Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial.

PURPOSE: A randomized unblinded phase III trial was designed to determine the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate recovery from febrile neutropenia induced by chemotherapy. PATIENTS AND METHODS: A total of 68 patients with febrile neutropenia following chemotherapy defined as axillary temperature greater than 38 degrees C and absolute neutrophil count (ANC) less than 1 x 10(9)/L were included. After stratification for high- and low-risk chemotherapy to induce febrile neutropenia, treatment was randomized between GM-CSF at 5 microg/kg/d or control, both being associated with antibiotics. RESULTS: GM-CSF significantly reduced the median duration of neutropenia from 6 to 3 days for ANC less than 1 x 10(9)/L(P < .001) and from 4 to 3 days for ANC less than 0.5 x 10(9)/L (P=.024), days of hospitalization required for febrile neutropenia, and duration of antibiotics during hospitalization. The greatest benefit with GM-CSF appeared for patients who had received low-risk chemotherapy, for which the median duration of ANC less than 1 x 10(9)/L was reduced from 7 to 2.5 days (P < .001) and from 4 to 2 days for ANC less than 0.5 x 10(9)/L (P=.0011), the duration of hospitalization during the study from 7 to 4 days (P=.003), and the duration on antibiotics during hospitalization from 7 to 3.5 days (P < .001). A multivariate analysis, using Cox regression, showed that variables predictive for recovery from neutropenia were GM-CSF (P=.0010) and time interval between the first day of chemotherapy and randomization (P=.030). There was no benefit for GM-CSF when high-risk chemotherapy was considered. CONCLUSION: GM-CSF significantly shortened duration of neutropenia, duration of neutropenic fever-related hospitalization, and duration on antibiotics during hospitalization when febrile neutropenia occurred after low-risk chemotherapy, but not high-risk chemotherapy.

Prognostic factors in inflammatory breast cancer and therapeutic implications.

223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987. Patients received chemotherapy and radiation treatment according to three consecutive randomised trials. Five- and 10- year survival rates were 41 and 32%, respectively. Disease-free interval rates were 25.5% at 5 years and 19% at 10 years. Parameters significantly linked with a pejorative prognosis in a multivariate analysis were: diffuse erythema, lymph node involvement, chest wall adherence, and age above 50 years. When therapeutic response parameters were included in the multivariate analysis, the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment (at 8 months), complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy, limited erythema at presentation and, less significantly, complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months. In conclusion, patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy. High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials. Detailed information on the biology of this disease should allow the design of new strategies aiming to improve patient management.

Low-dose splenic irradiation in the treatment of immune thrombocytopenia in HIV-infected patients.

PURPOSE: To determine the effect of low-dose splenic irradiation on severe Zidovudine-resistant, HIV-1-associated thrombocytopenia (HAT). METHODS AND MATERIALS: Between September 1994 and October 1996, 17 patients were included in a prospective study. The patients met the following criteria for inclusion: hemorrhagic symptoms or a platelet count below or equal to 50 x 10(9)/l and normal numbers of megakaryocytes on bone aspiration. The mean baseline platelet count was 20.3 (+/- 14.4) x 10(9)/l; four patients had a platelet count inferior to 10 x 10(9)/l. Splenic volume was defined by ultrasonography. A total dose of 9 Gy was given using an isocentric parallel pair field technique. RESULTS: One month after the end of treatment six patients had a significant rise in their platelet count. Clinically, hemorrhagic symptoms stopped for all patients that were symptomatic. Unfortunately, duration of response was short because for one patient only the platelet count remains stable with a follow-up of 6 months. All patients are alive and in recent evaluation, with four out of eight patients receiving a combination of antiretroviral therapy had a platelet count above 50 x 10(9)/l. CONCLUSION: Our results are disappointing concerning the duration of response, especially comparatively to those reported in autoimmune thrombocytopenia. Mechanisms of HAT are more complex, and megakaryocytes' infection may play an important role. Splenic irradiation should be considered as palliative treatment for the minority of patients with severe bleeding that does not respond to standard medical treatment.

Premenopausal patients with node-positive resectable breast cancer. Preliminary results of a randomised trial comparing 3 adjuvant regimens: FEC 50 x 6 cycles vs FEC 50 x 3 cycles vs FEC 75 x 3 cycles. The French Adjuvant Study Group.

Anthracyclines are among the most active drugs for the treatment of advanced breast cancer. Epirubicin has been found to be as effective as doxorubicin at equimolar doses but significantly better tolerated, especially in terms of alopecia, leucopenia, and cardiac toxicity. The role of anthracycline-containing regimens in adjuvant treatment of breast cancer has been studied by only a few clinical trial teams. In 1986, the French Adjuvant Study Group (FASG) began a randomised trial aimed to investigate the concept of dose intensity as well as the optimal duration of treatment in patients with early breast cancer. Between 1986 and 1990, 621 patients were included in the trial, of whom 595 were evaluable. Patients were randomised to 1 of 3 treatment groups: Group A (n = 207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193) received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 3 cycles. Locoregional radiotherapy was administered after the third cycle of chemotherapy in all treatment arms. Clinical prognostic factors were similar between treatment groups. Approximately 62% of all patients had 1 to 3 positive lymph nodes; 50% of patients were hormone receptor positive and 73% were Scarff-Bloom Richardson (SBR) grade 2 to 3. Toxicity was evaluated in 595 patients (207, 193 and 195 patients in Groups A, B and C, respectively), who received a total of 2301 chemotherapy cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I-II trial of intensification of the MAID regimen with support of lenograstim (rHuG-CSF) in patients with advanced soft-tissue sarcoma (STS).

