TNF-alpha gene polymorphisms can help to predict response to etanercept in psoriatic patients.

BACKGROUND: Genetic factors might have a role for lack of therapeutic response to anti-TNF-alpha agents, as previously suggested in patients with rheumatoid arthritis and inflammatory bowel disease. OBJECTIVES: We evaluated the role of the main TNF-alpha polymorphisms (-238G>A, -308G>A, -857C>T) in predicting the response to etanercept, an anti-TNF-alpha fusion protein. MATERIAL AND METHODS: Genomic DNA was extracted from buccal epithelial cells in a series of 97 psoriatic patients who received etanercept for at least 3 months. Patients were classified as responders, if they achieved a PASI improvement ≥ 75% after 12 weeks of etanercept treatment, and non-responders, if PASI improvement was <75%. Single-nucleotide polymorphisms (SNPs) in TNF-alpha gene (-238G>A, -308G>A, -857C>T) were genotyped by PCR restriction fragment length polymorphism (RFLP) assays. RESULTS: We found that patients heterozygous (GA) for the -238G>A polymorphism were more likely not responsive to therapy compared to the GG genotype. In fact, the GA genotype was found in 5/59 (8.5%) responders and in 14/38 (36.8%) non-responders (P = 0.001). A significant relationship with therapy was also observed for the -308G>A polymorphisms. In fact, the GG, GA and AA genotypes were detected in 48 (81.4%), 9 (15.3%) and 2 (3.4%) of the 59 responders and in 22 (57.9%), 11 (28.9%) and 5 (13.2%) of the 38 non-responder patients (P = 0.03). No association with therapy was observed for the -857C>T polymorphisms. CONCLUSION: Our study supports the role of TNF-alpha polymorphisms in predicting the response to anti-TNF-alpha agents. In particular, we found that the presence of -238G>A and -308G>A polymorphisms is associated with poor response to a 3-month therapy with etanercept. However, our data have yet to be validated in larger cohorts.

Circulating endothelial cell levels in psoriatic patients and their modification after an anti-TNF-alpha (Etanercept) treatment.

BACKGROUND: Endothelial function in psoriatic patients has been mainly evaluated through a high-resolution ultrasound measurement of flow-mediated vasodilation in the brachial artery, which is an operator-dependent and technically demanding technique: this characteristic, together with different patient selection criteria, could account for the conflicting results emerging from different studies. Recently, Circulating Endothelial Cells (CECs) level has been suggested as a novel biomarker of vascular injury. METHODS: The number of CECs was determined by a semi-automated immunomagnetic system (CellSearch system) in peripheral blood of psoriatic patients (n = 48) and healthy subjects (n = 50). In 15 patients, CEC level was also evaluated after 6 months of treatment with an anti-TNF-alpha agent, Etanercept. The plasma levels of high-sensitivity C-reactive Protein (CRP), E-selectin, VEGF and PAI-1 were measured by ELISA. The psoriasis severity was assessed by PASI score. RESULTS: A statistically significant difference (P = 0.001) was found between CEC level in psoriatic patients (10.6 ± 9.4 cells/mL) vs. the control group (3.9 ± 0.9 cells/mL). This count inversely correlated with sE-selectin levels (r(2) = 0.16; P = 0.03). After 6 months of therapy, patients experienced a significant (P < 0.05) decrease in CEC levels (3.4 ± 1.3 cells/mL) and in PASI score (from 11.7 ± 8.1 to 2.1 ± 4.0). CONCLUSIONS: The elevated CECs level that we found in a sample of high selected psoriatic patients could be expression of endothelial damage. Lowering of CECs count after treatment with Etanercept support the hypothesis that an effective systemic therapy of psoriasis may also improve the endothelial function.

Tacrolimus 0.1% ointment in nail psoriasis: a randomized controlled open-label study.

BACKGROUND: Despite recent advances in the treatment of psoriasis, the therapeutic options for nail psoriasis are very limited, particularly when this is the only manifestation of the disease. OBJECTIVE: We performed a randomized controlled open-label study to assess the efficacy and safety of a topical treatment with tacrolimus 0.1% ointment in nail psoriasis. METHODS: In each patient, tacrolimus 0.1% ointment was prescribed for application only on the affected nails of a randomly selected hand for 12 weeks, whereas nails of the other hand did not receive any treatment. Severity of nail psoriasis was evaluated using the Nail Psoriasis Severity Index (NAPSI) score. RESULTS: We enrolled 21 consecutive psoriatic patients. At week 12, a statistically significant (P < 0.001) improvement was obtained in the treated hands with respect to the hands used as control (NAPSI score absolute change 13.0 and 3.0 respectively). Each of the enrolled patients concluded the period of treatment, but one patient was withdrawn from tacrolimus application after 9 weeks because of the appearance of acute paronychia. DISCUSSION: Our study showed that tacrolimus 0.1% ointment may be an efficacious and safe therapeutic opportunity in the treatment of nail psoriasis. Our data should be confirmed by a double-blind study with a larger sample of patients.

