5-year results of cisplatin-epirubicin-vinorelbine (PEV) combination as primary chemotherapy in T2-3, N0-2 breast cancer patients: a multicentre phase II study.

UNLABELLED: The aim this study was to assess the efficacy of cisplatin-epirubicin-vinorelbine, as primary chemotherapy, in reducing the tumour burden in T2-3 N0-2 breast carcinomas. Breast conservative surgery (BCS) rate, clinical and pathological complete response (pCR), toxicity and 5-year disease-free survival (DFS) and overall survival (OS) were evaluated. PATIENTS AND METHODS: Eighty-eight women with tumours > or =2.5 cm were treated with cisplatin (P) 50 mg/m2, epirubicin (E) 100 mg/m2 and vinorelbine (V) 25 mg/m2, every 3 weeks. RESULTS: Fifty-six out of the 88 patients (63.6%) underwent BCS, notably including 12/23 patients with initial tumours >5 cm. The overall clinical response was 72.8% (cCR=11.4%), pCR 20.5% and pTO+pNO 17%. No cardiac toxicity was observed. Grade 3/4 adverse events were leukopenia (9.4%), neutropenia (7.9%), nausea and vomiting (7.3%). After a median follow-up of 5 years, 24 patients (27.3%) had developed local or distant metastases. The mean DFS and OS were 51.7 (SE 2.38) and 57.02 (SE 1.98) months, respectively, and were significantly higher in pCR patients in comparison to the others (63.05 vs. 48.76, p<0.01 and 64.59 vs. 55.04, p<0.05, respectively). CONCLUSION: The PEV regimen was highly effective in reducing the tumour burden, especially for large tumours. The rate of pCR was similar to that obtained by other, including taxane-based regimens, and was well-tolerated. The study demonstrated the feasibility of such a regimen even in small centres, and being of low cost this combination could be of value in the application of primary therapy.

[The new magnetic therapy TAMMEF in the treatment of simple shoulder pain]. / Il nuovo sistema di magnetoterapia TAMMEF nel trattamento della spalla dolorosa semplice.

AIMS: Numerous studies have demonstrated the utility of extremely low frequencies (ELF) electromagnetic fields in the treatment of pain. Moreover, the effects of these fields seems to depend on their respective codes (frequency, intensity, waveform). In our study we want to assess the effects of the TAMMEF (Therapeutic Application of a Musically Modulated Electromagnetic Field) system, whose field is piloted by a musical signal and its parameters (frequency, intensity, waveform) are modified in time, randomly varying within the respective ranges, so that all possible codes can occur during a single application. PATIENTS AND METHODS: Sixty subjects, affected by shoulder periarthritis were enrolled in the study and randomly divided into three groups of 20 patients each: A exposed to TAMMEF, B exposed to ELF, C exposed to a simulated field. All subjects underwent a cycle of 15 daily sessions of 30 minutes each and a clinical examination upon enrollment, after 7 days of therapy, at the end of the cycle and at a follow-up 30 days later. RESULTS: All the patients of groups A and B completed the therapy without the appearance of side effects: they presented a significant improvement of the subjective pain and the functional limitation, which remained stable at the follow-up examination. In group C, there was no improvement of the pain symptoms or articular functionality. CONCLUSIONS: This study suggests that the TAMMEF system is efficacious in the control of pain symptoms and in the reduction of functional limitation in patients with shoulder periarthritis. Moreover, the effects of the TAMMEF system cover those produced by the ELF field.

Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). CONCLUSIONS: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Atypical Manifestations in Glut1 Deficiency Syndrome.

Glucose transporter type 1 deficiency syndrome is a genetically determined, treatable, neurologic disorder that is caused by an insufficient transport of glucose into the brain. It is caused by a mutation in the SCL2A1 gene, which is so far the only known to be associated with this condition. Glucose transporter type 1 deficiency syndrome consists of a wide clinical spectrum that usually presents with cognitive impairment, epilepsy, paroxysmal exercise-induced dyskinesia, acquired microcephaly, hemolytic anemia, gait disturbance, and dyspraxia in different combinations. However, there are other clinical manifestations that we consider equally peculiar but that have so far been poorly described in literature. In this review, supported by a video contribution, we will accurately describe this type of clinical manifestation such as oculogyric crises, weakness, paroxysmal kinesigenic and nonkinesigenic dyskinesia in order to provide an additional instrument for a correct, rapid diagnosis.

