ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Genotoxicity Associated with Retroviral CAR Transduction of ATM-Deficient T Cells.

Somatic variants in DNA damage response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radiosensitivity, immunodeficiency, and predisposition to lymphoid malignancies. Patients with A-T diagnosed with malignancies have poor tolerance to chemotherapy or radiation. In this study, we investigated chimeric antigen receptor (CAR) T cells using primary T cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-), and healthy donors. ATM-/- T cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR T-cells was observed. Retroviral transduction of the CAR in ATM-/- T cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR T-cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity. Significance: CAR T-cells are clinically approved genetically modified cells, but the control of genome integrity remains largely uncharacterized. This study demonstrates that ATM deficiency marginally impairs CAR T-cell function and results in high rates of chromosomal aberrations after retroviral transduction, which may be of concern in patients with DNA repair deficiencies.

Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. METHODS: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. RESULTS: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. CONCLUSIONS: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

Spontaneous pneumothorax-When do we need to intervene?

BACKGROUND: Pneumothorax can be classified as traumatic, iatrogenic or spontaneous (SP), which can be subdivided into primary spontaneous pneumothorax (PSP), a condition without preexisting lung disease, or secondary spontaneous pneumothorax (SSP) a complication of a preexisting lung disease. Recurrence rate of PSP is 30% whereas for SSP rate is unknown. This article explores the experience of a tertiary center over 20 years. METHODS: A retrospective case review of patients hospitalized with pneumothorax to investigate the natural history and treatment of SP in a young population in a single tertiary center was conducted. A search of the digital archive (going back to 01/01/1995) of Sheba Medical Center identified hospitalized patients below the age of 40. RESULTS: The database was composed of the records of 750 patients (612 males, 138 females) who were hospitalized. The recurrence risk for SP after nonoperative treatment was significantly higher. Women were found to have an increased risk of SSP when having SP (OR 2.78). Asthma was the most prevalent disease causing SSP in young people. CONCLUSIONS: In this large cohort, we found that operative procedure has clear protective effect from recurrence in SP, so surgery should be positively considered when treating SP in hospitalized patients. Among young people and particularly in pediatric patients, when females have a SP, we strongly recommend looking for primary lung disease. More studies are needed to determine the risk factors and produce clear guidelines regarding surgery as first treatment.

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis.

RATIONALE: Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). OBJECTIVES: To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data. METHODS: Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature. RESULTS: Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit. CONCLUSIONS: Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

Advanced Lung Disease in Patients with Cystic Fibrosis Is Associated with Low Diffusion capacity.

BACKGROUND: The single-breath diffusing capacity of the lungs (DLCOSB) test measures the extent to which carbon monoxide (CO) passes from the lung air sacs into the blood. The accessible alveolar volume (VASB) is measured by inert gas during a 10-second period. The single-breath transfer coefficient of the lung for carbon monoxide (KCOSB) is the DLCOSB divided by VASB. Cystic fibrosis (CF) disease comprises progressive airway obstruction with bronchiectasis and parenchyma fibrosis. Yet, the KCOSB appears insignificant in the assessment of pulmonary function in CF. OBJECTIVES: To challenge the precision of normal KCOSB in CF. METHODS: The authors collected pulmonary function tests (PFT) data from 74 confirmed CF patients (mean age 26 ± 10 years) with various levels of pulmonary disease severity. Tests included spirometry, DLCOBP, and body plethysmography (BP). Anatomical dead space was calculated by deducting anatomical dead space from total lung capacity TLC(BP) to establish alveolar volume (VABP) and to determine KCOBP. We also included individual data of arterial pCO2 blood-gas level. RESULTS: KCOSB values were normal or higher in most patients, regardless of patient FEV1 value (R2 = 0.2204; P < 0.02). In contrast, the measurements of KCOBP were low corresponding with low FEV1 values, and negatively correlated with the elevation of trapped air and pCO2 levels (R2 = 0.1383; P = 0.0133, P > 0.05, respectively). CONCLUSIONS: The 10- second perfusion time of the inert gas during DLCOSB represent the communicative alveolar volume in CF patients with advanced pulmonary disease. The findings justify the use of DLCOSB with the deterioration of FEV1 and elevation of pCO2 levels.

