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Biomedical subjects

E Touboul

Publications and source records attributed to E Touboul.

At least 73 records · Page 4Linked to original sources
PubMed1998

Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients.

AIM: In order to assess the influence of total-body irradiation (TBI) on the outcome and incidence of complication after bone marrow transplantation (BMT), we retrospectively analyzed our patients treated for acute leukemia and conditioned with TBI prior to BMT. PATIENTS AND METHODS: Between 1980 and 1993, 326 patients referred to our department with acute non-lymphoblastic leukemia (ANLL, n = 182) and acute lymphoblastic leukemia (ALL, n = 144) in complete remission underwent TBI either in single dose (190 patients: 10 Gy administered to the midplane, and 8 Gy to the lungs [STBI]) or in 6 fractions (136 patients: 12 Gy on 3 consecutive days, and 9 Gy to the lungs [FTBI]) before BMT. The male-to-female ratio was 204/122 (1.67), and the median age was 30 years (mean: 30 +/- 11, range: 3 to 63). The patients were analyzed according to 3 instantaneous dose rate groups: 118 patients in the LOW group (< or = 0.048 Gy/min), 188 in the MEDIUM group (> 0.048 and < or = 0.09 Gy/min), and 20 in the HIGH group (> 0.09 cGy/min). Conditioning chemotherapy consisted of cyclophosphamide (CY) alone in 250 patients, CY and other drugs in 54, and 22 patients were conditioned using combinations without CY. Following TBI, allogeneic and autologous BMT were realized respectively in 118 and 208 patients. Median follow-up period was 68 months (mean: 67 +/- 29, range: 24 to 130 months). RESULTS: Five-year survival, LFS, RI and TRM rates were 42%, 40%, 47%, and 24%, respectively. Five-year LFS was 36% in the STBI and 45% in the FTBI group (p = 0.17). It was 36% in the LOW group, 42% in the MEDIUM group, and 30% in the HIGH group (p > 0.05). Five-year RI was 50% in STBI, 43% in FTBI, 55% in LOW, 41% in MEDIUM, and 44% in HIGH groups (STBI vs. FTBI, p = 0.48; LOW vs. MEDIUM, p = 0.03; MEDIUM vs. HIGH, p = 0.68). TRM was not influenced significantly by the different TBI techniques. When analyzing separately the influence of fractionation and the instantaneous dose rate either in ANLL or ALL patients, no difference in terms of survival and LFS was observed. Fractionation did not influence the 5-year RI both in ANLL and ALL patients. However, among the patients with ANLL, 5-year RI was significantly higher (58%) in the LOW group than the MEDIUM group (31%, p = 0.001), whereas instantaneous dose rate did not significantly influence the RI in ALL patients. The 5-year TRM rate was significantly higher in allogeneic BMT group both in ANLL (37%) and ALL (37%) patients than those treated by autologous BMT (ANLL: 15%, ALL: 18%; p = 0.002 and 0.02, respectively). The 5-year estimated interstitial pneumonitis (IP) and cataract incidence rates were 22% and 19%, respectively, in all patients. IP incidence seemed to be higher in the HIGH group (46%) than the MEDIUM (19%, p = 0.05) or LOW (25%, p = 0.15) groups. Furthermore, cataract incidence was significantly influenced by fractionation (STBI vs. FTBI, 29% vs. 9%; p = 0.003) and instantaneous dose rate (LOW vs. MEDIUM vs. HIGH, 0% vs. 27% vs. 33%; p < 0.0001). Multivariate analyses revealed that the best factors influencing the survival were 1st CR (p = 0.0007), age < or = 40 years (p = 0.003), and BMT after 1985 (p = 0.008). The RI was influenced independently only by the remission status (p = 0.0002). On the other hand, the TRM rate was lower in patients who did not experience graft-vs.-host disease (GvHD, p < 0.0001), and in those treated after 1985 (p = 0.0005). GvHD was the only independent factor involved in the development of IP (p = 0.01). When considering the cataract incidence, the only independent factor was the instantaneous dose rate (p = 0.0008). CONCLUSION: The outcome of BMT patients conditioned with TBI for acute leukemia was not significantly influenced by the TBI technique, and TRM seemed to be lower in patients treated after 1985. On the other hand, cataract incidence was significantly influenced by the instantaneous dose rate.

Adolescent↗
PubMed1998

Comparative evaluation by semiquantitative reverse transcriptase polymerase chain reaction of MDR1, MRP and GSTp gene expression in breast carcinomas.

Identification and quantitative evaluation of drug resistance markers are essential to assess the impact of multidrug resistance (MDR) in clinical oncology. The MDR1 gene confers pleiotropic drug resistance in tumour cells, but other molecular mechanisms are also involved in drug resistance. In particular, the clinical pattern of expression of the other MDR-related genes is unclear and their interrelationships are still unknown. Here, we report standardization of the procedures used to determine a reliable method of semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) using a standard series of drug-sensitive and increasingly resistant cell lines to evaluate the expression of three MDR-related genes, i.e. MDR1 (multidrug resistance gene 1), MRP (multidrug resistance related protein) and GSTp (glutathione-S-transferase p), reported to be endogenous standard genes for normalization of mRNAs. A total of 74 breast cancer surgical biopsies, obtained before any treatment, were evaluated by this method. When compared with classical clinical and laboratory findings, GSTp mRNA level was higher in diploid tumours. However, the main finding of our study suggests a clear relationship between two of these MDR-related gene expressions, namely GSTp and MRP. This finding provides new insight into human breast tumours, which may possibly be linked to the glutathione conjugate carrier function of MRP. Well defined semiquantitative RT-PCR procedures can therefore constitute a powerful tool to investigate MDR phenotype at mRNA levels of different related genes in small and precious tumour biopsy specimens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Potent antihyperglycaemic property of a new imidazoline derivative S-22068 (PMS 847) in a rat model of NIDDM.

Recent data suggest that some imidazoline derivatives can lower plasma glucose in experimental animal models of diabetes. We studied the activity of an imidazoline S-22068, in rat model of non-insulin-dependent diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg(-1), i.v.) in the adult. The respective increase over basal value in glucose (deltaG) and insulin (deltaI), and the rate of glucose disappearance (K), were measured during a 30 min intravenous glucose tolerance test. After an intraperitoneal injection of S-22068 (24 mg kg(-1)), deltaG (mM min(-1)) was decreased (91.67+/-5.83 vs 120.5+/-3.65; P<0.001), whereas K was increased (1.74+/-0.09 vs 1.18+/-0.05; P<0.001). Although insulinaemia was increased at time-point 0 of the test, deltaI was unchanged. During oral glucose tolerance tests (OGTT), S-22068 (24 mg kg(-1), p.o.) improved glucose tolerance, and its efficiency was potentiated after chronic treatment (15 days). Basal glycaemia was unaffected by the treatment. Under the same conditions, a higher dose of S-22068 (40 mg kg(-1)) further improved glucose tolerance without causing hypoglycaemia. Binding experiments revealed that S-22068 displays no affinity for either adrenoceptors or the two imidazoline receptors I1 or I2. These results demonstrate that S-22068 improves glucose tolerance without causing hypoglycaemia. Thus S-22068 represents a new potential option in the treatment of NIDDM.

Animals↗
PubMed1998

[Large volume stage I and II epidermoid carcinoma of the uterine cervix treated with primary radiotherapy and surgery].

