BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

BACKGROUND: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. MATERIALS AND METHODS: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. RESULTS: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. CONCLUSIONS: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

Late-onset Huntington's disease with 40-42 CAG expansion.

INTRODUCTION: Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40-42). METHODS: A retrospective analysis of 66 HD patients with 40-41-42 CAG expansion was performed. Patients were investigated with the Unified Huntington's Disease Rating Scale (subitems I-II-III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher's test, t test and Pearson's correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. RESULTS: The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. CONCLUSION: There were no clinical differences between CO and LO subgroups with 40-42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

Prognostic significance of inflammatory-related parameters in patients with anal canal cancer.

PURPOSE: To investigate the correlation between inflammatory-related parameters and overall survival (OS) and disease-free survival (DFS) in anal canal cancer population. METHODS AND MATERIALS: Patients diagnosed with anal canal carcinoma and treated with curative intent chemoradiotherapy (CRT) were included. Data about pre-treatment complete blood count were collected. Neutrophil to lymphocyte ratio (NLR), fibrinogen (F), and a combination of these (F-NLR score) were correlated with OS. RESULTS: A total of 58 patients were enrolled. In multivariate analysis, the strongest OS prognostic factor was NLR, with a hazard ratio (HR) for low NLR compared to high NLR of 1.30 (95% confidence interval 1.01-14.12). Kaplan-Meier survival analysis showed that patients with high NLR, F, and F-NLR had significantly shorter OS and DFS. CONCLUSION: To our knowledge, this is the first study providing evidence that elevated pre-treatment NLR, F, and F-NLR score significantly correlate with worse survival outcomes in patients with anal canal carcinoma. In view of our findings, future clinical trials in anal canal cancer patients are warranted to verify our results.

Mild brain injury and anticoagulants: Less is enough.

BACKGROUND: Despite the higher theoretical risk of traumatic intracranial hemorrhage (ICH) in anticoagulated patients with mild head injury, the value of sequential head CT scans to identify bleeding remains controversial. This study evaluated the utility of 2 sequential CT scans at a 48-hour interval (CT1 and CT2) in patients with mild head trauma (Glasgow Coma Scale 13-15) taking oral anticoagulants. METHODS: We retrospectively evaluated the clinical records of all patients on chronic anticoagulation treatment admitted to the emergency department for mild head injury. RESULTS: A total of 344 patients were included, and 337 (97.9%) had a negative CT1. CT2 was performed on 284 of the 337 patients with a negative CT1 and was positive in 4 patients (1.4%), but none of the patients developed concomitant neurologic worsening or required neurosurgery. CONCLUSIONS: Systematic routine use of a second CT scan in mild head trauma in patients taking anticoagulants is expensive and clinically unnecessary.

Antimicrobial use and Pseudomonas aeruginosa susceptibility profile in a cystic fibrosis centre.

The susceptibility patterns of 1315 mucoid and non-mucoid Pseudomonas aeruginosa strains from 224 patients were determined along with antibiotic utilisation in a Cystic Fibrosis Centre from 1993 to 1997. Ceftazidime was the most active agent (86.0% sensitive isolates), followed by piperacillin-tazobactam (81.7%), aztreonam (80.3%), imipenem (80%), piperacillin (76.8%), tobramycin (76.5%), ciprofloxacin (73.7%), ticarcillin (72.4%), ticarcillin-clavulanic acid (70.2%), amikacin (69.5%), netilmicin (56.5%), meropenem (79%) and imipenem (75.5%). The most frequently used compounds were nebulized colistin (mean+/-S.D., 109+/-45 defined daily doses per 1000 patients per day), followed by ciprofloxacin (98+/-8), tobramycin (55+/-9), ceftazidime (31+/-8) and amikacin (55+/-9). The mean antibiotic consumption by our CF patients was 413+/-47 defined daily doses per 1000 patients per day. Trend testing showed a significant decline of susceptibility to aminoglycosides, imipenem and ciprofloxacin, while the susceptibility of P. aeruginosa to piperacillin and ceftazidime was stable.

Epidemiology and clinical course of Burkholderia cepacia complex infections, particularly those caused by different Burkholderia cenocepacia strains, among patients attending an Italian Cystic Fibrosis Center.

In this study, the epidemiology of Burkholderia cepacia complex (Bcc) recovered from the sputum of 75 patients attending the Genoa Cystic Fibrosis (CF) Center at the Gaslini Children's Hospital (Genoa, Italy) was investigated, and the clinical course of the CF patients infected with the different species and genomovars of Bcc was evaluated. All isolates were analyzed for genomovar status by recA gene polymorphism and subsequently random amplified polymorphic DNA fingerprinting. Burkholderia cenocepacia is the predominant species recovered from the CF patients infected with Bcc at the Genoa CF Center. Of the other eight species comprising the Bcc, only a few isolates belonging to B. cepacia genomovar I, Burkholderia stabilis, and Burkholderia pyrrocinia were found. Of the four recA lineages of B. cenocepacia, most patients were infected by epidemic strains belonging to lineages IIIA and IIID, whereas only a few patients harbored IIIB strains. Patient-to-patient spread of Bcc among CF patients was mostly associated with B. cenocepacia, in particular with strains belonging to recA lineages IIIA and IIID. The mortality of CF patients infected with Bcc at the Genoa CF Center was significantly higher than mortality among CF patients not infected with Bcc. All of the deaths were associated with the presence of B. cenocepacia, except the case of a patient infected with B. cepacia genomovar I. Within B. cenocepacia, infection with epidemic strains belonging to lineages IIIA and IIID was associated with higher rates of mortality than was infection with lineage IIIB strains. No significant differences in lung function, body weight, and mortality rate were observed between patients infected with epidemic strains belonging to either B. cenocepacia IIIA or B. cenocepacia IIID.

Congenital bilateral absence of the vasa deferentia and related respiratory disease.

In a meaningful proportion of cases, CBAVD has been recognised as a probable consequence of cftr gene mutations. This lead to a further enlargement of the spectrum of clinical pictures due to "cftr deficiency". More recently, the identification of a polymorphism in intron 8 regulating the level of correct cftr transcription, shed new light on the genotype-fenotype correlation of cftr mutations. Unfortunately, little information is still available on the clinical manifestations of CBAVD other than infertility. History, clinical picture, sweat test and genotype were carefully evaluated in a series of 21 patients affected by CBAVD, selected on the basis of otherwise unexplained obstructive azoospermia. History collection was especially addressed to respiratory symptoms. Family history was always negative for CF. Nevertheless, personal history showed respiratory symptoms in 18 cases (86%) 9/21 (43%) patients suffered from chronic sinusitis and one of these had had a pneumothorax. Other 9 (43%) patients had chronic nasal obstruction, due to recurrent nasal poliposis in two cases. Sweat test was clearly abnormal in 15/21 (71%) and borderline in the remaining 6 patients (29%). Genetic analysis allowed detection of one mutation in 15/21 patients (71%). Our data show that respiratory symptoms may be present in CBAVD patients, so that CBAVD cannot be merely considered a "genital form" of CF.