[Consequences of oocyte dysmorphy on the fertilization rate and embryo development after intracytoplasmic sperm injection. A prospective multicenter study]. / Conséquences d'une dysmorphie ovocytaire sur la fécondation et le développement embryonnaire après injection intracytoplasmique, d'un spermatozoïde. Etude prospective, multicentrique.

OBJECTIVES: This prospective study aimed to evaluate the impact of oocyte dysmorphy on the fertilization rate and embryonic development rate in an ICSI programme. PATIENTS AND METHODS: Three hundred and two couples have been included during 302 ICSI cycles, and 1970 oocytes have been studied in 4 ART centres. After decoronisation, 18 morphological criteria, including the size and shape of the oocyte, the thickness of the zona pellucida, the presence or not of debris in the perivitelline space, as well as the appearance of the cytoplasm and polar body have been noted. RESULTS: In total 61.3% of the oocytes presented a dysmorphy, involving, almost equally, the different oocyte compartments. Among the dysmorphic oocytes, half presented more than one anomaly. On average, 9.2% of the oocytes were lysed the day after the micro-injection. The oocytes presenting an enlarged perivitelline space, or multiple vacuoles had a significantly raised lyse rate, 16.3% and 27.8%, respectively. The day after micro-injection, 61.3% of the intact oocytes were fertilized. The rate of fertilization was correlated to the number of abnormalities per oocyte: 1 anomaly: 64.6%, > or = 3 anomalies: 54.6%. The oocytes presenting a large perivitelline space had a slightly lowered fertilization rate (53.4%). On the other hand, those showing a cytoplasm containing refractile bodies had a slightly raised fertilization rate (68.6%). We did not see any statistically significant difference between the different types of oocytes concerning embryonic development at d2. CONCLUSION: These results confirm and contribute new elements with respect to previously published data, showing that (i) oocyte morphology little affects fertilization and the first stages of embryonic development; (ii) certain dysmorphies, (enlargement of the perivitelline space) are specifically deleterious at certain stages in the process (lowering the fertilization rate); (iii) certain morphological differences (the presence of refringent bodies) are not anomalies, but can reflect physiological cellular changes.

Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy: results of a retrospective survey.

A 2-year retrospective chart survey of 1064 patients with colorectal, breast, lung or ovarian cancer, Hodgkin's disease, or non-Hodgkin's lymphoma was conducted at 24 centres in France to determine the prevalence of anaemia (haemoglobin (Hb) levels < or = 120 g/l) and need for transfusion in patients who received non-platinum-based chemotherapy for more than three cycles or 3 months. Baseline Hb levels documented anaemia in 37.1% of patients (all tumour types). By cycle 3, the prevalence of anemia increased to 54.1% of patients and remained over 50% at cycle 4. At some time during chemotherapy 14.5% of patients were transfused. Predictive risk factors for anaemia requiring transfusion included low baseline Hb, decrease in Hb during the first month of chemotherapy, primary tumour site, prior blood transfusions and duration of chemotherapy. By early identification of patients at the highest risk of developing anaemia, interventions such as epoetin alfa can be employed to reduce or eliminate the need for transfusions.

Influence of the delay of adjuvant postoperative radiation therapy on relapse and survival in oropharyngeal and hypopharyngeal cancers.

PURPOSE: To determine whether the delay between surgery and the beginning of radiation therapy influences survival or the risk of local-regional relapse in oropharyngeal or hypopharyngeal squamous cell carcinomas. METHODS AND MATERIALS: From 2052 patients referred to the Henri Becquerel Center for the radiation therapy of an oropharyngeal or hypopharyngeal cancer between January 1, 1981 and December 31, 1992, 420 were included in a retrospective study. Exclusion criteria were another cancer, metastasis, incomplete resection, lack of homolateral lymph node resection, or previous chemotherapy. Radiation therapy delivered 45 to 75 Gy on initial location and lymph node. Follow-up was performed until December 31, 1997. A Cox proportional hazard regression analysis was used to evaluate the prognostic factors. RESULTS: The delay between surgery and radiation therapy was not found to be a significant prognostic factor for survival or risk of local-regional relapse. The only parameters found to influence local-regional and survival control were margins' pathologic state (respectively p < 0.0001 and p = 0.015) and T (p < 0.0001) and N (respectively p < 0.0001 and p = 0.0004) stages. In terms of local-regional relapse only, age was a prognostic factor (p = 0.048), and a trend was noted for tumor emboli in vessels or nerves (p = 0.061). CONCLUSION: In patients with oropharyngeal or hypopharyngeal squamous cell carcinoma, the delay between surgical procedure and radiation therapy does not influence survival or risk of local-regional relapse. Radiation therapy might be subjected to complete healing in these patients.

Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer.

This study was designed to evaluate new bone resorption and tumour markers as possible alternatives to serial plain radiographs for the assessment of response to treatment. Thirty-seven patients with newly diagnosed bone metastases from breast cancer, randomized to receive oral pamidronate or placebo tablets in addition to anticancer treatment within the context of a multicentre EORTC trial, who were both assessable for radiographic response in bone and had serum and urine samples collected for more than 1 month were studied. The markers of bone metabolism measured included urinary calcium (uCa), hydroxyproline (hyp), the N-telopeptide cross-links of type I collagen (NTx) and total alkaline phosphatase. The tumour markers measured were CA15-3 and cancer-associated serum antigen (CASA). Before treatment, levels of Ntx, uCa and Hyp were elevated in 41%, 24% and 28% respectively, and CA15-3 and CASA increased in 69% and 50%. For assessment of response and identification of progression, Ntx was the most useful bone marker. All markers behaved similarly in no change (NC) and partial response (PR) patients. There was a significant difference (P < or = 0.05) in Ntx levels (compared to baseline) at 1 and 4 months and in CA15-3/CASA at 4 months between patients with PR or NC and those with progressive disease (PD), and at 4 months between those with time to progression (TP) > 7 and those with TP < or = 7 months. The diagnostic efficiency (DE) for prediction of PD following a > 50% increase in Ntx or CA15-3 was 78% and 62% respectively. An algorithm to predict response to therapy has been developed for future prospective evaluation.

An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Vinorelbine is an active drug in the treatment of lung and breast cancers and has a favorable toxicity profile. Many clinical trials have demonstrated its antitumor activity in other tumor types including squamous cell carcinoma of the head and neck (SCCHN). We investigated the efficacy and tolerability of vinorelbine in patients with recurrent and/or metastatic SCCHN, previously untreated by chemotherapy. PATIENTS AND METHODS: Seventy-one patients with locoregional recurrent and/or metastatic SCCHN were treated with vinorelbine at a dose of 30 mg/m2/week i.v. by short-duration infusion on an out-patient basis. Doses were adjusted according to tolerance. RESULTS: Two complete and seven partial responses were observed among 56 evaluable patients, yielding a response rate of 16% (95% confidence interval (CI): 8%-28%). The overall response rate of all eligible patients (63) was 14%. The responses were seen in recurrent tumors, lymph nodes and in lung metastases, and their median duration was 19 weeks (12-63). The main toxicity, severe and reversible neutropenia (grade 3-4) occurred in 53% of the 69 evaluable (for toxicity) patients. Twelve patients developed severe bronchopulmonary infections, which caused two early deaths. Constipation was observed in 31 patients (45%). Other gastrointestinal toxicities, asthenia, acute pain syndrome and peripheral sensory neuropathy, were mild to moderate. The median number of treatments was seven cycles and the median relative dose intensity of vinorelbine was 85% (25.5 mg/m2/week). CONCLUSIONS: Vinorelbine is an active drug, with acceptable toxicity, in recurrent and/or metastatic SCCHN, at the dose and schedule administered in the present study. Further evaluation in association with other agents and/or radiotherapy is warranted.

A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.

[Male sterility caused by a lack of the acrosome in spermatozoa with a round shaped head]. / Nieplodnosc meska wywolana brakiem akrosomu w plemnikach z okragla glówka.

Only properly structured spermatozoa are able for transportation and penetrating the permeable membrane of oocyte. The key role in the process of fertilization belongs to the anterior part of acrosome, i.e., the spermatozoon's head. A case of a married couple, with diagnosed 8-year-long infertility, has been presented. A spermocytogram, run in the man, revealed all spermatozoa to be with rounded heads, i.e., without acrosome. That pathology was confirmed in electron microscopy. The significance of correct examination--spermocytogram--has been stressed in the diagnostic of male infertility.

[Chemotherapy in the treatment of brain metastases of breast cancers]. / La chimiothérapie dans le traitement des métastases cérébrales des carcinomes mammaires.