Double modulation of 5-fluorouracil in advanced colorectal cancer with low-dose interferon-alpha 2b and folinic acid. The "GISCAD" experience. Italian Group for the Study of Digestive Tract Cancer.

In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.

Transient blindness and seizure associated with cisplatin therapy.

A 38-year-old woman with adenocarcinoma of unknown origin was treated with cisplatin and etoposide. After the 4th course of chemotherapy she complained of blindness and had a seizure with spontaneous recovery in 4 days. The relationship between these events and the known neurotoxicity of other heavy metals indicate cisplatin as a possible etiologic factor.

Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study.

The influence of acute sleep deprivation during the first part of the night on 24-h blood pressure monitoring (ABPM) was studied in 36 never-treated mild to moderate hypertensive patients. According to a crossover design, they were randomized to have either sleep deprivation or a full night's sleep 1 week apart, during which they were monitored with ABPM. Urine samples for analysis of nocturnal urinary excretion of norepinephrine were collected. During the sleep-deprivation day, both mean 24-h blood pressure and mean 24-h heart rate were higher in comparison with those recorded during the routine workday, the difference being more pronounced during the nighttime (P < .01). Urinary excretion of norepinephrine showed a significant increase at night during sleep deprivation (P < .05). Blood pressure and heart rate significantly increased in the morning after a sleep-insufficient night (P < .05). These data suggest that lack of sleep in hypertensive patients may increase sympathetic nervous activity during the night and the following morning, leading to increased blood pressure and heart rate. This situation might represent an increased risk for both target organ damage and acute cardiovascular diseases.

Pharmacokinetics of VP16-213 given by different administration methods.

Plasma pharmacokinetics of VP16-213 were investigated after a 30-60 min infusion in 14 adult patients and six children. In adult the elimination half-life (T1/2 beta), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05 +/- 0.67 h, 26.8 +1- 2.4 ml/min/m2, and 15.7 +1- 1.8 l/m2; in children 3.37 +/- 0.5 h, 39.34 +1- 6.6 ml/min m2, and 9.97 +/- 3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20-30% of the dose. In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose. Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m2/24h) were around 2-5 micrograms/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.

VP16-213 and cyclophosphamide in non oat cell bronchogenic carcinoma.

Thirty-two patients with by non oat cell bronchogenic carcinoma were admitted to a protocol including Cyclophosphamide (CTX) 1,000 mg/m2 i.v. day 1, VP16-213 200 mg/m2 p.o. day 1-3, every 3 weeks. Partial remissions were seen in 2 of 27 evaluable patients; 16 of 27 showed no change. Mean survival was 36.4 weeks, median survival was 38 weeks.

Protein content and factor VIII complex in untreated, treated and monoclonal factor VIII concentrates.

Replacement therapy with clotting factor concentrates may expose the recipients not only to virus contamination but also to continuous stimulation of the immune system by repeated infusions of allogenic proteins. Concentrate purity is now a very important prerequisite to be taken into account in choosing what product can better meet the patient's needs. We compared protein content (albumin, fibrinogen, fibronectin, immunoglobulins) and factor VIII:C/vWF:Ag complex in untreated, treated and monoclonal factor VIII concentrates. Protein content is dramatically decreased in new treated ultrapure concentrates. Improved traditional fractionation methods allowed to obtain very high Factor VIII specific activity. New fractionation methods with immunoaffinity chromatography by means of monoclonal antibodies can give highly pure concentrates even if deliberately added albumin decreases factor VIII specific activity in final formulation. Otherwise monoclonal concentrates show a very high specific activity in terms of fibrinogen and immunoglobulin content, which, unlike albumin, are affecting the immune system in hemophiliacs.

Efficacy and safety of a musically modulated electromagnetic field (TAMMEF) in patients affected by knee osteoarthritis.

OBJECTIVE: Numerous studies have demonstrated the utility of extremely low frequencies (ELF) electromagnetic fields in clinical practice. Moreover, the effects of these fields seems to depend on their respective codes (frequency, intensity, waveform). In our study we want to value the effects of the TAMMEF (Therapeutic Application of a Musically Modulated Electromagnetic Field) system, which field is piloted by a musical signal. METHODS: Ninety subjects, affected by primary osteoarthritis of the knee, were enrolled in the study and randomly divided into three groups of 30 patients each: A exposed to TAMMEF, B exposed to ELF, C exposed to a simulated field. All subjects underwent a cycle of 15 daily sessions of 30 minutes each and a clinical examination upon enrolment, after 7 days of therapy, at the end of the cycle and at a follow-up 30 days later: RESULTS: All the patients of groups A and B completed the therapy without the appearance of side effects: they presented a significant improvement of the subjective pain and the functional limitation, which remained stable at the follow-up examination. In group C, there was no improvement of the pain symptoms or articular functionality. CONCLUSIONS: This study suggests that the TAMMEF system is efficacious in the control of pain symptoms and in the reduction of functional limitation in patients with knee osteoarthritis. Moreover, the effects of the TAMMEF system cover those produced by the ELF field.