A phase II study of induction chemotherapy with gemcitabine (G) and cisplatin (P) in locally advanced non-small cell lung cancer: interim analysis.

BACKGROUND: Gemcitabine-cisplatin (GP) combination is one of the most active and well tolerated regimens in advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the activity and toxicity of the GP regimen as a 21-day schedule in patients (pts) with stage IIIAN2-IIIB NSCLC. PATIENTS AND METHODS: From October 1997 to July 2000, 47 pts entered the study: 43 were eligible (40 men and three women); median age was 61 years (range 45-73); ECOG PS 0-1; histology was squamous (20 pts), adenocarcinoma (12 pts), large cell (five pts), and undifferentiated (six pts); stage was IIIAN2 (14 pts, 32.56%), and IIIB (29 pts, 67.44%). Malignant pleural effusion or superior vena cava syndrome was criteria of exclusion. Induction treatment consisted of three cycles of GP (G 1250 mg/m(2) i.v. on days 1 and 8, and P 100 mg/m(2) on day 8 every 3 weeks). Responding and stable pts underwent surgery (S) and/or radiotherapy (RT). RESULTS: Following a minimum of two cycles, 39 pts were evaluable for response and 42 for toxicity. Two pts had complete responses (CR; 5.2%), 24 had partial response (PR; 61.5%), eight had stable disease (SD; 20.5%), and five had progressive disease (PRO; 12.8%). WHO grades 3 and 4 anaemia, neutropenia and thrombocytopenia were observed in two, four and two pts, respectively; non-haematological toxicity was moderate. After induction, stable and responding pts received either RT (18 pts) or S+RT (13 pts). Among the 16 resected pts, a radical complete resection was possible in 13 cases (81.3%), whereas tumour down-staging was observed in nine pts (56.2%). CONCLUSION: GP, as a 3-week neoadjuvant schedule, appears a safe and active regimen.

Amifostine plus cisplatin plus vinorelbine in the treatment of advanced non small cell lung cancer: a multicenter phase II study.

PURPOSE: to evaluate the activity and toxicity of the combination cisplatin plus vinorelbine plus amifostine in advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: a two-stage Simon design was applied. To proceed after the first stage, responses from seven of 19 patients were needed. Overall, 17 responses from 40 treated patients were required to comply with the design parameter. Inclusion criteria were cyto-histologically proven stage IIIB-IV NSCLC; age of 70 years or less; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; normal cardiac, hepatic, renal and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination, biochemistry, chest radiograph, brain, thoracic and abdominal computed tomographic (CT) scans, and bone scan. All patients received cisplatin 100 mg/m(2) intravenously (iv) day 1, vinorelbine 25 mg/m(2) iv days 1-8-15-22, amifostine 740 mg/m(2) iv day 1 every 4 weeks up to six cycles. Eleven of 40 enrolled patients were stage IIIB and 29 stage IV, with a median age of 57 years (range, 38-70 years). RESULTS: all patients were evaluable for response and toxicity (intention to treat analysis). We observed 20 (50%) objective responses, with four (10%) complete responses. Median time to progression was 20 weeks, and median survival was 45 weeks. The toxicity was manageable. The reported main toxicities were neutropenia grade 4 in 10% of patients, grade 1 and grade 3 nephrotoxicity both in 5% of patients and grade 1 amifostine-related hypotension in 15% of patients. CONCLUSION: these data show that cisplatin plus vinorelbine plus amifostine is an active and feaseable regimen in stage IIIB-IV NSCLC. A phase III trial comparing cisplatin plus vinorelbine versus cisplatin plus vinorelbine plus amifostine in advanced NSCLC is warranted.

Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable nonsmall cell lung carcinoma: a multicenter randomized clinical trial.

