Federica Edith Pisa

Measures of Outcome in Metastatic Breast Cancer: Insights From a Real-World Scenario

No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological.

Residential radon and risk of lung cancer in an Italian alpine area.

Abstract To evaluate whether residential radon exposure explains the excess mortality for lung cancer in an Italian alpine valley with high natural radioactivity, the authors conducted a population-based case-control study on 138 deceased cases and 291 sex- and year-of-birth-matched controls. Year-long alpha-track measurements of radon were performed in the most recent residence, and information about occupational history and lifetime smoking habits was obtained. The authors adjusted for smoking, and radon was associated with lung cancer risk among men: compared with a radon level of < 40 becquerels (Bq) per cubic meter (m3), the odds ratios for 40–76 Bq/m3, 77–139 Bq/m3, 140–199 Bq/m3, and 200+ Bq/m3 were 2.1, 2.0, 2.7, and 1.4, respectively. The association between radon and lung cancer, as determined with a multiplicative model, was found only among male smokers.

Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset

Abstract ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [3H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

Clinical outcome of deep brain stimulation for dystonia: constant-current or constant-voltage stimulation? A non-randomized study.

Bilateral globus pallidus deep brain stimulation (GPi‐DBS) represents an effective and relatively safe therapy for different forms of refractory dystonia. The aim of this study was to assess, retrospectively, the effect of two different stimulation settings during GPi‐DBS in 22 patients affected by primary generalized or multi‐segmental dystonia.

Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns - Evidence from Two Mediterranean Birth Cohorts.

Background The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes. Objective To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg. Methods The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts. Results ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG. Conclusion The ABC transporters appear to play a role in accumulation of MeHg during early development.

The accuracy of discharge diagnosis coding for Amyotrophic Lateral Sclerosis in a large teaching hospital

To evaluate the accuracy of hospital discharge data as a source of Amyotrophic Lateral Sclerosis (ALS) cases for epidemiological studies or disease registries, a validation study was performed. All records of patients discharged in 2005 and 2006 with principal or secondary International Classification of Diseases, 9th rev., Clinical Modification (ICD 9 CM) diagnosis code of ALS (335.20), other anterior horn cell disease (335), spinal cord disease (336), hereditary and idiopathic peripheral neuropathy (356), inflammatory and toxic neuropathy (357), myoneural disorders (358), muscular dystrophies and myopathies (359), were selected from the electronic archive of discharge data of the University Hospital of Udine, Friuli Venezia Giulia Region, North East Italy. Corresponding clinical documentation was reviewed to ascertain the presence of El Escorial criteria, the gold standard. Sensitivity of the ICD 9 CM discharge code 335.20 was 93% (95%CI: 82–99%) and decreased to 91% (95%CI: 77–98%) when suspect ALS was excluded. Specificity was 99% (95%CI: 97–99%). The ICD 9 CM discharge code 335.20 can identify a high percentage of hospitalizations of patients truly affected by ALS and of patients with no ALS, among selected neurological diagnostic codes. To ensure complete ALS case ascertainment, prospective population-based registries or epidemiologic studies require active prospective surveillance and use of multiple sources, among them hospital discharge archives can provide accurate information.

Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer

AIM To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). MATERIALS & METHODS We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. RESULTS BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 × 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. CONCLUSION Extended mutational profile combined with clinical factors may impact on survival in mCRC.

The prevalence of vegetative and minimally conscious states: A systematic review and methodological appraisal

Objectives:To systematically review prevalence studies of vegetative state (VS) and minimally conscious state (MCS) in geographically defined populations, to appraise study methods and assess sources of heterogeneity. Methods:MEDLINE, EBM Reviews, and EMBASE databases were searched using key terms. Two reviewers independently identified pertinent articles and screened the references for additional studies. Studies measuring the prevalence of VS and/or MCS in a defined population were included, and information on characteristics, methods, and results was extracted. Heterogeneity was quantified through the statistic I2. Results:We identified 5 cross-sectional prevalence surveys of VS and 1 of MCS. Prevalence ranged from 0.2 cases per 100 000 inhabitants to 3.4 for VS and was 1.5 per 100 000 for MCS. Relevant heterogeneity (I2 = 99.0%) prevented us from calculating a summary estimate. The prevalence of trauma cases varied from 21.9% to 53.8%. Variability pertaining to diagnostic criteria, definition of case, and methods of ascertainment was found. Conclusion:In the few prevalence studies of VS and MCS that were identified, the estimates showed high variability and could not be pooled. Future studies should consider using comparable methods for the definition, ascertainment, and confirmation of cases.

The Incidence of Amyotrophic Lateral Sclerosis in Friuli Venezia Giulia, Italy, from 2002 to 2009: A Retrospective Population-Based Study

Background: We conducted a retrospective population-based study to estimate the incidence of amyotrophic lateral sclerosis (ALS) in Friuli Venezia Giulia, Italy, from 2001 to 2009. Methods: Multiple sources were used for case ascertainment: Health databases, archives of the neurology departments and of the regional chapter of the Italian ALS Association. The diagnosis was validated through clinical documentation review. Crude and standardized incidence rates (IRs) per 100,000 person-years were calculated. Results: We identified 262 incident ALS cases, 50.4% men, 4.2% familial. Half of the patients had spinal onset (56.8% in men) and 25.2% bulbar (29% in women). Bulbar onset had a similar frequency in women (31.7%) and men (31.5%) aged 67 or above at diagnosis. The crude IR was 2.72 (95% confidence interval, 95% CI, 2.39-3.05) and the male:female ratio 1.08. The IR peaked in the 65-74 age group, with a second increase in men 85 years and older. The IR standardized to the 2001 Italian population was 2.38 (95% CI 2.13-2.63) and to the 2000 European population 2.58 (95% CI 2.34-2.81). Conclusions: This retrospective study found IRs of ALS in the range of Italian and European prospective population-based registries, suggesting an almost complete case ascertainment.

Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti‐inflammatory drugs in Friuli Venezia Giulia, Italy

Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti‐inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers.