Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma.

BACKGROUND: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. PATIENTS AND METHODS: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). RESULTS: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. CONCLUSIONS: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.

Balance control impairment induced after OKS in patients with vestibular migraine: an intercritical marker.

The aim of the study was to assess the effects of optokinetic stimulation (OKS) on vestibular postural control in migraine patients with recurrent vertigo. 15 patients with vestibular migraine (VM) were enrolled in a posturographic study in eyes open (OE) and eyes closed (CE) condition. The tests were performed between attacks of headache and vertigo at three different time: before, during, and 60 min after OKS. Data of patients with VM were compared with those obtained from two control groups matched for sex and age (15 for each group): (a) normal subjects not suffering from migraine without history of recurrent vertigo (N group); (b) subjects suffering from migraine with no history of recurrent vertigo (M group). Mean sway path velocity and sway area were analyzed. OKS increased the instability in all groups during the stimulus, and both the velocity and area values were higher in M and VM group. However, there was not significant difference between these two groups when stability was examined in OE condition before, during and after OKS stimulation. Conversely, in CE condition a significant greater instability was induced after OKS stimulation only in VM. In particular, post-stimulus values were significantly higher than the pre-stimulus one only in this group, while no significant difference was observed in other groups. A spatial analysis of the sway area evidenced that the instability induced by the OKS in VM group occurred along the direction of OKS. We suggest that this enhanced instability observed after OKS during the intercritical period may be considered an useful marker to support the diagnostic definition of VM in the absence of other vestibular signs.

Benign paroxysmal positional vertigo and migraine: analysis of 186 cases.

OBJECTIVE: This retrospective study assessed several clinical, case history and functional parameters to investigate benign paroxysmal positional vertigo (BPPV) in patients with migraine. METHODS: Two groups of patients were compared: those affected by BPPV and migraine (group A), as defined by International Headache Society criteria, and those with BPPV without migraine or with another form of headache (group B). The following parameters were investigated: onset of BPPV, recovery time, residual dizziness, recurrence of BPPV, atypical eye movement patterns and Meniere-like vertigo in the inter-critical BPPV period. RESULTS: Mean age at BPPV onset was 39 years +/- 9.2 in Group A and 53 years +/- 7.3 in Group B (p = 0.00). No significant difference emerged in the number of manoeuvres needed to achieve recovery (Group A: 1.7 +/- 0.94; Group B: 1.9 +/- 0.89; p > 0.05). Highly recurrent BPPV (at least 4 documented episodes) was observed in 15 patients from group A (19.4%) and in 8 patients from group B (7.3%). Atypical eyes movements and Meniere-like vertigo were more frequent in migraineurs with highly recurrent BPPV (Chi square = 5.76; p < 0.016). CONCLUSIONS: A high prevalence of BPPV and earlier onset in migraine are the main findings of this study. There is a higher incidence of a range of neurotological patterns in the intervals between BPPV episodes in migraineurs with recurrent vertigo. No direct pathophysiological link between migraine and BPPV has yet been established; comorbidity seems to affect clinical features in a sub-population of patients and make BPPV more debilitating.

Developmental regulation of re-uptake of phosphatidylcholine by type II alveolar epithelium.

Type II alveolar epithelia produce, store and secrete pulmonary surfactant, a phospholipid and protein mixture which stabilizes alveoli at low lung volumes and, thereby, prevents alveolar collapse. We determined the developmental changes in the uptake, metabolism and reutilization of surfactant-related phospholipid in primary cultures of type II cells derived from fetal rat lung. Primary cultures of fetal and neonatal type II cells were incubated in media containing labelled liposomes. After the incubation phospholipids were extracted from the cells and uptake of label was analyzed. Re-uptake of radiolabelled dipalmitoyl phosphatidylcholine (DPPC) was concentration-dependent in undifferentiated fetal cells, differentiated fetal cells and neonatal cells. Re-uptake of DPPC by undifferentiated fetal cells was lower than re-uptake by both differentiated fetal and neonatal cells at 15 and 75 microM PC. Binding of DPPC to the cell surface involved a protein interaction, since trypsin was able to dissociate this trypsin-releasable fraction from internalized label. Undifferentiated fetal, differentiated fetal and neonatal cells all exhibited approx. 50% metabolic degradation of internalized phospholipid. Degraded lipids were reutilized in the synthesis of phosphatidylglycerol, but neonatal cells resynthesized twice as much phosphatidylglycerol as did undifferentiated fetal cells. These are the first studies which show that morphologically undifferentiated fetal type II cells are capable of the uptake of surfactant phospholipid as well as the degradation and reutilization of internalized phospholipid. Re-uptake, degradation and reutilization of internalized phospholipid appear to be under developmental control.

Energy intake and in-hospital starvation. A clinically relevant relationship.

BACKGROUND: Malnutrition is a common finding in the acute-care hospital. OBJECTIVES: To assess the adequacy of nutritional intake to individual needs and the effects of the hospitalization on nutritional status and to identify the reasons for inadequate energy intake. METHODS: A total of 286 patients with a mean ( +/- SD) age of 79 +/- 6 years (range, 70 to 99 years), consecutively admitted to the geriatrics and internal medicine wards of an acute-care university hospital, underwent multidisciplinary assessment on admission and at discharge and daily dietary data collection. The needed, prescribed, and actual daily energy intake for each individual was measured. Nutritional depletion was diagnosed if midarm circumference decreased by 3.6% or more from admission to discharge. RESULTS: Nutritional depletion occurred in 27% of the patients and correlated with anorexia (86.4% vs 65.5% and 40% in patients whose midarm circumference was unchanged and increased, respectively; P < .001), Mini-Mental State Examination score (21.6 +/- 8.3 vs 23 +/- 6.9 and 26.5 +/- 3.6; P < .05), simplified premorbid Activities of Daily Living score (4.4 +/- 2.2 vs 5.1 +/- 1.8 and 5.0 +/- 1.8; P < .03), lymphocyte count (1.32 +/- 0.63 x 10(9)/L vs 1.62 +/- 0.88 x 10(9)/L and 1.47 +/- 0.50 x 10(9)/L; P < .03), serum albumin level (38 +/- 5g/L vs 40 +/- 4 g/L and 39 +/- 8 g/L; P < .002), ratio of actual to needed energy intake (56.9% +/- 22.1% vs 69.3% +/- 30.4% and 60.0% +/- 14.1%; P < .01), ratio of actual to prescribed energy intake (50.5% +/- 16.9% vs 60.5% +/- 20.%% and 65.5% +/- 15.7%; P < .001). Patients who consumed less than 40% of the prescribed food complained of anorexia and masticatory inefficiency and were unsatisfied with quality and timing of meals compared with other patients. CONCLUSIONS: In-hospital starvation affects mainly patients with baseline nutritional, functional, and cognitive deficits and is strongly related to the inadequate energy intake.

Critical issues in pediatric lung transplantation.

Forty children (aged 1 to 18 years, 27 female and 13 male) have undergone heart-lung (21), double lung (17), and single lung (2) transplant procedures at our center from 1985 through April 1994. The indications for transplantation have been diverse, primary pulmonary hypertension (10), cystic fibrosis (11), congenital heart disease (10), arteriovenous malformation (3), emphysema (1), graft-versus-host disease (1), rheumatoid lung (1), cardiomyopathy (1), desquamative interstitial pneumonitis (1), and Proteus syndrome (1). The actuarial 1-year survival was 73% (mean follow-up 2 years). One-year actuarial survival for disease groups ranged from 60% for cystic fibrosis to 90% for congenital heart disease. We have identified six issues critical to the patient and programatic survival of pediatric lung transplantation. Our experience and management strategies in these areas are reviewed. Cytomegalovirus: Cytomegalovirus disease developed in six of eight patients with cytomegalovirus mismatching (donor +/recipient-) and in seven of 32 patients who survived more than 30 days (23%). All but cytomegalovirus donor -/recipient- patients were treated with ganciclovir for 4 weeks after transplantation. Obliterative bronchiolitis: Obliterative bronchiolitis developed in seven of 32 (25%) patients who survived more than 30 days. Obliterative bronchiolitis was manifest within the first posttransplantation year as a rapid decline in small airway function. Aggressive augmentation of immunosuppression has been used with little success. Posttransplantation lymphoproliferative disease: Posttransplantation lymphoproliferative disease developed in five of 32 (15%) patients who survived more than 30 days developed. One patient died (17% mortality) despite retransplantation. In four patients the disease resolved with reduction in immunosuppression alone, and one required the addition of interferon alfa. Cystic fibrosis: We have changed our management strategies to avoid triple drug immunosuppression, perioperative blood and bronchial cultures, aggressive antimicrobial therapy, and exclusion of patients with panresistant organisms; this has resulted in elimination of infectious mortalities thus far in the pediatric cystic fibrosis group. Airways: In 21 heart-lung recipients with tracheal anastomoses we have had no airway complications. The double and single lung transplant recipients accounted for 34 bronchial and one tracheal anastomoses. Three (9%) bronchial stenoses developed. Two were treated with silicone stents and one with balloon dilation.(ABSTRACT TRUNCATED AT 400 WORDS)

New-onset diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression.

