan or with scans showing only mild (grade 1) MR changes (55%) had normal outcomes. One subject showing moderate (grade 2) changes on MRI had a moderate outcome (5%), while another had an atypical pattern of MR changes with a normal outcome (5%). Conclusions: Assessment of full-term neonates with suspected HIE using the simplified MR criteria is highly predictive of neurodevelopmental outcome. An erratum to this article can be found at     

Live/Real Time Three‐Dimensional Transesophageal Echocardiographic Findings in Caseous Mitral Annular Calcification

We describe a 77‐year‐old female with hypertrophic cardiomyopathy in whom live/real time three‐dimensional transesophageal echocardiography (3DTEE) provided incremental value over two‐dimensional transthoracic and transesophageal echocardiography (2DTTE, 2DTEE) and three‐dimensional transthoracic echocardiography (3DTTE) in making a more comprehensive assessment and a more confident diagnosis of caseous mitral annular calcification. 3DTEE revealed a portion of the mass to consist of small, multiple, highly echogenic discrete band‐like and punctate areas within a relatively much less echogenic stroma and surrounded by a well defined highly echogenic border. This appearance correlated with the pathological findings of calcific granules/strands located in a liquefied or semiliquefied interior providing a typical toothpaste like appearance. The highly echogenic outer border represented the residual outer portion or rim of the calcific mass which did not undergo liquefaction. These findings on 3DTEE which correlated with the toothpaste like appearance seen at surgery were not visualized on 2DTTE, 2DTEE, and 3DTTE. (Echocardiography 2010;27:1147‐1150)     

Emergency video-assisted thoracoscopic foreign body removal and decortication of lung after chest trauma

Video-assisted thoracoscopy can be a useful tool in selected chest trauma patients for diagnostic and therapeutic purposes. A metallic foreign body, embedded in peripheral lung parenchyma, was removed successfully with blood clot evacuation and limited decortication of lung in a hemodynamically stable 10-year-old patient using a video-assisted thoracoscopic technique.