Normative data for a user-friendly paradigm for pattern electroretinogram recording

PURPOSE: To provide normative data for a user-friendly paradigm for the pattern electroretinogram (PERG) optimized for glaucoma screening (PERGLA). DESIGN: Prospective nonrandomized case series. PARTICIPANTS: Ninety-three normal subjects ranging in age between 22 and 85 years. METHODS: A circular black-white grating of 25 degrees visual angle, reversing 16.28 times per second, was presented on a television monitor placed inside a Ganzfeld bowl. The PERG was recorded simultaneously from both eyes with undilated pupils by means of skin cup electrodes taped over the lower eyelids. Reference electrodes were taped on the ipsilateral temples. Electrophysiologic signals were conventionally amplified, filtered, and digitized. Six hundred artifact-free repetitions were averaged. The response component at the reversal frequency was isolated automatically by digital Fourier transforms and was expressed as a deviation from the age-corrected average. The procedure took approximately 4 minutes. MAIN OUTCOME MEASURES: Pattern electroretinogram amplitude ( micro V) and phase (pi rad); response variability (coefficient of variation [CV] = standard deviation [SD] / mean x 100) of amplitude and phase of 2 partial averages that build up the PERG waveform; amplitude ( micro V) of background noise waveform, obtained by multiplying alternate sweeps by +1 and -1; and interocular asymmetry (CV of amplitude and phase of the PERG of the 2 eyes). RESULTS: On average, the PERG has a signal-to-noise ratio of more than 13:1. The CVs of intrasession and intersession variabilities in amplitude and phase are lower than 10% and 2%, respectively, and do not depend on the operator. The CV of interocular asymmetries in amplitude and phase are 9.8+/-8.8% and 1.5+/-1.4%, respectively. The PERG amplitude and phase decrease with age. Residuals of linear regression lines have normal distribution, with an SD of 0.1 log units for amplitude and 0.019 log units for phase. Age-corrected confidence limits (P<0.05) are defined as +/-2 SD of residuals. CONCLUSIONS: The PERGLA paradigm yields responses as reliable as the best previously reported using standard protocols. The ease of execution and interpretation of results of PERGLA indicate a potential value for objective screening and follow-up of glaucoma.     

Early detection of recurrences in the follow-up of primary breast cancer in an asymptomatic or symptomatic phase

AIMS AND BACKGROUND: Periodic follow-up after primary treatment for breast cancer is a common procedure for the early detection of recurrent disease in the asymptomatic state. Anyway, there is no clinical evidence that treatment of metastases may improve the prognosis if applied in the asymptomatic state. The aim of the present study was to investigate the modality of detection of the first relapse in the asymptomatic vs the symptomatic state. METHODS: We retrospectively analyzed 717 breast cancer patients who had been consecutively referred to the Parma Oncology Division during the period 1986 to December 1988. Recurrences were detected in the course of periodic follow-up. RESULTS: A total of 211 of the 408 patients evaluated had a first relapse with a median follow-up of 94.7 months. Local and distant recurrences were 49% and 47%, respectively. Bone recurrences represented 24% of the total first recurrences, then chest wall recurrences in 23%, local regional nodes in 13%, lung in 7%, liver in 4%, and brain in 2%. The distribution of the studied patients according to recurrence site and asymptomatic or symptomatic state was different: 69% of asymptomatic patients (110) had a local recurrence vs 31% of symptomatic patients (101). A difference in survival was recorded in favor of cases detected in the asymptomatic state (P <0.001). CONCLUSIONS: The present study suggests that an early detection of local recurrence might have a favorable impact on the prognosis of patients followed after primary treatment for breast cancer. It should be considered that any difference in survival could also be explained by several "biases" and that breast cancer follow-up is still an area of investigation open to discussion in which many questions remain to be clarified.     

Vascular endothelial growth factor concentrations in the plasma-activated platelets rich (P-APR) of healthy controls and colorectal cancer patients

