Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women.

Women who have experienced childhood sexual abuse (CSA) have an increased risk of alcoholism and antisocial personality disorder (ASPD). Among male subjects, a functional polymorphism (MAOA-LPR, monoamine oxidase A linked polymorphic region) in the promoter region of the monoamine oxidase A gene (MAOA) appears to moderate the effect of childhood maltreatment on antisocial behavior. Our aim was to test whether MAOA-LPR influences the impact of CSA on alcoholism and ASPD in a sample of 291 women, 50% of whom have experienced CSA; we also tested whether haplotypes covering the region where both MAOA and monoamine oxidase B (MAOB) genes are located predict risk of alcoholism and ASPD better than the MAOA-LPR locus alone. Participants included 168 alcoholics (39 with ASPD (antisocial alcoholics) and 123 controls (no alcoholics, no ASPD). Antisocial behavior was also modeled as a continuous trait: ASPD symptoms count. The MAOA-LPR low activity allele was associated with alcoholism (P=0.005), particularly antisocial alcoholism (P=0.00009), only among sexually abused subjects. Sexually abused women who were homozygous for the low activity allele had higher rates of alcoholism and ASPD, and more ASPD symptoms, than abused women homozygous for the high activity allele. Heterozygous women displayed an intermediate risk pattern. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women. The MAOA-LPR low activity allele was found on three different haplotypes. The most abundant MAOA haplotype containing the MAOA-LPR low activity allele was found in excess among alcoholics (P=0.008) and antisocial alcoholics (P=0.001). Finally, a MAOB haplotype, which we termed haplotype C, was significantly associated with alcoholism (P=0.006), and to a lesser extent with antisocial alcoholism (P=0.03). In conclusions, MAOA seems to moderate the impact of childhood trauma on adult psychopathology in female subjects in the same way as previously shown among male subjects. The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of CSA. Haplotype-based analysis of the MAOA gene appeared to strengthen the association, as compared to the MAOA-LPR locus alone. A MAOB haplotype was associated with alcoholism independently from ASPD.

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index.

Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

In vitro effects of different concentration of PRP on primary bone and gingival cell lines. Preliminary results.

AIM: Platelet rich plasma (PRP) is utilized in oral surgery to enhance bone healing and it has been suggested to accelerate soft tissue healing. Nevertheless, there is no evidence on biological concentration of platelets needed to determine the higher biological response. Therefore, aim of this study is to evaluate the action of PRP in vitro on osteoblasts and fibroblasts and to evaluate which is the most effective concentration of PRP. METHODS: PRP was obtained from volunteers donors by standard apheresis. Osteoblasts were growth for 72 hours in a medium added with platelet concentration of 230%. Fibroblasts were treated with different platelet density for 24 hours and 72 hours. Platelet density was increased of 230%, 350%, 460% and 700% the normal blood count. Cell proliferation was evaluated with MTT test. ANOVA test was used to assess cells proliferation data. RESULTS: Osteoblasts proliferation, at 72 hours, showed an increase of proliferation in PRP group compared to plasma (P < 0.001). Fibroblast proliferation after 24 hours increases when PRP is added (P < 0.05). However, no significant differences were detected among the various concentration of PRP. Yet, at 72 hours, MTT values increases when platelet concentrate is 230% and 350%. At 700% platelet density MTT values were lower than control group (P < 0.05). CONCLUSIONS: Our results indicated that PRP has an enhancing effect on osteoblasts and fibroblasts proliferation when it is prepared only within certain ranges of concentrations. However, further experimental studies are needed to confirm our hypothesis.

Postoperative adjuvant chemoradiotherapy for rectal cancer: analysis of acute and chronic toxicity.