Randomised trial of gemcitabine versus flec regimen given intra-arterially for patients with unresectable pancreatic cancer.

Gemcitabine is considered the golden standard treatment for unresectable pancreatic adenocarcinoma. Intra-arte-rial drug administration had shown a deep rationale with some interesting results. In a multicenter phase III trial, we compared gemcitabine given weekly with a combination of 5-fluoruracil, leucovorin, epirubicin, carboplatin (FLEC) administered intra-arteriously as first-line therapy in unresectable pancreatic adenocarcinoma. Patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arteriously at three-weekly interval for 3 times. The primary end point was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=.036). Survival at 1 year was increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both group (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, FLEC regimen given intra-arteriously, improved survival in patient with unresectable pancreatic adenocarcinoma.

Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology.

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Pharmacokinetic study of intravenous and oral idarubicin in cancer patients.

Idarubicin (4-demethoxydaunorubicin) is a new anthracycline analogue which lacks the methoxyl group at the C-4 position of the aglycone moiety. The present study was undertaken to investigate the pharmacokinetics and bioavailability of idarubicin in man. The drug was administered at 3-week intervals to six patients by both intravenous and oral routes. Doses used were 13-15 mg/m2 intravenous and 45 mg/m2 p.o. Plasma levels of unchanged idarubicin and of its metabolite idarubicinal were assayed by high performance liquid chromatography (HPLC). After intravenous administration the plasma levels of the unchanged drug declined very rapidly reaching the sensitivity limits of the analytical method (1-2 ng/ml) 24 h after dosing. Plasma levels of idarubicinal reached a peak of about 10 ng/ml within two hours then decreased very slowly with a plasma t1/2 of about 2.5 days. After the oral dose of 45 mg/m2, the plasma level patterns of both parent compound and the idarubicinal were roughly similar to those after 15 mg/m2 intravenous except for the obvious difference linked to the absorption of idarubicin. The absorption of oral idarubicin was rapid and, in terms of area under curve of the metabolite, the availability after oral administration can be estimated as about 30% of the dose. The urine findings reflected the plasma situation. The metabolite levels were much higher and longer lasting than those of the parent compound. Urinary recovery after intravenous (16% of the dose in four days) and oral administration (approximately 5% of the dose) confirmed the 30% absorption estimated on the basis of plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-over study of pharmacokinetics and haematological toxicity of 4'-epi-doxorubicin and doxorubicin in cancer patients.

Eight cancer patients were given 4'-epi-DX and DX (70 mg/m2) by i.v. route at three-week intervals according to a randomized cross-over design. Blood samples were drawn at different intervals of time after each drug administration and plasma levels of the unchanged drugs and of their main metabolites were determined by HPLC. 4'-epi-DX gave plasma levels constantly lower than those observed after DX; the pharmacokinetic study showed that 4'-epi-DX was eliminated from the body more rapidly (t1/2 30 hours as compared with 43 hours). The 13-dihydroderivatives of both drugs behaved in much the same way as the unchanged drugs; in fact the AUC values were lower for 13-OH 4'-epi-DX than for 13-OH DX. The cross-over design gave statistical confirmation of the lower haematological toxicity of 4'-epi-DX in comparison to DX. The reduced toxicity of 4'-epi-DX with respect to DX may be related to its pharmacokinetic behaviour.

Plasma and tissue distribution of adriamycin in patients with pelvic cancer.

The levels of adriamycin in plasma, ascitic fluid and normal and neoplastic tissues sampled during surgery of 3 patients with advanced pelvic cancer were measured by fluorimetry. The highest content of fluorescent compounds was found in tumoral masses in necrotic or scarcely viable tissue; viable and invasive tumor areas scored fluorescence levels comparable with normal adnexa. Ascitic fluid contained levels of fluorescence comparable to the last observed phase of plasma levels. Adipose and cutaneous tissue scored the lowest concentrations.