In the natural history of breast cancer the brain metastasis are associated with a median survival of a few months. Brain metastases are usually managed by radiation therapy and corticosteroids. The indications of surgery are limited. This report concerns four patients with brain metastases from breast carcinoma treated initially by systemic chemotherapy. The objective response to chemotherapy was similar to the results obtained in patients treated for extracranial metastases. This findings suggest that systemic chemotherapy is effective in the treatment of patients with brain metastases from breast cancer.

The Centre H. Becquerel studies in inflammatory non metastatic breast cancer. Combined modality approach in 178 patients.

One hundred and seventy-eight patients with non metastatic inflammatory breast cancer (IBC) have been treated at the Centre H. Becquerel. Median follow up is 67 months (6-178). Every patient received neoadjuvant chemotherapy (mean number of cycles = 4; range: 2-8), followed by a loco regional treatment (radiotherapy = XRT or modified radical mastectomy = S), followed by adjuvant chemotherapy. During this period, the types of chemotherapy and locoregional treatment have been the following: Study I: 64 patients treated with CMF or AVCF and XRT; Study II: 83 patients, treated with either AVCF, FAC or VAC followed by S (n = 38) or XRT (n = 22) in case of complete or partial response, or followed by XRT (23) in case of initial supraclavicular lymph node involvement or lack of response after chemotherapy; Study III: 31 patients treated with FEC-HD + Estrogenic recruitment followed by S and XRT after adjuvant chemotherapy, except seven patients who received XRT (refusal of surgery). Although objective response rates (= 56.2, 73.5 and 93.5% for study I, II and III respectively) are statistically better in the 3rd study, this does not translate in dramatically different disease free survival (median = 16.7, 19 and 22.2 months respectively for study I, II and III) or overall survival (median = 25, 45.7 and 32.6 months respectively for study I, II and III). Analysis of subset of patients without supra clavicular lymph node involvement where neoadjuvant chemotherapy obtained at least a 50% response reveals a median disease free survival and median overall survival of respectively 38.3 and 60.1 months for patients who underwent S vs 19 and 38.3 months for those who received XRT (P = 0.15). These studies suggest that surgery has no deleterious effect on outcome of IBC. Advantage on disease free survival or overall survival from intensive chemotherapy in IBC remains to be proven with appropriate randomised trials.

Tetracosactrin vs. methylprednisolone in the prevention of emesis in patients receiving FEC regimen for breast cancer.

0.5 mg tetracosactrin is considered to be equivalent to 40 mg methylprednisolone with regard to the induced cortisol secretion. 97 female breast cancer patients who received their first two FEC courses (epirubicin 50-75 mg/m2, 5-fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2) entered this randomised crossover study (76 had previously received an adjuvant treatment); tetracosactrin was administered intramuscularly and methylprednisolone intravenously immediately before chemotherapy administration. The tolerability was evaluated using a diary card during 5 days and patients were asked for their preference at the end of the two cycles. There was no difference either for vomiting (dry heaves were included) or nausea between the two treatments (the analysis was performed on day 1, the worse day of days 2 and 3 and the worse day of days 4 and 5). At day 1, 49% of the patients experienced no or mild nausea after tetracosactrin and 62% after methylprednisolone (not significant) (first period analysis); a complete control of vomiting (including dry heaves) was observed in 49% of the patients after tetracosactrin and 53% after methylprednisolone (not significant). No difference was observed between patients with or without previous chemotherapy. However, slightly more patients preferred tetracosactrin (P = 0.048).

[Dynamics of gonadotropin secretion in oligospermia with isolated elevation of follicle stimulating hormone (FSH)]. / Dynamique de la sécrétion gonadotrope dans les oligospermies à FSH isolément élevée.

The mechanism of oligospermia with high level of follicle stimulating hormone (FSH) and normal levels of luteinizing hormone (LH) and testosterone is subject to controversy: pituitary origin with slowing down of LH pulses, or primary gonadal deficiency? We studied 23 men presenting with this hormonal profile. Compared with a control population, these men had decreased mean testosteronaemia, increased mean LH level, both at baseline and under LHRH, and increased area under the LH pulsatility curve. A positive correlation was found between LH and FSH plasma levels. These data are in favour of a primary gonadal deficiency, and we therefore expected to find an increased frequency and amplitude of LH pulses. In fact, the frequency was normal and the amplitude increased in one half of these men, while the frequency was reduced and the amplitude also increased in the other half. There was no difference in plasma FSH levels between these two groups. Pulsed administration of LHRH restored physiological stimulation, but it did not result in normalisation of the FSH/LH ratio and cannot be regarded as a suitable treatment. It would therefore seem that the mechanism of oligospermia with isolated high FSH level is an abnormal feedback of gonadal peptides and steroids.