AIMS AND BACKGROUND: The aim of the study was to evaluate acute and chronic toxicity of combined postoperative standard radiation therapy to the pelvis and 5-fluorouracil plus levamisole in resectable rectal cancer. METHODS: Between July 1990 and September 1993, 58 patients with histologically confirmed adenocarcinoma of the rectum entered the prospective study. The schedule consisted of 5-fluorouracil, 450 mg/m2 i.v. for 5 days, and from day 28 5-fluorouracil, 450 mg/m2 i.v. weekly for 24 weeks, plus levamisole given orally at the dose of 150 mg every day for 3 days every 2 weeks for 6 months; radiotherapy (180 cGy/day) 5 days a week for a total dose of 45 Gy was administered from day 28. RESULTS: After the first cycle of chemotherapy (before radiotherapy), overall toxicity was mild. During chemoradiotherapy, dose-limiting toxicity was grade 3 diarrhea and proctitis, for which the combined treatment was interrupted for more than 7 cumulative days in 28 patients. During the 24 weeks of weekly 5-fluorouracil (after radiotherapy), no severe toxicity was reported. Three-year survival and progression-free survival were 65% and 50-55%, respectively. CONCLUSIONS: Although adjuvant chemoradiotherapy is usually feasible, in our study toxicity was severe in a substantial proportion of patients, probably due to the schedule applied. We are evaluating the feasibility and toxicity of a combined treatment which includes 5-fluorouracil in continuous chronomodulated infusion during radiotherapy.

Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment.

PURPOSE: A new radiotherapy schedule to treat glioblastoma multiforme after surgery, combining nicotinamide and carbogen. METHODS AND MATERIALS: We analyzed 36 patients with glioblastoma multiforme treated after surgery with radiotherapy, Nicotinamide and Carbogen as follows: 7 patients were treated with accelerated fractionation: two fractions/day, 1.5 cGy/fraction, 6 h interval, 5 days/week, total dose 60 Gy in 4 weeks; 8 patients were treated with the same irradiation scheduling plus Nicotinamide at the dose of 4 g and 2 g in capsules, respectively, 1 h before the first and the second irradiation fraction; 21 patients were treated with accelerated radiotherapy, Nicotinamide, and Carbogen (inhaled 10 min before radiotherapy and during the whole course of irradiation). On the basis of surgical removal our patients were subdivided in three groups: totally resected, with residual tumor <50%, or >50%. Radiotherapy with accelerated fractionation was completed in the scheduled time without side effects on the whole group of patients and Carbogen inhalation did not cause significant change of cardiopulmonar parameters. The toxicity observed was predominant in the gastrointestinal tract and was related to Nicotinamide. RESULTS: The median survival time (M.S.T.) was 10 months, as reported by others authors with conventional treatment, but in patients without surgical residual tumor and submitted to the complete treatment schedule, the survival at 35 months was around 25%. CONCLUSIONS: We conclude that this method is feasible with acceptable toxicity; analyzing the survival curves appears to be a trend towards an improvement in survival in the subgroup of patients with gross total removal treated with the combination of Carbogen, Nicotinamide, and accelerated fractionation.

Carbogen breathing in patients with glioblastoma multiforme submitted to radiotherapy. Assessment of gas exchange parameters.

It has been reported that carbogen breathing yields a remarkable increase of radiosensitivity in murine tumour models. Hence, application of carbogen might be promising in radiotherapy of human tumours. We describe a method to increase arterial oxygenation and to ensure stability of O2 and CO2 during carbogen breathing in patients with malignant disease. We measured in 6 patients with histologically proven intracranial glioblastoma multiforme arterial blood gases, inspired and expired gas concentrations and vital signs either baseline and during carbogen breathing. The highest values of arterial oxygenation were achieved after 10 min of carbogen breathing and they remained stable up to 15 min. In none of our patients was N2 wash-out from the lungs completed in 15 min of carbogen breathing. In conclusion, carbogen breathing increased arterial oxygenation in patients with intracranial malignant diseases. The system used is reliable and of practical use. Monitoring of expired gas concentrations is highly recommended.

Pharmacokinetics and tolerance of nicotinamide combined with radiation therapy in patients with glioblastoma multiforme.

The pharmacokinetic properties of nicotinamide and its tolerance were studied in seven patients affected by glioblastoma multiforme and treated with two fractions per day of radiation therapy. Nicotinamide was given orally at two daily doses of 4 g and then 2 g separated by a 6-h-interval. The treatment was well tolerated in almost all patients and had no effect on blood pressure, cardiac rhythm or body temperature. Pharmacokinetic analysis showed peak plasma levels (Cmax) above 100 mg/l 45 minutes after the administration of both doses. This was followed by a biexponential decay of plasma concentrations with a thermal half life of 9.4h. Tumours were irradiated 1 hour after each drug dose to match with drug Cmax in plasma, and although it is too early to evaluate the tumour response, the drug levels achieved should be sufficient to improve radiation therapy.