Fifty-two women with stage Ib2 and II bulky squamous cell carcinoma of the uterine cervix (mean size: 5.65 +/- 0.12 cm, range: 5-8 cm) were treated between July 1982 and December 1993. The median follow-up was 73 months. Their patient's age ranged from 25 to 77 years (median: 45 years). There were 18 stage Ib2, 8 stage IIa and 26 stage IIb operable patients. External radiotherapy was delivered using photons of 6 MV to 25 MV and a four-field "box" technique (upper limit situated between L4-L5). Mean total dose at mid-plane to the whole pelvis was 38.6 Gy (range: 37.4-40.6 Gy) in 18 fractions over 30 days. A boost dose of 20 Gy was given by intracavitary brachytherapy (utero-vaginal). After a mean rest of 48 days, total abdominal hysterectomy and bilateral salpingo-oophorectomy combined with bilateral pelvic lymphadenectomy was performed. Following surgery, no remaining tumor on pathological examination of uterine cervix was observed in 39 cases (75%) and positive external iliac nodes were found in 4 cases. Five- and 10-year specific survival rates were 80% and 75%, respectively. The 5- year local tumour recurrence and nodal recurrence rates were 18% and 15%, respectively. There were 7 para-aortic nodal recurrences (3 were isolated para-aortic nodal relapses). There were five late severe complications necessiting surgical intervention. A combination of preoperative radiation therapy and concomitant chemotherapy, and the extended dissection of common iliac and para-aortic lymph nodes or a post operative prophylactic extended field irradiation including para-aortic lymph nodes is now being attempted in order to improve the locoregional tumour and para-aortic lymph node control rates.

Adult↗
PubMed1998

[Infiltrating carcinoma of the uterine cervix: epidemiology, prognostic factors, therapeutic strategies].

In industrialized countries cervical cancer has decreased over the past decades. This, thanks to wide spread screening campaigns of precancerous lesions and microinvasive diseases through regular pap smears starting from the beginning of sexual activity. The diagnostic is realized earlier, thus increasing the rate of curability. Unfortunately, the absence of such programs in underdeveloped countries has made cervical cancer the second cause of death by cancer among the world female population. This general review treats in a non exhaustive manner epidemiology and prognostic factors and secondly exposes the therapeutic methods that has become available in recent years.

Female↗
PubMed1997

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 1. Synthesis and biological activities of N-benzyl-N'-(arylalkyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines .

The physiopathology of non-insulin-dependent diabetes mellitus is associated with a dysfunction in the regulation of insulin secretion. The alpha 2-adrenoceptors have been reported to be involved in this alteration, although alpha 2-antagonists containing an imidazoline ring may stimulate insulin secretion independently of alpha 2-adrenoceptor blockage. Recently, a new "imidazoline-binding site" involved in the control of K(+)-ATP channels in the B cell has been proposed. In the course of searching for new antidiabetic agents, 1-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines, 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-alkylpiperazines, and 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines have been designed and evaluated as potential adrenoceptor antagonists. Pharmacological evaluation was performed in vivo using glucose tolerance tests performed on a rat model of type II diabetes obtained by injection of a low dose (35 mg/kg) of streptozotocin (STZ). For some compounds, binding experiments were performed on alpha 2 adrenoceptors and I1 and I2 imidazoline-binding sites. The biological and physicochemical data have been combined with molecular modeling studies to establish structure-activity relationships. The most active compound was 1-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)- 4-methylpiperazine (7f); intraperitoneal administration (100 mumol/kg) of 7f strongly improved glucose tolerance in STZ diabetic rats. This effect seemed at least partly mediated by a significant increase of insulin secretion. Other compounds of the same family (7b, 16f, 23b) have also shown potent activity. We found no correlation between in vivo antihyperglycemic properties and in vitro affinities for alpha 2-adrenoceptors or I1, and I2 binding sites. These compounds can be considered as antihyperglycemic agents potentially useful for treatment of type II diabetes and are currently under complementary investigation.

Animals↗
PubMed1997

Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer.

BACKGROUND AND PURPOSE: To evaluate possibility of breast-conserving therapy and outcome for patients with locally advanced non-inflammatory breast cancer (LABC) and stage II >3 cm in diameter after primary chemotherapy (CT) followed by external preoperative irradiation (RT). MATERIALS AND METHODS: Between 1982 and 1990, 147 patients were treated by four courses of induction CT (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative RT (45 Gy to the breast and nodal areas) and a fifth course of CT. Three different loco-regional approaches were proposed depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of CT and a maintenance adjuvant CT regimen without anthracycline. RESULTS: Mastectomy and axillary dissection were performed in 52 patients, and conservative treatment in 95 patients (48 achieved complete remission and received additional radiation boost to initial tumour bed; 47 had a residual mass < or =3 cm in diameter and were treated by wide excision and axillary dissection followed by a boost to the excision site. Ten-year actuarial loco-regional failure rate was 20% after RT alone, 23% after wide excision and RT and 6% after mastectomy (P = 0.85). After multivariate analysis, possibility of breast-conserving therapy was related to initial tumour size. Ten-year overall survival rate was 66%; it was not influenced by local treatment (conservative vs. non-conservative local treatment, P = 0.89). However, local failure significantly decreased overall survival (P < 0.0001). After multivariate analysis, tumour response after induction CT and clinical stage had a significant impact on survival. CONCLUSIONS: The present data indicate that induction CT followed by preoperative RT may permit the selection of some patients with LABC or stage II >3 cm for conservative treatment. The impact of this treatment modality on long term survival remains to be established.

