Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study.

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.

Weekly paclitaxel/cisplatin with concurrent radiotherapy in patients with locally advanced non-small cell lung cancer: a phase I study.

We designed a phase I study to determine the maximum tolerated doses of weekly cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (doses escalated alternately) when given concurrently with standard or hyperfractionated radiotherapy (RT) and to define the nature of the dose-limiting toxicity. Chemotherapy-naive patients with locally advanced non-small cell lung cancer received weekly combination cisplatin/paclitaxel with concurrent local RT. Radiation therapy was initially given at the dose of 1.2 Gy twice daily x 5 d/wk x 5 weeks (total dose, 60 Gy). In the last two patient cohorts, the single daily dose was decreased to 2 Gy x 5 d/wk x 6 weeks. Overall, 25 patients were recruited into five different cohorts. Esophagitis was the main nonhematologic toxicity, occurring in 16 of 25 patients (64%; grade 3 or 4 in five). Neutropenia was the most prevalent hematologic toxicity, occurring in 33 of 141 weekly courses, but grade 4 neutropenia was seen in only four courses. Cisplatin/paclitaxel doses of 35 mg/m2/wk and 45 mg/m2/wk, respectively, were safe when standard RT was used, while the cisplatin dose had to be decreased to 30 mg/m2/wk in patients receiving bifractionation. Two complete and 13 partial responses were observed, for a 60% overall response rate (95% confidence interval, 39% to 79%). Median survival was 16 months, with a 66% 1-year actuarial probability. We thus conclude that the cisplatin/paclitaxel combination given weekly can be safely administered concurrent with both standard or hyperfractionated RT. Hyperfractionation is associated with a higher incidence of severe esophagitis and required a slight reduction in cisplatin dose. To verify whether the use of a daily schedule translates into a better therapeutic index, a new phase I study is under way, testing twice-daily cisplatin/paclitaxel concurrently with hyperfractionated RT.

Thoracic radiotherapy and daily vinorelbine as radiosensitizer in locally advanced non small cell lung cancer: a phase I study.

Experimental studies have shown that vinorelbine is a powerful radiosensitizer in vitro. To date, no reports on clinical activity of the single agent vinorelbine as radiosensitizer have been published. The aim of the present phase I study was to determine the maximum tolerated dose (MTD) of vinorelbine administered daily concurrently with thoracic radiotherapy, with or without amifostine support, in the treatment of locally advanced non small cell lung cancer. In vitro studies have shown that vinorelbine can potentiate the antitumor effects of radiation therapy. Amifostine is a sulphydril compound that has shown to protect normal tissues from chemotherapy and radiotherapy-induced toxicities. Radiotherapy lasted 6 weeks and the total dose was 55 Gy. The daily fraction was 1.8 Gy, administered 5 days a week for 5 weeks and increased to 2.0 Gy during the sixth and last week. Concurrent vinorelbine was administered daily with a planned escalation of the dose from 4, to 5 and 6 mg/m(2). Fourteen patients were enrolled in the study. The first dose of vinorelbine was 4 mg/m(2) and it showed to be feasible without dose-limiting toxicity (DLT). Instead, the second dose level of 5 mg/m(2) was unfeasible because three out of six patients had DLT (grade 4 neutropenia, treatment interruption longer than 2 weeks for prolonged grade 2 neutropenia and treatment interruption longer than 2 weeks for prolonged grade 3 esophagitis together with grade 4 dyspnea). At that time, the study continued adding amifostine to vinorelbine in order to increase its MTD. Amifostine was administered by means of subcutaneous injection 15 min before each radiotherapy fraction at the fixed dose of 300 mg/m(2). However, 5 mg/m(2) of vinorelbine were considered unfeasible even with amifostine support because three out of five patients showed DLT (grade 4 neutropenia, febrile grade 4 neutropenia and grade 3 liver toxicity). Among 14 patients enrolled in the study, eight completed the planned treatment because six patients experienced DLT, which determined treatment interruption. Overall, four partial and two complete responses were observed. Two partial and one complete response were observed in those three patients who had been treated with the first dose of vinorelbine. In conclusion, our data show that the MTD of daily vinorelbine is 4 mg/m(2). Therefore, this is the recommended dose of daily vinorelbine to be administered with concurrent thoracic radiotherapy in a phase II trial. Finally, amifostine administered subcutaneously failed to increase the MTD of daily vinorelbine.