A phase I-II study of oral doxifluridine plus radiotherapy in radiosensitive tumors of the pelvic region.

AIMS AND BACKGROUND: Fluoropyrimidines have shown synergic effects in combination with radiotherapy in several tumor types. Doxifluridine is a novel 5-fluorouracil (5-FU) prodrug which is transformed into 5-FU in neoplastic tissue. This would imply enhancement of radiotherapy by 5-FU in neoplastic tissue, where the drug is concentrated higher than in surrounding healthy tissues. METHODS: A phase I-II study was carried out on 10 patients with radiosensitive tumors of the pelvic area (4 uterine carcinomas). Escalating doses of oral doxifluridine were administered in combination with standard radiotherapy to assess the efficacy and toxicity profile of the combined treatment. The 9 evaluable patients (3 groups of 3 patients each) received oral doxifluridine, at daily doses of 500, 750, or 1000 mg, for 6 consecutive weeks in combination with a standard (1.8-2.0 Gy) dose of radiotherapy. Assessment of physical and laboratory parameters was made at baseline, then weekly up to the end of the treatment and at follow-up. RESULTS: At the final evaluation, one patient with a diagnosis of uterine carcinoma showed a complete response that lasted 10 weeks. One patient had a partial response, and 7 patients had no change. The most frequent adverse events were gastrointestinal: 27 episodes of mild to moderate nausea/vomiting and diarrhea. Three patients complained of severe diarrhea of 5-7 days duration: all patients spontaneously recovered. There were no significant changes in laboratory or clinical parameters, and no serious toxicity requiring reduction or interruption of the radiotherapy. CONCLUSIONS: The maximum tolerated dose of oral doxifluridine in combination with standard radiotherpay was assessed at 1000 mg/patient/day (equivalent to 36-38 g monthly, previously reported as mTD in phase I studies).

Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma.

Between January 1988 and June 1990, seven previously untreated patients with histologically confirmed and clinically staged IIIa invasive thymoma (IT) were enrolled in a prospective, single treatment arm study of neoadjuvant chemotherapy (NC) followed by surgery and postoperative radiation therapy (4600 to 6000 cGy). The NC included three cycles of cisplatin (75 mg/m2 on day 1), epirubicin (100 mg/m2 on day 1), and etoposide (120 mg/m2 on days 1, 3, and 5), every 3 weeks. All patients showed a partial response (greater than 50%) and underwent complete (n = 4) or incomplete (gross [n = 1] or microscopic [n = 2] residual tumor) surgical resection. Histologic examination was negative for two completely resected patients. Projected 2-year survival was 80%; all patients but one currently are alive and disease-free. This approach appeared to be feasible and may be a new therapeutic choice in the management of IT, but its use on a regular basis should be reserved until a larger number of patients and longer follow-up are available.

Surgery and radiotherapy in the treatment of early stage uterine sarcomas.

Twenty-three patients with early stage uterine sarcomas underwent surgery (5 patients) or surgery and pelvic irradiation (18 patients). Twelve (52%) of the patients developed a recurrence: relapsing disease was pelvic in 3 (25%) of them, extrapelvic in 8 (66.7%) and both pelvic and extrapelvic in one (8.3%). Out of the whole series the 2- and 5-year actuarial survival rates were 61% and 33% respectively. Among the patients with leiomyosarcoma the 2- and 5-year actuarial survival rates were 54% and 39% respectively. Among the patients with carcinosarcoma the 2- and 5-year actuarial survival rates were 66% and 23% respectively. The high incidence of extrapelvic recurrences after locoregional treatment seems to suggest the use of an adjuvant chemotherapy in the management of patients with early stage uterine sarcomas.

[Radiotherapy of giant-cell tumour of the vertebral column (author's transl)]. / La radioterapia del tumore giganto-cellulare della colonna vertebrale

Five cases of successfully irradiated giant-cell tumours of the backbone, are reported; the problems of the radiotherapy of such tumours are discussed.