Adenocarcinoma↗
PubMed1997

Structure-activity relationships in platelet activating factor. 9. From PAF-antagonism to PLA2 inhibition.

Many important mediators of inflammation result from the liberation of free arachidonic acid from phospholipid pools, which arise from the action of phospholipase A2 (PLA2). Therefore the inhibition of this enzyme would be an important treatment in many inflammatory disease states. Starting from a series of compounds which are known as PAF-antagonists, we have synthesized new molecules. These new compounds inhibited various secretory PLA2s, with IC50's in the mumol range. This allowed us to analyze the structure-activity relationships for PLA2 inhibition. The results showed that inhibition of secretory PLA2 depends on the length of the alkyl chain, with an optimum for 13 to 17 carbons, which is in agreement with X-ray crystallographic and nuclear magnetic resonance (NMR) studies on the active site of PLA2s, and that a free nitrogen on the piperazine ring is required to ensure a good inhibitory potency.

Animals↗
PubMed1997

Design and modeling of new platelet-activating factor antagonists. 3. Relative importance of hydrophobicity and electronic distribution in piperazinic series.

Extensive analysis of results obtained in earlier publications (Lamouri et al. (1993); Tavet et al. (1996) led us to reexamine our interpretations and conclusions about hydrophobic and electronic distribution effects. In terms of hydrophobicity balance, a bilinear regression has been derived between lipophilicity of the appendix in position-2, f(Z), versus anti-aggregant activity for 45 homogeneous compounds including data from both papers (Parts 1 and 2). These features reinforce the conclusion that the kinetic phase in the experimental medium is probably determinant. Consequently, the role of electronic distribution is preponderant at the level of the receptor. Two specific studies demonstrated that decrease of negative electrostatic potential effects of the largest "cache-oreilles' system lowered the anti-aggregant activity (comparison of compounds 1f, 2, 3 and 4), on one hand and, on the other hand, the combined effect of phenyl groups created negative wells, as observed there with a diphenyl-methyl moiety, instead of an usual trimethoxybenzoyl function (comparison of compounds 8 and 10). It was clearly demonstrated that this moiety does not work by means of a hydrophobic anchorage: comparison of compounds 9, 10 and 11.

Chemical Phenomena↗
PubMed1997

Design and modeling of new platelet-activating factor antagonists. 2. Synthesis and biological activity of 1,4-bis-(3',4',5'-trimethoxybenzoyl)-2-alkyl and 2-alkyloxymethylpiperazines.

In the continuation of our investigations on the structure of platelet-activating factor (PAF)-receptor, 25 additional 2-substituted 1,4-bis-(poly- and mono methoxybenzoyl)-piperazines were synthesized and their in vitro biological activities measured. Substituent at position 2 is representative of the classical balance lipophilicity/hydrophilicity, i.e. alkyl, phenylalkyl, alkoxy and polyalkoxy groups. A potent PAF-induced platelet aggregation inhibitory activity measured in PRP medium is obtained with 5c, IC50 = 6 x 10(-8) M, which displaces the [3H]PAF from platelet membrane with an EC50 = 6 x 10(-8) M, and compound 4 presents an EC50 of 3 x 10(-8) M. Examination of structure-activity relationships shows that molecules bearing a hydrophilic or slightly hydrophobic appendix in position-2 are still potent; their IC50 being included between 10(-6) and 10(-7) M. After quantitative analysis, it seems that in PRP medium, the role of serum albumin must be taken into account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a potent antagonistic activity is demonstrated by syntheses of several 2-octylpiperazine analogs. These specific features will be quantitatively analysed in the following related publication (part 3).