Phenotypic and molecular characteristics of CF patients carrying the I1234V mutation.

BACKGROUND: The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies. METHODS: We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR. RESULTS: Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22-30 in the F508del group versus 76-82 ± 14-19 in the I1234V group (p < 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected. DISCUSSION: This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.

Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age.

OBJECTIVE: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. METHODS: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. RESULTS: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], p = .04) and older age (OR 3.9 [2.1-7.3] p < .0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility. CONCLUSIONS: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF.

Secondary enuresis and urological manifestations in children with ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (AT) is a neurodegenerative cerebellar disorder, caused by mutations in the ATM gene, involved in DNA repair. Radiosensitivity, progressive ataxia, immune deficiency and malignancies, are well known symptoms, but urological manifestations are scarcely described. OBJECTIVE: To characterize urologic manifestations in a large cohort of AT patients. METHODS: Retrospective cross-sectional chart study comprising 52 AT patients followed at a National AT Center. RESULTS: 25% of the cohort (13 patients/8 males) had urologic symptoms, which presented at 11 ± 4.3 years. The most common symptom was secondary enuresis affecting 15% of the patients (8 children/4 males). Incontinence appeared at 8 ± 6.2 years of age, and resolved spontaneously within 15 ± 8.3 months in 6 patients. It preceded loss of ambulatory capacity by 1-2 years in 7 patients. Lumbosacral MRI were normal (4 children) and urine cultures (all) were negative. Urodynamic evaluation that was performed in only one patient revealed overactive bladder. Additional manifestations were macroscopic hematuria due to bladder telangiectasia in a 12-year-old, and renal cell carcinoma in a 22-year-old. Other manifestations unrelated to AT were neprolithiasis, vesico-ureteral reflux and scrotal pain, each in 1 patient. DISCUSSION: Transient secondary enuresis is a frequent finding in AT patients, heralding loss of ambulatory capacity, tough it's pathophysiological mechanism is largely no understood.

The Value of Measuring Inspiratory Capacity in Subjects With Cystic Fibrosis.

BACKGROUND: Inspiratory capacity (IC) is often overlooked as an important measured index of spirometry in patients with cystic fibrosis (CF). Abnormally low IC may indicate the onset of static/dynamic hyperinflation, which may be accompanied by dyspnea and an increase in the work of breathing. This cross-sectional study sought to determine whether measuring IC during spirometry, may add clinical value to FEV1 measurements in CF subjects. METHODS: Anthropometric, clinical, spirometry, and static lung volume data were gathered retrospectively from 98 of 165 subjects with CF (mean ± SD age 26.8 ± 11.0 y) registered in The Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Israel. We compared the IC (% predicted) to FEV1, static lung volumes, and hospitalization days/year. RESULTS: IC decreased alongside FEV1 decline but at a slower pace (r2 = 0.32). Incremental trapped air, as measured by residual volume (RV), and a rapid elevation in the ratio of RV to total lung capacity occurred when IC deteriorated below 60% predicted values. The unique combination of IC < 50% predicted and FEV1 > 40% predicted induced an increase of up to 125 hospitalization days/year compared to subjects having IC > 50% predicted (up to 73 d/y, P < .001). CONCLUSIONS: Measuring IC in CF subjects may reveal silent worsening of lung function as indicated by a decline in IC < 50% predicted while FEV1 is still > 40% predicted. This condition may lead to inefficient breathing at high lung volumes, which may explain a subjective sensation of breathlessness and lead to an increase in hospitalization days/year.

Omalizumab in allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by a Th2 response, serum eosinophilia, and increased total serum IgE to Aspergillus fumigatus. ABPA occurs in cystic fibrosis (CF) and asthma. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Previous studies reported borderline results when treating ABPA with omalizumab. METHODS: A retrospective study to investigate the efficacy of omalizumab in the treatment of ABPA in CF patients was conducted at 3 CF centers in Israel and Belgium. Data were obtained from the digital archive. We measured 4 outcome parameters: forced expiratory volume in 1 second, body mass index, pulmonary exacerbations, and steroid sparing. RESULTS: The database was composed on the records of 9 patients. None of the outcome parameters showed any improvement. A favorable outcome was observed in patients with higher levels of posttreatment total IgE than those with lower levels. CF-related diabetes and male gender showed trends for poorer outcomes. CONCLUSION: No benefits were detected on treating ABPA in CF with omlaizumb. Monitoring the total IgE was not helpful. A prospective randomized double-blind study is needed.

Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. In the current study we aimed to better characterize this group of patients. METHODS: We performed a retrospective review of 46 patient records, followed from January 1986 to January 2015 at the Israeli National AT Center. Demographic, clinical, radiological, laboratory data was reviewed and compared between AT patients with elevated IgM levels (EIgM) and patients with normal IgM levels (NIgM). RESULTS: 15/46(32.6%) patients had significantly elevated IgM levels. This group had a unique phenotype characterized mainly by increased risk of infection and early mortality. Colonization of lower respiratory tract with Mycobacterium gordonae and Pseudomonas aeruginosa as well as viral skin infections were more frequent in EIgM patients. Patients with NIgM had a significantly longer survival as compared to patients with EIgM but had an increased incidence of fatty liver or cirrhosis. T-cell recombination excision circles and kappa-deleting element recombination circle levels were significantly lower in the EIgM group, suggesting an abnormal class switching in this group. CONCLUSIONS: EIgM in AT patients are indicative of a more severe phenotype that probably results from a specific immune dysfunction. EIgM in AT should be considered a unique AT phenotype that may require different management.

Ivacaftor for the p.Ser549Arg (S549R) gating mutation - The Israeli experience.

BACKGROUND: Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. AIM: Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. METHODS: Data obtained from CF patients receiving ivacaftor for one year. RESULTS: Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV1, increasing from 74% to 88% (p < 0.001), FVC, 89% to 101% (p = 0.019), and FEF25-75, 59%-76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p < 0.001), and BMI increased from 20 ± 3 to 22 ± 4 (p = 0.003). Glucose tolerance improved in five patients. There was no significant change in bacterial colonization. CONCLUSIONS: Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Consequences of Expiratory Flow Limitation at Rest in Subjects with Cystic Fibrosis.

RATIONALE: Expiratory flow limitation at resting tidal volume (EFLTV) presents a severe mechanical constraint in chronic lung diseases and has not yet been studied longitudinally in cystic fibrosis. OBJECTIVES: To study the effect of EFLTV as it emerged from simple spirometry on lung function and clinical status in cystic fibrosis. METHODS: Best year spirometry that included tidal flow/volume curves and the related clinical data were retrospectively collected over 12 ± 3.0 yr/person from 108 subjects with cystic fibrosis. The year in which forced expiratory flow, midexpiratory phase (FEF25-75%, L/s) was equal to tidal peak expiratory flow (L/s) was defined as EFLTV-onset year. MEASUREMENTS AND MAIN RESULTS: EFLTV occurred in 55 (51%) subjects, at age 23 ± 6 years. At EFLTV onset, tidal peak expiratory flow and FEF25-75% values were 1.44 ± 0.23 L/s and FEV1 was 62 ± 10% predicted. Within the following 2 years, FEV1 dropped to 48 ± 11% predicted, and 35 (63%) of the subjects reported shortness of breath at rest. Hospital days increased from 5.3 ± 24.6 to 24.12 ± 9.0 d/yr (P = 0.0001). Of the 55 subjects, 29 (53%) received transplant or died, with survival time being 6.9 ± 3.9 years. CONCLUSIONS: EFLTV onset may be an important pathophysiological event that could influence the natural history of lung function decline in subjects with cystic fibrosis. This may lead to a significant deterioration in lung function in the following 2 years alongside an increase in the number of hospitalization days. The monitoring of FEV1 alone does not offer as good a threshold signal, because values are only moderately reduced. Therefore, identifying EFLTV appearance is potentially a signal for therapeutic intervention. Further studies are warranted to confirm our findings.

Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort.

BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.

Tracheal diverticula in cystic fibrosis-A potentially important underreported finding on chest CT.