BACKGROUND: Lonidamine (LND) is an indazol-carboxylic acid derivative that selectively inhibits the energy metabolism of neoplastic cells, and increases the permeability of cell membranes. In vitro studies have demonstrated that LND can potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the acquired multidrug resistance of neoplastic cells. Some clinical trials have suggested a synergism of LND with alkylating agents, cisplatin, and anthracyclines in various solid tumors. METHODS: From June 1990 to June 1993, 158 previously untreated patients with Stage IIIB and IV nonsmall cell lung cancer (NSCLC) were enrolled into a multicentric randomized trial to evaluate the addition of LND to a cisplatin-epirubicin-vindesine regimen. Eighty patients in the control arm (A) received cisplatin, 60 mg/m2 intravenously (i.v.); epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. (PEV), on Day 1 every 4 weeks, whereas 78 patients in the experimental arm (B) received the same regimen with the addition of LND from 75 mg orally three times on Day 1 to 150 mg orally three times on Day 7+ until tumor progression occurred. RESULTS: The experimental treatment achieved a significantly higher proportion of major responses in comparison with the control regimen (43% vs. 24%; P=0.02). The addition of LND apparently potentiated the activity of this cytotoxic treatment, particularly in patients with metastatic disease (overall response rate, 39% vs. 17%). The median time to progression (5 vs. 8 months; P=0.0007) and the median survival time (7.6 vs. 11 months; P=0.0013) were also statistically improved in Arm B. The acute toxicity of the 2 treatments was low: only 6% of patients in Arm A and 4% of patients in Arm B had to withdraw from treatment due to Grade 4 World Health Organization toxicity. The main additional side effects related to the administration of LND were epigastralgia, myalgia, asthenia, and orchialgia. However, these symptoms were mild and controlled by the concomitant administration of low doses of steroids. CONCLUSIONS: The mild acute toxicity of the PEV regimen and the acceptable and nonoverlapping additional side effects of LND render our experimental therapy worthy of consideration for the management of NSCLC patients with poor performance status or low tolerance to more aggressive therapeutic approaches.

Alternated approach with local irradiation and combination chemotherapy including cisplatin or carboplatin plus epirubicin and etoposide in intermediate stage non-small cell lung cancer.

BACKGROUND: Prognosis of unresectable non-small cell lung cancer (NSCLC) patients is disappointing; their median survival time does not exceed 8-12 months. Recently, some authors reported an increased response rate and sometimes a prolonged survival for patients with intrathoracic disease treated with local irradiation combined with cytotoxic drugs. METHODS: Fifty-eight consecutive patients with Stage IIIA or IIIB NSCLC were enrolled in a randomized Phase II trial of alternated treatment composed of four courses of combination chemotherapy and three cycles of local irradiation. Chemotherapy consisted of a randomly selected platinum compound (cisplatin [60 mg/m2] or carboplatin [300 mg/m2]) intravenously (i.v.) on Day 1, epirubicin (50 mg/m2) i.v. on Day 1, and etoposide (100 mg/m2) i.v. on Days 1-3. A course of radiotherapy consisted of 5 consecutive fractions (3 Gy per fraction, 1 fraction per day) for a total dosage of 15 Gy per course. Each course of chemotherapy was alternated every 2 weeks with a course of irradiation so that the entire treatment was performed in 13 weeks. RESULTS: Of the 58 patients, 53 were evaluable for response: 7 showed a complete clinical remission, and 25 reached a partial response, giving an overall response rate of 60% (95% confidence interval, 46%-74%). The tumors of four patients who showed a complete or partial response subsequently were surgically resected, and the complete disappearance of any residual tumor cells was documented histologically in two of them. No difference in response was observed between cisplatin- (16 of 26 [62%]) and carboplatin-treated patients (16 of 27 [59%]), and no correlation was found between response and either stage or histology. Patients enrolled in the carboplatin arm experienced less severe leukopenia and vomiting than did those in the cisplatin arm. Median freedom from progression and overall survival time were 28 and 39 weeks, respectively. Patients who responded had a significantly longer median duration of survival (49 weeks) as compared to non-responders (15 weeks). CONCLUSIONS: The alternated chemoradiotherapy treatment obtained a high response rate with substantial toxicity. This approach did not seem to improve the prognosis of patients significantly. In this setting, the administration of carboplatin instead of cisplatin appeared to be tolerated better by the patients.

Carboplatin, epirubicin, and VP-16 chemotherapy in the treatment of small cell lung cancer.