Serum CA-125 levels do not depend on ovarian steroidogenesis.

To investigate the relationship between CA-125 production and ovarian steroidogenesis, serum CA-125 levels were evaluated in patients with normal pelvis in different ovarian endocrine situations: (1) during the menstrual cycle, (2) during stimulatory treatment with gonadotropin for the induction of ovulation, and (3) during suppression treatment with gonadotropin-releasing hormone agonists. In spite of the spontaneous or the markedly induced variations of estradiol (E2) or ovarian volume, CA-125 levels remained unvaried in all patients. Moreover, CA-125 serum levels did not correlate with the increasing values of the plasma E2 or ovarian volume. In conclusion, steroidogenetic activity of the ovary is unlikely to affect CA-125 production.

Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin as a trigger of ovulation in polycystic ovarian disease gonadotropin hyperstimulated cycles.

OBJECTIVE: To compare the use of GnRH agonist (GnRH-a) versus hCG in triggering the follicular rupture in patients with polycystic ovarian disease (PCOD) in whom ovulation was induced by gonadotropins. DESIGN: Polycystic ovarian disease gonadotropin hyperstimulated cycles outcome was investigated in a prospective study. PATIENTS AND INTERVENTIONS: Thirty-three PCOD patients (40 cycles) with gonadotropin-induced mild to moderate degree of ovarian hyperstimulation received 5,000 IU IM hCG or 200 microg [corrected] SC GnRH-a. A subgroup of GnRH-a-treated patients received P for luteal support. Five GnRH-a-treated patients underwent a GnRH test during luteal phase. MAIN OUTCOME MEASURES: Echographic and endocrine characteristics both during the therapy and the luteal phase. RESULTS: There was a similar percentage of ovulation and pregnancy rate in both groups of patients. The ovarian enlargement during the luteal phase in the GnRH-a-treated patients was lower than in the hCG group. Progesterone plasma levels (at midluteal phase) and the length of luteal phase was significantly lower in GnRH-a-treated patients with respect to the hCG-treated group. These differences disappeared in patients receiving luteal support. After GnRH injection, LH secretion decreased in GnRH-a-treated patients with respect to controls; however, corpus luteum was able to respond with a normal increase of P production. CONCLUSION: The GnRH-a appears to be an effective alternative to hCG for inducing the follicular rupture in stimulated cycles in women who are at risk for developing ovarian hyperstimulation syndrome. However, GnRH-a administration can induce short luteal phase. This defect may be ascribed to the pituitary desensitization rather than to a direct effect on corpus luteum. Luteal phase support is needed to prevent luteal phase deficiency.

CT-guided biopsy of lung lesions.

CT is the most accurate method for guiding fine needle biopsies in deep and/or small sized lung and mediastinic lesions. The authors have performed 2109 CT-guided lung biopsies (FNAB). The results are given in terms of sensitivity, specificity and rate of complications. In ever examination, Westcott or Chiba needles (22 or 21 gauge) were used. From 2109 lung examinations performed, 1413 (66.99%) were positive, 538 (25.5%) negative, 15 (0.7%) suspicious and 143 (6.78%) inadequate for diagnosis, 267 patients underwent surgical or clinical follow-up and, in all cases, the cytological diagnosis was confirmed. Other considerations were made on lesion topography, histological type, dimensions, complication rate, sensitivity, specificity and diagnostic accuracy. CT, of course, is the best method for guiding fine needle biopsy of the lung for its high spatial resolution and excellent anatomical definition, so that samples with smaller than 2 cm lesions, even in continuity with large vessels or other critical organs, are performed. Nevertheless, the result quality depends on the ability of the operator.

Intraosseous mucoepidermoid carcinoma. Report of a long-term evolution case.