Animals↗
PubMed1997

A new phospholipase A2 inhibitor, unrelated to substrate analogues: kinetic characterization of the inhibition of secretory phospholipases A2 by PMS 832.

Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA2s of groups I or II, with IC50 in the micromolar range (Binisti et al., 1997). In this report we investigate the mechanism of inhibition of bovine and porcine pancreatic phospholipases A2 (group I), and platelet lysate phospholipase A2 (group II) by one of these compounds, 1-(4'-methoxybenzoyl)-2-n-tridecylpiperazine (PMS 832). We show that PMS 832 behaves as a reversible, competitive inhibitor, with Ki values of 4.1 +/- 1.2 and 1.5 +/- 0.4 microM for porcine pancreatic phospholipase A2 and platelet lysate phospholipase A2, respectively. PMS 832 failed to inhibit platelet activation induced by several agonists and was also found to be inactive towards phospholipase C from Bacillus cereus, indicating a high specificity for phospholipase A2 inactivation. Thus, PMS 832 and its derivatives could serve as interesting tools to investigate the role of extracellular phospholipases A2 in inflammatory processes, and may be useful in the development of new anti-inflammatory agents.

Animals↗
PubMed1996

Total body irradiation prior to bone marrow transplantation: efficacy and safety of granisetron in the prophylaxis and control of radiation-induced emesis.

PURPOSE: Radiation-induced emesis is one of the most disturbing side effects of total body irradiation (TBI). To evaluate the efficacy and to determine the best schedule of granisetron (a selective 5-hydroxytryptamine3 serotonin receptor antagonist) administration in the prevention of radiation-induced nausea and vomiting, we conducted a trial involving patients receiving single-dose TBI before bone marrow transplantation (BMT). METHODS AND MATERIALS: Thirty-six patients with non-Hodgkin's lymphoma (n = 12), multiple myeloma (n = 8), acute lymphoblastic leukemia (n = 7), acute nonlymphoblastic leukemia (n = 6), and chronic myeloid leukemia (n = 3) referred to our department between March 1992 and February 1994 were enrolled in this study to assess the efficacy of granisetron during single-dose TBI before autologous BMT (n = 26), allogeneic BMT (n = 8), or syngeneic BMT (n = 2). The male-to-female ratio was 22:14 (1.57), and the mean age was 41 +/- 11 years (range 16-58). Before TBI, conditioning chemotherapy consisted of cyclophosphamide (CY) alone (60 mg/kg per day on 2 successive days) in 24 patients, CY combined with other drugs in 6, and combinations without CY in 6. All patients received single-dose TBI (10 Gy administered to the midplane at L4, and 8 Gy to the lungs). The mean instantaneous and average dose rates were 0.039 +/- 0.012 Gy/min (range 0.031-0.058), and 0.025-0.006 Gy/min (range 2.08-3.96), respectively. Granisetron was administered 30-45 min before TBI according to two different modalities: a total dose of 3 mg as a 5-min intravenous (i.v.) infusion (Treatment A, n = 15; 42%) or the same treatment plus 3 mg of granisetron as a 24-h continuous i.v. infusion (total dose: 6 mg, Treatment B, n = 21; 58%). Depending on the BMT teams, hyperdiuresis was continued (n = 19, 53%) or suspended (n = 17, 47%) during TBI. Nausea and vomiting were assessed during the TBI session and the following 12 h, and were scored as follows: S1 = no nausea or vomiting; S2 = moderate nausea; S3 = severe nausea and/or single episode of vomiting; and S4 = multiple episodes of vomiting. RESULTS: During TBI, 18 (50%) patients were scored as complete responders (S1), 1 (3%) as a major responder (S2), 9 (25%) as minor responders (S3), and 8 (22%) as nonresponders (S4). During the following 12 h, 28 (78%) patients were free of severe nausea and vomiting (S1 or S2), whereas 8 (22%) vomited (S3 or S4). In univariate analyses, the 12-h probability of emesis was significantly higher in patients undergoing hyperdiuresis (63% vs. 30%; p = 0.05), and in patients older than 45 years (65% for age > 45 vs. 33% for age < or = 45; p = 0.05). The probability of S3 or S4 emesis was 50% with Treatment A and 47% with Treatment B (p = 0.86). Sex, body weight, and type of conditioning chemotherapy did not influence the 12-h probability of emesis. Multivariate analysis revealed that hyperdiuresis (p = 0.02) and Treatment A (p = 0.04) were independently associated with radiation-induced emesis, whereas sex (p = 0.85), body weight (p = 0.13), age (p = 0.12), and type of conditioning chemotherapy (p = 0.92) were not. No early toxicity related to granisetron was observed. CONCLUSION: Granisetron is a well-tolerated and effective antiemetic agent that can be used as monotherapy during single-dose TBI. Good control of nausea and vomiting is obtained with this antiemetic drug, and its effect is increased when hyperdiuresis is suspended during TBI.