Vascular endothelial growth factor (VEGF) is known to play a key role in tumour angiogenesis. Our preliminary published data suggest that plasma-activated platelets rich (P-APR) rather than other plasma compartments (i.e. plasma, plasma-platelets poor) or serum is the more suitable blood fraction for measuring VEGF in a miscellaneous series of gastrointestinal cancer patients. The aim of this confirmatory study was to assess VEGF in P-APR blood compartments of 30 healthy control subjects (HCS) and a homogeneous series of 62 colorectal cancer patients (CRCP), prospectively collected, to evaluate its possible clinical-biological significance. Samples of plasma (P) in both sodium citrate (SC) and sodium citrate-theophylline-adenosine-dipyridamole (CTAD) were collected from venous blood. After the centrifugation and separation methods VEGF levels were detected by ELISA in P-APR. The best differentiation between HCS and CRCP in VEGF level was seen for P-APRCTAD (median value: 255 pg/ml versus 142 pg/ml; p=0.000 by Mann-Whitney U test). No significant correlation among the P-APR VEGF concentrations and the main clinical pathological features was found. We suggest that P-APRCTAD fraction, obtained according to well standardised conditions, could represent the suitable blood compartment for the assessment of VEGF as marker of malignant intestinal transformation.     

Oral versus intravenous vinorelbine: clinical safety profile

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.     

Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study

PURPOSE: To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. PATIENTS AND METHODS: We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. RESULTS: Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P < 0.001), and more likely to be histological grade 3 (100% vs 14%, P < 0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P < 0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors (P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. CONCLUSION: In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.     

Serum testosterone levels and breast cancer recurrence

Prospective studies show that high serum levels of androgens and estrogens are associated with increased incidence of postmenopausal breast cancer. The aim of the present analysis was to study the prognostic value of serum testosterone, estradiol and related factors in postmenopausal breast cancer patients. One hundred and ten patients without clinical recurrence were included in the study. After 5.5 years of follow-up, 31 patients developed distant metastasis (16), local relapse (4), or contralateral breast cancer (11). The risk of adverse events in relation to hormone level was examined by Cox' proportional hazard modeling, adjusting for hormone receptor status and stage at diagnosis. Body mass index and serum levels of testosterone, estradiol and glucose were significantly higher in patients who recurred than those who did not. The hazard ratios were 1.8 (95% CI = 0.5-6.3) for the middle and 7.2 (95% CI = 2.4-21.4) for the upper tertiles of baseline testosterone distribution. Other hormones had only minor influence on prognosis. High testosterone predicts breast cancer recurrence. Further studies are required to determine whether dietary or other medical intervention to reduce testosterone can reduce the recurrence of breast cancer.     

Effects of viscoelasticity on volume distribution in a two-compartmental model of normal and sick lungs

Among the models describing respiratory mechanics none has been published with the characteristics of two lung compartments including the viscoelastic properties. We used such a model to describe the inspiratory compartmental volume distribution under homogeneous and inhomogeneous conditions. The present mathematical model was tested against actual data and proven accurate. The volume distribution was studied using data from normal subjects and from patients with COPD and ARDS. In a normal lung, changes in viscoelastic constants in one compartment can modify substantially the volume distribution diverting more or less gas to the other compartment. In diseased compartments, the increase of viscoelasticity increased the difference between the compartments and the opposite was true in the less affected compartment. In conclusion, the viscoelastic properties are of paramount importance in determining gas distribution in normal and sick lungs.     

Mitral regurgitation: overview of current surgical techniques and future developments

Mitral regurgitation is a complex disease with many different etiologies, underlying dysfunctions and histologic alterations. Surgical correction of this condition dramatically improves the life expectancy and life quality of affected patients. The structure of the mitral valve lends itself to many surgical techniques. The purpose of this review is to offer readers an overview on this subject.     

Lysozyme: a paradigmatic molecule for the investigation of protein structure, function and misfolding

BACKGROUND: The term amyloidosis encompasses a wide group of conditions characterised by the tissue deposition of autologous proteins assembled in homogeneous regularly spaced antiparallel beta strands. The mechanism by which the different proteins gain a conformation, allowing monomers to bind to each other to form the regular amyloid fibril, is under intensive investigation. The discovery that human lysozyme, a protein thoroughly structurally and functionally characterised, can form amyloid fibrils has offered unique opportunities to unveil the molecular mechanisms involved in amyloid formation. Four amyloidogenic mutations have been identified and an apparently non-amyloidogenic polymorphism has been recently described. RESULTS AND CONCLUSIONS: Lysozyme is well characterised for structure, function, folding dynamics and metabolism and comparative studies are becoming available that highlight pathogenic differences between the wild-type and the amyloidogenic variants. The chemical structure of lysozyme in natural amyloid fibrils was characterised in high detail in the early cases, but it is still lacking in the cases most recently discovered. Amyloidogenic lysozymes represent a prototypic molecule for new pharmaceutical approaches in which the formation of amyloid fibrils is abrogated through a stabilisation of the precursor.