Primary central mucoepidermoid carcinoma (CMC) of the jaws accounts only for 2-3% of all mucoepidermoid carcinomas reported. Bhaskar in 1963 first analysed the criteria for his central origin, histology and pathogenesis. The authors report a long-term evolution case of CMC of the mandible with peculiar clinical features observed at the Department of Maxillo-Facial Surgery of the School of Medicine and Surgery of the "Federico II" University of Naples (Naples, Italy) examining histopathologic and clinical features and problems related to the treatment.

Carboplatin plus oral etoposide in elderly patients with advanced non small cell lung cancer. A phase II study.

More than 30% of lung cancers arise in patients over 70 years old. Elderly patients are not considered to tolerate chemotherapy, are generally excluded from clinical trials, and are not considered eligible for aggressive cisplatinbased chemotherapy in clinical practice. The aims of the present study were to test the activity and toxicity of a combination of carboplatin and oral etoposide in patients over 70 years old with advanced non small cell lung cancer. Carboplatin was given at a dose of 300 mg/m2, i.v., at day 1, and oral etoposide (50 mg capsules) at a total dose of 100 mg/die from day 1 to day 7, recycled every 4 weeks. Fourteen patients entered the study. Median age was 73 years (range 70-77), 42.9% of patients had at least one concomitant illness. The trial, according to the Gehan design, was terminated earlier because no objective response was observed among the first 14 patients. We reported, according to intent to treat analysis, 2 stable and 12 progressive diseases. Median time to progression was 2 months and median survival 6 months. Remarkable hematological toxicity was recorded. Finally, we do not recommend the combination of carboplatin and oral etoposide, at the doses and schedule used in the present study, in the treatment of elderly patients with advanced NSCLC. The combination might be reconsidered using a different etoposide schedule with chronic administration (21 days).

Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial.

BACKGROUND: Although the use of salvage chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial, pretreated symptomatic patients often need some kind of treatment to achieve symptoms relief. Gemcitabine is one of the most active new drugs in advanced NSCLC and preliminary reports suggest that it is active also in patients previously treated with platinum compounds. AIM: to evaluate activity and toxicity and the effect on quality of life of gemcitabine in platinum-pretreated patients with advanced NSCLC. METHODS: single-stage phase 2 trial with p0 = 5%, p1 = 20%, alfa = 5%, beta = 10%; 34 patients required and 4 objective responses expected to warrant further studies. Gemcitabine was administered at dose of 1000 mg/m2, i.v., d 18-15, every 4 weeks, for a maximum of 6 cycles. Quality of life was measured by EORTC C-30 and LC-13 questionnaires. RESULTS: from September 1996 to July 1998, 30 patients have been enrolled. There were 6 (20% exact 95% CI 8-39%) partial responses (2 responses were in pts with brain metastases and 2 in patients progressed during first-line chemotherapy). All patients (but one died because myocardial infarction, progressed; median time to progression was 10 weeks (95% CI 7-12); 28 patients died; median survival was 22 weeks (95% CI 17-29). Quality of life analysis showed no significant change but for the improvement of cough after 3 cycles of chemotherapy. There was no severe toxicity. CONCLUSION: gemcitabine is active as second line for patients with advanced NSCLC who received platinum-based first line treatment. In view of such results randomized trials comparing gemcitabine versus best supportive care are warranted.

Single agent docetaxel plus granulocyte-colony stimulating factor (G-CSF) in previously treated patients with advanced non small cell lung cancer. A phase II study and review of the literature.

The use of salvage chemotherapy in advanced non small cell lung cancer (NSCLC) is controversial. However, many patients need to be treated in order to achieve relief of their symptoms. Docetaxel (taxotere) is one of the most active drugs for the treatment of advanced NSCLC and several studies have also shown its effectiveness in pretreated patients. In the present study, 23 patients were treated in order to evaluate both the effectiveness and toxicity of the single agent docetaxel. Furthermore, granulocyte-colony stimulating (G-CSF) factor was administered in order to reduce neutropenia related to docetaxel. Docetaxel was administered intravenously at a dose of 100 mg/m2, on day 1, and it was repeated every 3 weeks. G-CSF was administered for primary prophylaxis of neutropenia at the standard dose of 30 mg/day from day 4 to day 10 of each cycle. The treatment was tolerated well and 5 (21.7%) partial responses were obtained. The median time to progression and the median survival time were 3 and 5 months, respectively. The main side effect noted was fatigue, the intensity of which was grade 2 in 43.4% of cases and grade 3 in 8.7% of patients, respectively. One patient (4.3%) had grade 4 cutaneous toxicity. No cases of grade 4 neutropenia were reported. In conclusion, docetaxel is active when used for salvage chemotherapy in advanced NSCLC whilst concurrent primary prophylactic administration of granulocyte-colony stimulating factor seems to decrease severe neutropenia.

Carboplatin + epirubicin +VP-16 + lenograstim followed by radiotherapy + carboplatin as radiosensitizer in limited small cell lung cancer. A multicenter phase II study.

UNLABELLED: A phase II trial was undertaken to test the activity and toxicity of carboplatin (300 mg/m2, i.v. day 1) + epirubicin (75 mg/m2, i.v. day 1) + VP-16 (100 mg/m2, i.v. days 1 to 3) + lenograstim (5 mcg/kg, s.c. days 6 to 15) administered every 3 weeks for 4 cycles and subsequent chest irradiation (50 Gy) + daily carboplatin (25 mg/m2) in the first-line treatment of adults affected by limited small cell lung cancer (SCLC). PATIENTS AND METHODS: A single-stage phase II design was used; the complete response (CR) rate after chest radiotherapy was the primary end-point. Twenty-three CRs were required out of 38 patients to consider the treatment worthy of further study. Prophylactic cranial irradiation (PCI) was planned in case of CR. Patients aged < or = 70 were eligible if they had limited SCLC, a performance status not worse than 2 by the ECOG scale and no prior chemotherapy or radiotherapy. RESULTS: From January 1995 to April 1999, 33 patients were enrolled; the median age was 60 years. All the patients started chemotherapy; 23 patients received chest irradiation and concurrent daily carboplatin; 11 patients also received PCI. Toxicity was generally mild. Sixteen CRs (48.5%, 95% CI: 30.8-66.5) were recorded; the objective response rate was 72.7% (95% CI: 54.5-86.7). The median time-to-progression was 7.9 months (95% CI: 6.5-10.4). The median-survival was 10.7 months (95% CI: 9.2-16.1). CONCLUSION: Induction chemotherapy with carboplatin + epirubicin + VP-16 followed by chest irradiation plus concurrent daily carboplatin is well-tolerated but not sufficiently active to warrant further study in the treatment of patients with limited SCLC.

Importance of echographic and endocrine monitoring for the assessment of ovulation by follicle stimulating hormone in polycystic ovarian disease.

Sixteen patients with polycystic ovarian disease (PCOD) were treated for 39 cycles with pure follicle-stimulating hormone (FSH) for the induction of ovulation. At ovulation time human chorionic gonadotropin (hCG) was administered. Twenty-one cycles were ovulatory. Twenty-three were classified as normostimulated (N): six pregnancies and three abortions were observed. In the remaining eight hyperstimulated (H) cycles there were four full-term pregnancies. Dosage and length of treatment were greater in patients with excess body weight (P less than 0.01). H cycles were characterized in respect to N cycles by: (1) higher baseline values of 17-hydroxy progesterone (17-OHP) plasma levels and LH/FSH ratios; (2) higher plasma concentrations and rate of increase of 17-OHP periovulatory levels. E2 plasma levels did not permit a clear differentiation between H and N cycles, and it was not useful for the timely recognition of hyperstimulation. Our data show that a slight controlled degree of ovarian hyperstimulation is beneficial to pregnancy rate and outcome.

Preoperative radio-chemotherapy response as prognostic factor in colorectal cancer.

In order to demonstrate if radiotherapy (RT) is able to reduce the number of local recurrences and to increase the survival rate of patients (pts) with colorectal cancer, the authors are participating in a large randomized international trial with the goal of comparing patients treated with preoperative radiotherapy plus surgery and patients treated only by surgery. The authors noticed that some patients treated with preoperative radiotherapy showed a reduction in tumor size at the time of endorectal ultrasonography. The authors considered the incidence of recurrences in patients responsive to radiotherapy (RT responsive group), in patients non responsive to radiotherapy (RT non responsive group) and in patients not treated with radiotherapy (no RT group) with the aim of establishing if the responsiveness to preoperative radiotherapy could be considered a prognostic factor in colorectal cancer. After a three year follow-up RT responsive group (41 pts) showed no recurrences (0%); RT non responsive group (27 pts) showed 7 (25%) recurrences; no RT group (66 pts) showed 27 (41%) recurrences. Our data indicates that responsiveness to preoperative RT can be considered a prognostic factor. A large number of patients is required to confirm this observation.

[Early evaluation using PET-FDG of the efficiency of neoadjuvant radiochemotherapy treatment in locally advanced neoplasia of the lower rectum]. / Valutazione precoce con PET-FDG della efficacia del trattamento radiochemioterapico neoadiuvante nelle neoplasie del retto inferiore localmente avanzate.

BACKGROUND AND PURPOSE: Preoperative chemoradiation allows downstaging of locally advanced rectal cancer and in selected patients also a sufficient downsizing to ensure sphincter preservation. Selection of patients warranting a preoperative approach is improved by magnetic resonance imaging (MRI) which is able to define the involvement of mesorectal circumferential margin. Similarly it would be crucial to define the response to chemoradiation during the treatment but traditional morphologic imaging techniques may fail in differentiating neoplastic tissue from scarring. PET-FDG has been successfully used in the detection of metastatic colorectal cancer allowing imaging of deposits as small as 0.5 cm and may have a role in evaluating early response to chemoradiation. METHODS: In the present study, in patients with T3-T4 rectal cancer undergoing preoperative chemoradiation PET-FDG and flow cytometry analysis on endoscopic biopsy specimen have been performed before, during and after preoperative chemoradiation. RESULTS: Chemoradiation treatment has been successful in terms of downsizing and downstaging of the tumor. PET-FDG was able to demonstrate local response at only ten-fifteen days after the beginning of neoadjuvant therapy, also identifying non responding patients. CONCLUSIONS: FDG-PET may have a role in defining the response to chemoradiation and modulate the treatments strategy in patients with advanced rectal cancer.

Ovulation induction with human menopausal gonadotropin versus follicle-stimulating hormone after pituitary suppression by gonadotropin releasing hormone agonist in polycystic ovary disease. A cross-over study.

Ten patients with polycystic ovary disease (PCOD) had ovulation induction after pituitary suppression by gonadotropin releasing hormone agonist (GnRHa) with GnRHa plus pure follicle-stimulating hormone (FSH) or plus human menopausal gonadotropin (hMG). Duration of the stimulation period and gonadotropin doses were superimposable. A multifollicular response was observed in both treatments. Bioassay and radioimmunoassay of luteinizing hormone, androstanedione and testosterone plasma levels were higher in hMG cycles compared to FSH-treated cycles. No differences was found in FSH and estradiol (E2) plasma concentrations, whereas in hMG-treated cycles the E2/number of follicles and E2/ovarian volume ratios were greater than in the FSH-treated cycles. Clinical results in terms of percentages of ovulation and pregnancies were the same in the two protocols. We conclude that the presence of luteinizing hormone in induction of ovulation in patients with PCOD does not seem to influence follicular recruitment and development, but it may have a role in the enhancement of steroid production.

The role of granulocyte growth factors in the treatment of non small cell lung cancer.

In the past years granulocyte growth factors have been introduced in clinical practice. Their use is intended to reduce the risk of infection related to chemotherapy and to increase the dose-intensity of chemotherapy agents. Very few randomized trials have been reported in advanced non small cell lung cancer on chemotherapy plus or minus granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor. No benefit for granulocyte growth factors use was observed in terms of response rate and survival. Recently, several investigators used growth factors to support new promising drug combinations including vinorelbine, gemcitabine, taxol or taxotere. However, outside controlled clinical trials the role of granulocyte growth factors in the treatment of non small cell lung cancer should be within the American Society of Clinical Oncology guidelines.

[Nephrologists and porphyrias]. / I nefrologi e le porfirie.