BACKGROUND: Tacrolimus has a negative effect on the pancreatic beta islet cell, and both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid organ transplant recipients. METHODS: To determine the association between tacrolimus and new-onset diabetes mellitus in childhood, we reviewed data on 78 pediatric heart and heart-lung/lung recipients receiving tacrolimus-based immunosuppression. Trough tacrolimus levels, fasting and random blood glucose levels, and corticosteroid requirements were reviewed. Diabetes was defined as glucose intolerance requiring long-term insulin treatment more than 30 days after transplantation. RESULTS: No patient had diabetes before introduction of tacrolimus. In heart-lung/lung recipients, 12 of 28 (43%) had development of diabetes at a median follow-up of 7 months (range 1 to 39). In this group diabetes developed in three of eight (38%) patients with cystic fibrosis and nine of 20 (45%) without (p = NS). In contrast, only two of 50 (4%) heart transplant recipients had development of diabetes. Of the 14 patients with diabetes, 10 had development of diabetes during augmentation of immunosuppression with pulsed corticosteroids. Tacrolimus trough levels were significantly lower in heart compared with heart-lung/lung transplant recipients (9.4 +/- 3.3 versus 15.3 +/- 0.9 ng/ml) (p < 0.01), and at latest follow-up significantly fewer heart transplant recipients were treated with maintenance corticosteroids (28% versus 75%; p < 0.01). In the heart-lung/lung group, no significant difference in tacrolimus levels was found between patients with and without diabetes, nor was there a significant difference in the average corticosteroid dose or number of pulses of corticosteroids per patient. CONCLUSIONS: New-onset diabetes mellitus is rare in pediatric heart transplant recipients receiving tacrolimus-based immunosuppression, but it occurs with a high incidence after pediatric heart-lung/lung transplantation and usually develops during pulsed corticosteroid therapy. However, it is currently not possible to predict which heart-lung/ lung transplant recipients will have development of this serious complication.

Ostium secundum atrial septal defect in the elderly.

Atrial septal defect (ASD) is one of the most common congenital cardiac anomalies in adults. Life expectancy is shortened, and almost 90% of patients die by the age of 60 years. The progression of this congenital disease to congestive heart failure has been related to several factors such as the onset of pulmonary hypertension, arrhythmias, bronchopulmonary infections, or the development of other cardiovascular disease. We describe three cases of very old patients with significant ASDs and late development of symptoms. Given the higher risks and poorer long-term results of surgical closure of the defect in advanced age, the indications for such an intervention in elderly patients should be carefully evaluated.

Nutritional assessment: a primary component of multidimensional geriatric assessment in the acute care setting.

OBJECTIVE: To test the prognostic role of nutritional variables as a component of geriatric multidimensional assessment and to study the effect of hospitalization on nutritional status. DESIGN: Validation cohort study: multidimensional assessment on admission and at discharge and a weekly nutritional assessment. SETTING: General Medicine and Geriatrics wards in an acute-care university hospital. PATIENTS: A consecutive sample of 302 patients aged 79 +/- 6 years, range 70-96 years. MAIN OUTCOME MEASURES: Mortality, longstay (> 29 days), loss of lean body mass as expressed by a negative change in mid-arm muscle circumference (MAMC). RESULTS: Incidence of mortality, longstay, and decreased MAMC was 6.9%, 24.8%, and 64.2%, respectively. According to logistic regression analysis, mortality was independently predicted by preadmission dependency in at least one Activity of Daily Living (odds ratio = 2.08, confidence limits = 1.19-3.65), clinical diagnosis of malnutrition (OR = 1.89, CL = 1.11-3.21), serum albumin < 3.5 g/dL (OR = 1.82, CL = 1.06-3.14). This predictive model allowed us to recognize 75% of the patients at risk of death by targeting 23% of the population. Longstay was independently predicted by stroke (OR = 1.54, CL = 1.01-2.35), clinical diagnosis of malnutrition (OR = 1.41, CL = 1.04-1.93), and more than five comorbid diseases (OR = 1.39, CL = 1.01-1.94). Dependency in at least one ADL was the only independent predictor of decreased MAMC (OR = 1.71, CL = 1.27-2.30). CONCLUSIONS: Nutrition variables are a cardinal component of multidimensional assessment in the acute-care setting. Nutritional status deteriorates during the hospital stay, mostly in physically dependent patients.

[Malnutrition in the acute care hospital: a very common problem]. / La denutrizione in ospedale per acuti: un problema molto comune.

The adequacy of caloric intake of geriatric patients in medical and surgical wards in the acute care hospital was assessed in a prospective, observational study. Fifty-one surgical and 80 medical nonterminal patients aged over 70 years underwent a multidimensional assessment on admission and a nutritional reassessment on discharge. The average daily caloric intake was also measured. Patients were divided into two groups according to whether the ratio of the actual to the needed caloric intake was inferior to 40% or not, and their differences, with regard to baseline values, were assessed. Patients whose caloric intake was inferior to 40% of the needed were older than the remaining ones (79.4 +/- 6.6 vs 76.6 +/- 4.9 years, p < 0.05), had higher prevalence of preadmission functional dependency (21.6% vs 15%, p < 0.001), lower body mass index (22.9 +/- 5.4 vs 24.8 +/- 3.9, p < 0.004) and higher comorbidity (coexisting diseases: 3.6 +/- 1.9 vs 2.8 +/- 1.6, p < 0.02) on admission. In conclusion, a simple assessment on admission allows targeting geriatric patients at risk for in-hospital starvation. No difference exists between surgical and medical wards in the quality of nutritional support.