In our study, 72 SCLC patients, 23 with limited and 49 with extensive disease, were treated with carboplatin, epirubicin, and VP-16 (CEV) chemotherapy (CBDCA 300 mg/m2 day 1, EDX 50 mg/m2 day 1, VP-16 100 mg/m2 i.v. days 1-3, every 4 weeks). Patients with limited disease were also subjected to concurrent "split-course" chest radiotherapy followed by surgery in responders if they were not staged IIIB at diagnosis. In limited disease we obtained 96.5% objective responses (OR) with 52.5% complete responses (CR), a median survival of 14 months, with 13% long-term survivors at 30 months. In extensive disease we obtained 83.6% OR with 28.5% CR, and a median survival of 10 months. Toxicity consisted mainly of manageable myelosuppression, especially for limited disease. These data show high activity of CEV chemotherapeutic regimen.

Age-related risk factors for ischemic stroke in Italian men.

We evaluated the age-related stroke risk factors in 164 Italian male patients with a diagnosis of first-ever ischemic stroke. Based on the age, we divided the patients into two groups: 42 patients ranging in age from 40 to 55 years, and 122 patients ranging in age from 56 to 75 years. For each case, an age-matched control without a history or symptoms indicating vascular disease was randomly selected from hospital patients. Information were obtained on the various risk factors. Univariate analysis showed that for the younger patients high systolic blood pressure, diabetes mellitus, hypertriglyceridemia, smoking and family history of ischemic stroke were significantly related to stroke. In the older patients, high diastolic blood pressure and smoking had a strong association with stroke. Multivariate analysis showed that high systolic blood pressure, hypertriglyceridemia, smoking and family history of stroke remained significantly and independently associated with stroke in patients up to the age of 55 years. Among patients 56 years or older, only high systolic and diastolic blood pressure, and smoking were significant predictors of stroke. In conclusion, the sets of factors associated with the risk of stroke among young and old male patients appear to be different.

Three primitive reflexes in HIV-1-infected individuals: a possible clinical marker of early central nervous system involvement.

We studied one hundred and six neurologically asymptomatic HIV-1-seropositive patients, mostly drug abusers, in various stages of HIV-1 infection to evaluate the frequency of three primitive reflexes: snout, palmomental, and glabellar. We also examined one hundred HIV-1-seronegative drug abusers and one hundred healthy heterosexual individuals. We observed the presence of one or more primitive reflexes in 41% of HIV-1-seropositive subjects, in 8% of HIV-1-seronegative drug abusers and in 3% of healthy individuals. We elicited more than one primitive reflex in 22% of patients, but never among the subjects of the two control groups. The associations of multiple reflexes were significantly more frequent in the most severe CDC stages. Our observations suggest that including evaluation of primitive reflexes in a standard neurologic examination may be useful in screening for early non specific cerebral dysfunction in neurologically asymptomatic HIV-1-seropositive subjects.

Cytokines in the pathogenesis of multiple sclerosis.

The authors evaluate the involvement of various cytokines (interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha and gamma-interferon) in the pathogenesis of multiple sclerosis. The cytokines might participate in nervous tissue damage by promoting demyelination and oligodendrocyte injury or by enhancing local immune response. In addition, several authors reported increased levels of some cytokines in serum and cerebrospinal fluid of patients with multiple sclerosis. These findings suggest that cytokines can play a significant role in the immunopathogenesis of the disease.

Cerebrospinal fluid beta-2-microglobulin in multiple sclerosis and AIDS dementia complex.

Cerebrospinal fluid (CSF) and serum concentrations of beta-2-microglobulin (beta-2-m) were evaluated in 19 patients with clinically definite multiple sclerosis (MS), in 21 with AIDS dementia complex (ADC), and in 20 subjects with other neurological diseases (OND). CSF beta-2-m and CSF/serum beta-2-m ratio were significantly higher in the patients with ADC than in the MS and OND patients. The CSF and serum levels of beta-2-m in MS patients were not significantly different from those of OND patients. These findings indicate that CSF beta-2-m and CSF/serum ratio may be a useful marker in the diagnosis of ADC. In MS patients the beta-2-m CSF determinations are of no value.

[Post-traumatic diaphragmatic hernia with late symptoms]. / Le ernie diaframmatiche post-traumatiche a sintomatologia differita.

The authors report a case of post-traumatic diaphragmatic hernia with non specific clinical findings. They consider the etiopathogenetic factors, clinical findings, therapy and underline the importance of well-performed remota anamnestic procedure to recognise the illness fastly.