Transcriptional phenocopies of deleterious KEAP1 mutations correlate with survival outcomes in lung cancer treated with immunotherapy.

PURPOSE: Co-occurring mutations in KEAP1 and STK11KRAS have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC) patients treated with immunotherapy. However, these mutational contexts identify a fraction of non-responders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations, and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. EXPERIMENTAL DESIGN: The TCGA was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of advanced NSCLC patients treated with immunotherapy and profiled by RNA-Seq (SU2C n=153; OAK/POPLAR n=439). The NSCLC TRACERx421 multi-region sequencing study (tumor regions n=947) was used to investigate evolutionary trajectories. RESULTS: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of NSCLC patients treated with immunotherapy (SU2C PFS P=0.042, OS P=0.008; OAK/POPLAR PFS P=0.0014, OS P<0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. CONCLUSIONS: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in NSCLC patients treated with immunotherapy.

Efficacy of Epley's canalith repositioning procedure according to the number of repetitions in the same session: comparison of three protocols.

BACKGROUND: The canalith repositioning manoeuvre (CRM) described by Epley remains a grade A recommended treatment for Benign Paroxysmal Positional Vertigo (BPPV) of the posterior semicircular canal (PSC). However, significant variability in the efficacy of Epley CRM has been reported. AIMS: To compare the treatment efficacy of different combinations of the Epley CRM and Dix-Hallpike retest. MATERIAL AND METHODS: Patients with PSC BPPV were divided into one of the following three treatment groups. Manoeuvre group (M): patients underwent a single Epley CRM without subsequent Dix-Hallpike retesting. Manoeuvre-Control group (MC): patients underwent up to three Epley CRM followed by Dix-Hallpike retesting until nystagmus resolution. Manoeuvre-Control-Manoeuvre group (MCM): A similar procedure to that used in the MC group except that, after the negative Dix-Hallpike retest, there was an additional CRM. RESULTS: A more favourable tendency for recovery was observed in the MCM group. There was a positive odds ratio of 1.1 between groups M and MC at the first control, 2.7 between groups M and MCM, and 2.5 between groups MC and MCM. CONCLUSIONS AND SIGNIFICANCE: Close repetition of a single Epley CRM after the first effective one would allow a positional retest to be combined with a reduction in the risk of persistent/recurrent BPPV.

Long-Term Results of Tinnitus Retraining Therapy in Patients Who Failed to Complete the Program.

Purpose: We aimed to evaluate the results of Tinnitus Retraining Therapy (TRT) in patients who did not complete the program. Methods: We divided 90 patients who failed to complete the TRT program were into 3 groups: 36 patients who only completed the first phase of the TRT program (Missing group; M), 34 patients who attended counselling for less than 6 months (Noncompliant group; NC) and 20 patients who attended counselling for more than 6 months but did not complete the TRT program (Compliant group; C). The Tinnitus Handicap Inventory (THI), tinnitus Visual Analogue Scales (VAS) and a questionnaire regarding the reasons for dropout were obtained through a telephone survey. Results: Telephonic THI and VAS scores were significantly lower than the initial scores in the M and C groups but not in the NC group. Patients who were unsure about the effectiveness of TRT were prevalent in the NC group, and the poorest long-term THI results were registered in those patients. Conclusions: A fundamental cause of very poor TRT results was when patients were unsure about TRT. On the other hand, a single counselling session could be effective in reducing tinnitus annoyance in patients who accepted the TRT approach and trusted its efficacy.

Reliability of an anamnestic questionnaire for the diagnosis of benign paroxysmal positional vertigo in the elderly.

BACKGROUND: There is common agreement in the literature that it can result in an underestimation of benign paroxysmal positional vertigo (BPPV) in the elderly. AIMS: The aim of this work was to analyze the role of anamnesis in the diagnosis of BPPV in patients of different ages through the development and validation of a scored questionnaire. METHODS: The questionnaire is based on the presence/absence of six typical anamnestic features of BPPV. The Mini-Mental State Exam (MMS) was also administered to patients over 65 years of age. Bedsides, examination for BPPV was then carried out, assigning the outcome of the questionnaire and eventual MMS to the final diagnosis for each patient. RESULTS: The sensitivity and specificity of the questionnaire for high scores (>8) were found to be, respectively, 86 % and 80 % in all patients, 94 and 71 % in those under 65 years of age, 78 and 90 % in patients over 65, and, in particular, 63 and 83 % in those with MMS >24 and 100 and 100 % in those with MMS ≤24. DISCUSSION: The reliability and average score of the questionnaire were statistically significantly lower in the group of elderly patients without cognitive deficits. The lower reliability of the questionnaire in the geriatric population, rather than the presence of cognitive deterioration, seems to correlate with other comorbidities or simply to a lower mobility of the head triggering positional symptoms. CONCLUSION: The use of the questionnaire could however reduce the risk of a missed diagnosis of BPPV given its good reliability across all ages.