Adolescent↗
PubMed1996

Tandem high-dose chemotherapy with ifosfamide, carboplatin, and teniposide with autologous bone marrow transplantation for the treatment of poor prognosis common epithelial ovarian carcinoma.

BACKGROUND: A phase I or II trial was conducted to assess the toxicity and the efficacy of a tandem high dose chemotherapy combining ifosfamide, carboplatin, and teniposide in patients with poor prognosis ovarian carcinoma. METHODS: Thirty-seven patients were scheduled to receive tandem high dose therapy combining ifosfamide 7500 to 11250 mg/m2, carboplatin 875 ot 1000 mg/m2 and teniposide 750 to 1000 mg/m2, followed by autologous bone marrow transplantation (ABMT). Eight patients were refractory to the platin-based regimen, 7 were treated in chemosensitive relapse, and 22 in partial or complete response (PR/CR) were treated. Sixty-six cycles were administered. Sixteen patients were evaluated for response. RESULTS: The overall response rate was 56% (CR rate: 12%). Toxic effects consisted of mainly renal toxicity, esophagitis, and enterocolitis. Three patients died of therapy-related complications. Since the time of ABMT, the median overall survival (OS) duration of the whole population was 18 months and the survival rate was 14% at 60 months. For the 22 patients treated after PR or CR, the median OS duration was 24 months and the survival rate was 32% at 60 months. Tandem high dose therapy with ABMT was unable to circumvent resistance to conventional chemotherapy or to prolong the duration of survival for patients treated in chemosensitive relapse. For patients treated after CR or PR, the survival results were similar to that achieved with conventional therapy. CONCLUSIONS: Prospective, randomized studies, including patients only after CR or with minimal residual disease, are urgently required to evaluate the activity of high dose therapy in the treatment of advanced ovarian carcinoma.

Adult↗
PubMed1996

Cataractogenesis after total body irradiation.