Phase II study of oral idarubicin in elderly patients with advanced breast cancer.

Thirty-one elderly patients with measurable advanced breast cancer entered this phase II study. A dose of 15 mg/m2/day of Idarubicin (IDA) for 3 consecutive days every 3 weeks was given orally. Mean total cumulative dose of IDA received was 175 mg/m2 (range: 45-475 mg/m2). Mean number of cycles given was four (range: 1-15). Out of 27 evaluable patients, three achieved a complete response (CR), four had a partial response (PR) (CR + PR = 26 +/- 17%), nine showed no change, and 11 had a progressive disease. Median time to progression was 83 days (range: 19-728 days). Out of 26 patients evaluable for toxicity, hematologic toxicity at day 21 was moderate: neutropenia grades 3 and 4 = 16% of cycles: two patients had grade 1 thrombopenia; and three patients, grade 3. No cumulative hematologic toxicity was detected. Nonhematologic toxicities consisted of nausea and vomiting in 72% of patients [World Health Organization (WHO) grades 3 and 4 = 8%)] and alopecia in 76% (WHO grades 2-3 = 38%). Grade 1 stomatitis occurred in 4% of cycles. Chemotherapy was discontinued in one patient because of drop of left ventricular ejection fraction (LVEF) from 0.62 to 0.44 at a cumulative IDA dosage of 322 mg/m2. The results of this study show that IDA is an active drug in elderly patients with advanced breast cancer. Due to its simplicity of administration IDA deserves further investigations in combination with other drugs.

Serum hyaluronan (hyaluronic acid) in breast cancer patients.

Eighty-three women with breast cancer (57 with systemic metastasis, 26 without) were investigated for serum hyaluronan (HA) and compared to 50 patients with benign diseases of the breast. Hyaluronan was significantly increased in sera of metastatic patients compared to sera of non-metastatic patients (p less than 0.0001) and also in sera of non-metastatic patients when compared to control sera (p less than 0.01). The difference was not related to the number of metastatic sites involved. Three months after starting cytotoxic chemotherapy in metastatic patients, lower HA concentrations were observed in patients responding to chemotherapy. The initial level of serum HA had no predictive value concerning response to chemotherapy.

A prognostic score in histological node negative breast cancer.

Between October 1977 and December 1983, 379 consecutive patients have been treated for unilateral, non-metastatic breast cancer, either with conservative (n = 205) or radical surgery (n = 174), with axillary dissection in all the cases. None of them had histologically proved lymph node involvement. Oestrogen receptor (ER) and progesterone receptor (PR) levels were measured on each tumour. Levels greater than 5 fmol mg-1 cytosolic protein were considered as positive for both ER and PR. At 5 years, overall survival (OS) and disease-free survival (DFS) are respectively 88% and 78%. Unifactorial analysis using Kaplan and Meier estimates and the log rank test revealed that OS was significantly related to age (P less than 0.05), tumour size (P less than 0.001), histological grading (SBR) (P less than 0.01), ER (P less than 0.001) and PR (P less than 0.001). DFS was significantly related to the same factors. Menopausal status, number of breast tumour foci and previous familial history of breast cancer were not significant. Multifactorial analysis revealed that DFS was significantly related to age (bad prognosis (b.p.) less than or equal to 37 years old), tumour size and histological grading (b.p. SBR = 3), and that OS was significantly related to tumour size and PR (b.p. PR less than or equal to 5 fmol mg-1 protein). A prognostic score has been constructed for both DFS and OS. These scores divide our patients into three significantly different (P less than 0.0001) groups with good, intermediate and bad prognosis.

[A hormone assay as a therapeutic choice in male sterility]. / Apport de l'enquête hormonale au choix thérapeutique d'une stérilité masculine.