Six-drug sequential chemotherapy in non small cell lung cancer. A North Milan Group Study.

Forty-five patients with inoperable non small cell lung carcinoma were treated according to a sequential polychemotherapeutic regimen with cisplatin-vinblastine (A), cyclophosphamide-etoposide (B), and adriamycin-vincristine (C). Patients were evaluated every two cycles. Ten patients (22.2%) showed a partial response with a mean duration of 20 weeks, and mean survival of 50.8 weeks. It is remarkable that, among them, 6 patients (13.3%) lived over 12 months and three (6.6%) over 18 months. The mean survival for all patients was 35.7 weeks. Toxicity was acceptable and reversible.

Phase II study of the activity and tolerability of a combined regimen of high-dose epirubicin and cisplatin in stage IIIb and IV non-small cell lung cancer.

AIM: To explore the feasibility and activity of a combined regimen of high-dose epirubicin and cisplatin as an alternative to current treatments for non-small cell lung cancer (NSCLC). METHOD: Forty-four patients with stage IIIb or IV NSCLC, median Karnofsky index 90, were enrolled. Epirubicin (60 mg/m2) was administered on days 1 and 2 and cisplatin (100 mg/m2) on day 1. Treatment was repeated every 21 days for a maximum of six cycles. A hematopoietic growth factor (G-CSF) was used only for patients reaching codified nadir count values. RESULTS: A total of 130 cycles were administered with a mean of 2.9 cycles per patient. Of 41 assessable patients one showed a complete response and 15 had partial responses (overall response rate, 39%). Grade 3 or 4 leukopenia and grade 3 hemoglobin toxicity were seen in 40% and 14%, respectively, of the administered cycles. The most common nonhematologic toxic events were nausea and vomiting, mucositis, anorexia, and asthenia. CONCLUSIONS: This epirubicin-cisplatin regimen seemed effective and was generally well tolerated, and therefore suitable for use in an outpatient setting.

Cisplatin-vinorelbine combination chemotherapy in locally advanced non-small cell lung cancer.

AIM: The North Milan Group presents the results of a phase II study on a cisplatin-vinorelbine combination schedule in the treatment of locally advanced non-small cell lung cancer to evaluate its activity and tolerability. METHODS: Seventy-six consecutive patients entered the study. Patients' characteristics were the following: males/females 69/7; median age, 61.4 years (range, 40-73); ECOG performance status, 0-1; 17 stage IIIa and 59 stage IIIb. There were 49 squamous cell carcinomas, 20 adenocarcinomas, and 7 large cell carcinomas. All patients had not been previously treated and showed measureable disease. Treatment consisted of vinorelbine, 25 mg/m2 on days 1 and 8, plus cisplatin, 80 mg/m2 on day 1, administered intravenously every 21 days for three standard courses. RESULTS: Seventy-four patients were evaluable for response. Objective responses were documented in 42/74 patients with an overall response rate (CR+PR) of 56.7%; 18/74 patients (24.3%) showed stable disease and the remaining 14/74 (18.9%) went into progression. Twelve patients (16.2%) were suitable for a subsequent surgery. The median duration of response was 13.3 months. Survival time ranged from 4 to 36 months; it was 14.6 months for PR patients, 8.6 months for NC and 5 months for PD. Mean survival time is presently 12.85 months (SE, 1.2 months). Toxicity evaluated on 222 cycles administered was acceptable, and it was necessary to use G-CSF or delay the treatment because of severe leukopenia in only a few cases. CONCLUSIONS: The regimen is active and safe: the slight survival increase is likely due to the small amenability to surgery achieved (16.2%). However, our results are fully comparable to others obtained with vinorelbine in two/three drug combination chemotherapy regimens.

[Analysis of the risk of backache in the occupational environment]. / Analyse du risque lombalgique en milieu professionnel.

In a cross-sectional, and one year retrospective study low back pain risk was analysed in a sample of 1812 subjects stratified by five professions: nurses, industrial workers, truck drivers, construction workers and white collar workers. Data were collected by occupational physicians during annual systematic examinations. Relative risks were significantly higher in nurses and industrial worker occupations than in the control group of white collar employees. Multivariate analysis points out that heavy or light handling, bad postures, non-sitting jobs and exposure to vibration or inclemency are the prevalent occupational factors of low back pain. Housekeeping among females and gardening or odd jobs in males are less but significant extra-professional factors. Prevention should include instruction in lifting techniques and improvement in work conditions.