As usually occurs for rare diseases, the word "PORPHYRIA" often recalls a confused topic with shaded boundaries, presenting "bullous" skin lesions, rare opportunity of diagnosis in clinical practice, unknown pathogenesis, and almost absent therapeutic options. The goal of this review is to draw attention to this topic, as new diagnostic and therapeutic tools might change the natural history of this disease. Porphyrias are disorders resulting from abnormalities of porphyrin metabolism. Porphyrins are molecules made up of four pyrrol rings, which constitute haeme-proteins, including haemoglobin. Following the "trigger" enzyme delta-aminolevulinic acid (ALA) synthase, which is capable of condensing succynil CoA and glycine, seven additional enzymes are involved in the process that eventually leads to haeme biosynthesis. Porphyrias are the result of total or partial deficiencies in these seven enzymes involved in haeme synthesis. Usually, the final haeme product exerts a negative feed-back on its synthesis. The enzyme deficiency that occurs in porphyrias is responsible for reduced haeme production, which, in turn, allows the cascade to be stimulated by increased activity of the trigger enzyme, ALA-synthase (ALA-s). However, due to the subsequent enzyme defects, notwithstanding increased ALA-s activity, haeme synthesis is blunted and intermediate metabolites accumulate. Clinical manifestations depend on which step the enzymatic defect occurs: if enzymatic defects are in the initial steps of the metabolic cascade, early metabolic intermediates will accumulate [i.e. ALA and porphobilinogen (PBG)] responsible for attacks of neurological dysfunction; if the enzymatic defects are in the final steps, sunlight-induced cutaneous lesions (phtotosensitivity) due to porphyrin accumulation in the skin will develop. The seven major human porphyrias may be classified into "hepatic or erythropoietic porphyrias" depending on the organ/tissue where metabolic alterations are more evident, or "acute or chronic porphyrias" depending on the prevalence of clinical symptoms, if neurologic (acute) or cutaneous (chronic). Only a small number of people with inherited enzyme deficiency will develop overt clinical disease, mainly because of the role of acquired aggravating and precipitating factors, such as drugs, hormonal causes, infection, caloric restriction, alcohol. The biochemical diagnosis of porphyrias relies on the detection of the consequences of increased ALA-s activity in the liver: overproduction, accumulation and increased excretion of early (ALA, PBG) or late (porphyrins) intermediate compounds in plasma, faeces and urine. A major difficulty arises from the knowledge that such abnormalities may be completely absent during the remission phases of the disease. Only in very specialised Centres it is now possible to measure specific haeme synthesis enzyme defects, and to perform molecular diagnosis by DNA analysis. The true prevalence of the diseases is unknown, ranging from 1:500 to 1:50,000. Therapeutic strategies include withdrawal of all common precipitants (drug, alcohol, fasting, infection), use of opiates and chlorpromazine, carbohydrates (300-400 g/day) and infusion of human haemine. Genetic therapies are being studied for the future.

Apoptosis as a specific biomarker of diazinon toxicity in NTera2-D1 cells.

The NTera2/D1 (NT2) cell line, which was derived from a human teratocarcinoma, exhibits properties that are characteristics of a committed neuronal precursor at an early stage of differentiation. Its property to express a whole set of molecules related to the cholinergic neurotransmission system, including active acetylcholinesterase (AChE, EC 3.1.1.7) makes it a good alternative model for testing the effects of neurotoxic compounds, such as organophosphorus (OP) insecticides, whose primary target is the inhibition of AChE activity. Recent findings have elucidated the role of AChE in the modulation of apoptosis, but the mechanisms are still rather obscure. NT2 cells exposed to the OP insecticide diazinon at concentrations ranging between 10(-4) and 10(-5)M showed a time-dependent enhancement of cell death. When exposed at 10(-6)M diazinon showed higher cell viability than control samples up to 72 h, followed by a decreasing phase. The cell death caused by the exposures showed a number of features characteristic of apoptosis, including membrane and mitochondrial potential changes. We suggest the hypothesis that such behaviour is due to a dynamic balance between activated and blocked acetylcholine receptors that in turn trigger electrical events and caspase cascade.