In order to study the function of the hypothalamic-pituitary-testicular axis in men referring for severe oligospermia, the hormonal pattern of 57 oligospermic men was compared to those of 19 healthy volunteers. Fourteen patients had plasma gonadotrophin levels in the normal range contrasting with low plasma testosterone (T) levels. An hyperprolactinemia was found in 2 of these men who were treated with bromocriptine. A dramatic increase in sperm count was obtained on month 9 to 12 of the therapy and 5 pregnancies were obtained. Two men with hypogonadotrophic hypogonadism and azoospermia were treated with gonadotrophins. Such a treatment induced a desquamation of immature germinal cells in the sperm on month 6 and the maturation et spermatozoa on month 18. By contrast to the latter patients, 8 men had a decrease in plasma T levels without clinical signs of hypoandrogenism. The spermocytogram showed numerous immature germinal cells. On month 7 of a treatment using gonadotrophins, the sperm count rose and 4 pregnancies were obtained after 3 to 12 months of therapy. In 2 patients an isolated FSH deficiency was suspected on the basis of undetectable FSH levels unresponsive to the infusion of GnRH. These patients were treated with hMG. This treatment induced a sharp increase in sperm count on month 6. Forty-three patients had an increase in either LH and/or FSH: 24 men had plasma testosterone and LH levels in the normal ranges, contrasting with an increase in plasma FSH level. In such men, the mean of testosterone level was significantly (p less than 0.001) lower than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

[Phase II trial as 2nd line chemotherapy with 5 fluorouracil and cisplatin (5FU-CDDP) for advanced breast cancer]. / Essai phase II de chimiothérapie de seconde intention par le 5 fluoro-uracile et le cisplatine (5 FU-CDDP) dans les cancers avancés du sein.

Thirty patients with advanced breast cancer, previously treated with anthracycline and 5 fluorouracil in bolus administration, were evaluated with a chemotherapy regimen generally used in head and neck cancer. Treatment schedule consisted of: cisplatin 100 mg/m2 on d 1 and 5 fluorouracil 1000 mg/m2 continuous infusion on d 2-3-4-5 every 21 d. With all measurable lesions and 27 evaluable patients, the response rate was 29% (95% confidence interval: 12-47%), with 5 complete responses (3 soft tissue - 2 lung) and 3 partial responses (1 lung - 2 liver). The median duration of response is 4.5 months (range 2-11 months). The 30 patients (93 courses) are evaluable for toxicity. Hematologic toxicity was mild: anemia 68% grade 0, neutropenia 68% grade 0 and thrombocytopenia 83% grade 0. Nausea and vomiting were severe 83% grade 3 + 4 at d 1. Others side effects were mild including 5/91 mucositis grade 2 + 3, peripheral neuropathy 1/31 grade 2 and 2/91 reversible rise in serum creatinine greater than 1.5 mg/dl.

Pirarubicin in advanced breast cancer: a French cooperative phase II study.

79 patients with advanced breast cancer were given Pirarubicin 20-25 mg/m2 during 3 consecutive days every 3 or 4 weeks. 78 were evaluable for response (41 without previous chemotherapy and 37 with only one previous regimen). The overall response rate was 35% (95% CI 24-45) and the complete response rate was 8%. In previously untreated patients, the response rate reached 41.5%. The limiting toxicity was a non-cumulative granulocystopenia, sometimes severe at these high doses, with a prompt recovery. The non-haematological toxicities were mild, and included 13% with grade 3 alopecia.

Phase II study of epirubicin in advanced soft tissue sarcoma.

Thirty-seven patients (pts) with previously untreated and measurable advanced soft tissue sarcoma entered this phase II study: 22 men and 15 women were included. Median age was 58 (range: 20-71). The starting dose of epirubicin was 100 mg/m2 IV bolus every 3 wks. In the case of minimal myelosuppression, the dose was increased by 10 mg/m2 to 130 mg/m2 (Mean dose per cycle: 105 mg/m2). Median cumulative dose of epirubicin administered was 445 mg/m2 (range: 200-1320 mg/m2). From 32 evaluable pts, one had a complete response (CR), 5 a partial response (PR), (CR + PR = 18.7% +/- 13.8%), 12 showed no change (37.5%) and 14 had progressive disease. The number of complete or partial responses observed was not modified by increasing the doses of epirubicin. Median time to progression was 4 months. From 32 pts evaluable for toxicity, hematologic toxicity at d 21 was mild. Non hematological toxicities consisted of nausea and vomiting in 74% of pts (WHO grade 3 = 5%), stomatitis in 12.2% (WHO grade 3 = 3%) and alopecia in 91% (WHO grade 2-3 = 72%). No cardiac dysfunction was recorded during the treatment, even though 7 patients received more than 800 mg/m2 of epirubicin (median: 850 mg/m2, range: 810-1320 mg/m2). The results of this study show that epirubicin is an active drug in advanced soft tissue sarcoma.