PURPOSE: To evaluate the prognostic factors and the ophthalmologic follow-up on cataract formation following total body irradiation (TBI) prior to bone marrow transplantation (BMT). METHODS AND MATERIALS: Between 1980 and 1992, 494 patients were referred to our department for TBI prior to BMT. The mean age was 32 +/- 11 (median: 32, range: 2-63) years and the male to female ratio was 1.6 (304:190). The majority of patients were treated for acute leukemia (lymphoblastic, n = 177, 36%; or nonlymphoblastic , n = 139, 28%); 80 (16%) for chronic myeloid leukemia, 60 (12%) for non-Hodgkin's lymphoma, 23 (5%) for multiple myeloma, and 15 (3%) for other malignancies. Two hundred and fifty-four (51%) patients were grafted in the first complete remission (CR), 118 (24%) in second CR. Allogenic BMT was performed in 210 (43%) patients, and autologous BMT in 284 (57%). Methotrexate combined to steroids (n = 47, 22%) or to cyclosporine (n = 163, 78%) was administered for graft-versus-host disease (GvHD) prophylaxis. In 188 patients (38%), heparin was used in the prevention of veno-occlusive disease (VOD) of the liver. Furthermore, steroid administration was registered in 223 (45%). The conditioning chemotherapy consisted of cyclophosphamide (Cy) alone in 332 (67%) patients. Total-body irradiation was administered either in single dose (STBI; 10 Gy in 1 day, n = 291) or in six fractions (FTBI; 12 Gy over 3 consecutive days, n = 203) before BMT. The mean instantaneous dose rate was 0.0574 +/- 0.0289 Gy/min (0.024-0.1783). It was < 0.048 Gy/min in 157 patients (LOW group), > or = 0.048 Gy/min and <0.09 Gy/min in 301 patients (MEDIUM group), and > or = 0.09 Gy/min in 36 patients (HIGH group). RESULTS: When considering all patients, 42 (8.5%) patients developed cataracts after 13 to 72 months (median: 42 months) with a 5-year estimated cataract incidence (ECI) of 23%. Thirty-three (11.3%) out of 291 patients in the STBI group, and 9 (4.4%) out of 203 patients in the FTBI group developed cataracts with 5-year estimated incidences of 34 and 11%, respectively (p = 0.0004). Seven (19.4%) out of 36 patients in the HIGH group, 33 (10.9%) out of 301 in the MEDIUM group, and 2 (1.2%) out of 157 in the LOW group developed cataracts with respective 5-year cataract incidences of 54%, 30%, and 3.5% (HIGH vs. MEDIUM, p = 0.07; MEDIUM vs. LOW, p = 0.0001; HIGH vs. LOW, p < 0.0001). On the other hand, patients who received heparin as prophylactic treatment against VOD of the liver had less cataracts than those who did not receive (5-year ECI of 16% vs. 28%, respectively; p = 0.01). There was no statistically significant difference in terms of 5-year ECI according to age, sex, administration of steroids, GvHD prophylaxis, type of BMT, or previous cranial radiotherapy in children. Multivariate analysis revealed that the instantaneous dose rate (p = 0.001), and the administration of heparin against VOD (p = 0.05) were the two independent factors influencing the cataract incidence, while age, fractionation, and use of steroids were not. Among the 42 patients who developed cataracts, 38 had bilateral extracapsular cataract extraction and intraocular lens implantation, and only 4 (10%) developed secondary cataracts in a median follow-up period of 39 months. CONCLUSION: Among the abovementioned TBI parameters, high instantaneous dose rate seems to be the main risk factor of cataract formation, and the administration of heparin appears to have a protective role in cataractogenesis. On the other hand, ionizing radiation seems to have a protective effect on posterior capsule opacification following extracapsular cataract extraction and intraocular lens implantation.

Adolescent↗
PubMed1996

[Surveillance of patients treated with tamoxifen].

Tamoxifen is a nonsteroidal anti-estrogen frequently used in breast cancer therapy. Side effects to tamoxifen are uncommon (2%) but should be recognized and detected early by careful follow-up. Tamoxifen adjuvant therapy is absolutely indicated in postmenopausal breast cancer with estrogen-receptor--positive nodes. Recently, this indication has been extended to negative-node postmenopausal breast cancer. Mild acute side effects are the most frequent: hot flushes, menstrual irregularity, nausea, headache, vertigo, minimal modifications in blood cell counts. However, more serious accidents can occur. Increased risk of thromboembolism is linked to a fall in the level of antithrombin III. Ocular toxicity can occur. If such ocular lesions are diagnosed early enough, they can be cured by promptly withdrawing treatment. For patients given tamoxifen, there appears to be a small increase in risk of endometrial carcinoma, especially if the daily dose is > 30 mg. This over-risk requires adequate detection based on sufficient knowledge of the usual tamoxifen-related modifications in the endometrium. Physicians should also be aware of two favorable effects. Tamoxifen therapy leads to decreased cardiovascular morbidity and mortality in postmenopausal women and is associated with a significant increase in lumbar bone density. Risk of interaction with oral anticoagulants has been reported. We discuss here practical steps in the follow-up of women treated with tamoxifen.

Breast Neoplasms↗