BACKGROUND: We aim to assess the prevalence and describe characteristics of tracheal diverticula (TD) in patients with cystic fibrosis (CF). METHODS: This retrospective study included 92 patients with known CF treated in our medical center who had available chest CT, performed between 2001 and 2013. Presence, number, size, and location of TD were recorded on the most recent chest CT. The severity of CF-related pulmonary CT findings and pulmonary function tests were recorded and correlated with the presence of the diverticula. RESULTS: Twenty-six (28%) of the 92 patients (17 males, 9 females, age range 5-59years) had one or more TD. The size of TD ranged from 2mm to 32mm. TDs were on the right posterolateral aspect of the upper tracheain nearly all patients. Small TDs appeared as a focal paratracheal lucency and larger ones as a soft tissue mass with central air bubbles. There was no significant difference in the Bhalla score between patients with and without TD. There was no correlation between the Bhalla score and patients' age, size, or number of diverticula. Pulmonary function tests were worse and declined faster in patients with TD compared to those without. CONCLUSIONS: TDs are quite common on chest CT of CF patients. Those with diverticula have significantly worse pulmonary function tests than those without.

The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers.

Cancer risks in heterozygous mutation carriers of the ATM, BLM, and FANCC genes are controversial. To shed light on this issue, cancer rates were evaluated by cross referencing asymptomatic Israeli heterozygous mutation carriers in the ATM, BLM, and FANCC genes with cancer diagnoses registered at the Israeli National Cancer Registry (INCR). Comparison of observed to expected Standardized Incidence Rates (SIR) was performed. Overall, 474 individuals participated in the study: 378 females; 25 Arab and 31 Jewish ATM carriers, 152 BLM carriers, and 170 FANCC carriers (all Ashkenazim). Age range at genotyping was 19-53 years (mean + SD 30.6 + 5 years). In addition, 96 males were included; 5, 34, and 57 ATM, BLM, and FANCC mutation carriers, respectively. Over 5-16 years from genotyping (4721 person/years), 15 new cancers were diagnosed in mutation carriers: 5 breast, 4 cervical, 3 melanomas, and one each bone sarcoma, pancreatic, and colorectal cancer. No single cancer diagnosis was more prevalent then expected in all groups combined or per gene analyzed. Specifically breast cancer SIR was 0.02-0.77. We conclude that Israeli ATM, BLM, and FANCC heterozygous mutation carriers are not at an increased risk for developing cancer.

Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report.

OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6 ±â€Š5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ±â€Š5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ±â€Š73.8 IU/L, aspartate aminotransferase 70 ±â€Š50 IU/L, alkaline phosphatase 331 ±â€Š134 IU/L, and gamma glutamyl transferase 114.7 ±â€Š8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.

Glucose intolerance in cystic fibrosis as a determinant of pulmonary function and clinical status.

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is associated with a decrease in pulmonary function and nutritional status. We investigated the clinical significance of impaired glucose tolerance (IGT) in cystic fibrosis (CF) patients. METHODS: Fifty-five CF patients (aged 22.8 ± 9.2 years, 29 males, mean FEV1 67.9 ± 22% predicted, mean BMI-SDS -0.23 ± 1.1) underwent a 2-h Oral Glucose Tolerance Test (OGTT) with 30-min interval measurements of glucose and insulin. Additional clinical and laboratory data were obtained from the medical charts. RESULTS: Thirty-eight participants (69%) had normal glucose tolerance (NGT), 13 (23.7%) had IGT, and 4 (7.3%) had newly diagnosed CFRD. Compared to patients with NGT, patients with IGT had significantly lower BMI-SDS (-1.1 ± 0.8 vs. 0.1 ± 1.1, p<0.001), mean FEV1 (57 ± 19 vs. 74 ± 21% predicted, p<0.01), and albumin (3.9 ± 0.3 vs. 4.3 ± 0.2g/dl, p=0.004), and higher fibrinogen (376 ± 56 vs. 327 ± 48 g/dl, p=0.02). Patients with IGT had impaired ß-cell function, with reduced first phase insulin secretion, a delayed insulin peak, and significantly lower total insulin secretion, HOMA-%B and insulinogenic index. Seven patients had HbA1c in the "diabetic" range (≥6.5%; 47.5 mmol/mol), however, HbA1c was not a sensitive or specific marker of glucose tolerance status. CONCLUSIONS: IGT in CF patients is associated with increased inflammation and decreased nutritional status and pulmonary function.