This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.

[A phase II study with mitoxantrone-vinorelbine association in the treatment of advanced breast cancer in elderly women]. / Etude de phase II d'association mitoxantrone-vinorelbine dans le traitement du cancer du sein de la femme âgée.

To assess efficacy and toxicity of less toxic analogs for advanced breast cancer in elderly women, we performed a phase II study using the combination mitoxantrone (MTZ)-vinorelbine (VNR). From January 1991 to May 1993, 25 women older than 70 years received a chemotherapy consisting in 10 mg/m2 of MTZ on day 1, followed by 20 mg/m2 of VNR on day 1 and 8. Cycles were repeated every 21 days for a maximum of ten cycles in the case of an objective response. Sixteen women previously received first line hormonotherapy, eight with only one metastatic site. Twenty-three patients are evaluable for response and toxicity. An objective response was observed in five cases (22%), with a median time to progression of 13 months. More than 75% of the planned dose-intensity, for MTZ and VNR was received by 90 and 57.2% of patients, respectively. Dose-limiting toxicity was myelosuppression but no febrile neutropenia was observed. Extra haematologic toxicities were unfrequent. This combination is well tolerated by elderly women, but best results could be achieved by increasing delivered dose intensity.

[Intraperitoneal high dose chemotherapy as consolidation treatment for advanced ovarian carcinoma: a pilot study]. / Traitement de clôture des adénocarcinomes ovariens de stade avancé: étude pilote de chimiothérapie haute dose par voie intrapéritonéale.

Consolidation treatment of advanced ovarian carcinoma, especially the place of intraperitoneal chemotherapy, remains a controversial subject. From January 1988 to July 1995, 39 patients, median age 54 years, received intraperitoneal chemotherapy as consolidation treatment after second-look surgery. At the time of intraperitoneal chemotherapy, 30 patients had no residual disease. Intraperitoneal drug administration used a Tenckoff catheter or a lumbar needle. Treatment combined 5 fluorouracil 1 g/m2 and cisplatin 200 mg/m2, associated with a systemic sodium thiosulfate rescue as nephroprotector. A pharmacological analysis was done for 9 patients: the exposure of peritoneal cavity to cisplatin exceeded that of the plasma by 11 fold. Hematologic and nephrologic toxicity were acceptable. The median follow-up is 43 months. The disease free survival is 36,6 months, but 48,5 months if no residual disease at the time of intraperitoneal chemotherapy. Consolidation treatment by intense intraperitoneal chemotherapy is a feasible approach and might be beneficial in chemosensitive patients devoid of macroscopic remnants, but must be compared with others approaches.

[Clear cell soft tissue sarcoma. Clinical, histopathological and prognostic study of 36 cases]. / Sarcome à cellules claires des tissus mous. Etude clinique, histopathologique et évolutive de 36 cas.

Thirty six cases of clear cell sarcoma of soft tissue are reported. The median age was 44 years (5 to 80 years). The principal sites were the foot (11 cases), the hand and wrist (7 cases) and the knee (6 cases). The architecture was fascicular with lobular arrangement of cells delimited by delicate fibrous septa intimately bound to tendons or aponeuroses. Tumoral cells were round or fusiform with abundant clear cytoplasm sometimes epithelioid with round nuclei and prominent nucleoli. The mitotic rate was evaluated to 9/10 HPF. S100 protein was expressed in 33/36 cases and HMB45 marked 29/31 cases, without expression of cytokeratin. Three-year and 5-year survival rate were respectively 72% and 62%. Prognosis factors for global survival were efficiency of initial treatment with distal location and necrosis and FNCLCC grade. The distinction of clear cell sarcoma from metastatic melanoma is important because of the difference of prognosis.

[Pure dysgerminomas of the ovary. Retrospective analysis of 17 cases treated at the Claudius Regaud Center from 1974 to 1989]. / Dysgerminomes purs de l'ovaire. Analyse rétrospective de dix-sept cas traités au Centre Cladius Regaud de 1974 à 1989.

From 1974 to 1989, 17 dysgerminomas of the ovary were treated at the Centre Claudius Regaud. The mean age of the patients was 21 years: 53% were FIGO stage IA, 17% were stage IB, 6% were stage IIB and 24% were stage IIIC. Conservative surgery was performed in 13 patients (unilateral salpingo-oophorectomy) and non-conservative surgery was performed in the others patients. 70% of the patients underwent complete resection. Post-operative treatment was administered in every case but one (radiotherapy: 15 patients; combined chemo-radiotherapy: 1 patient). All patients achieved complete remission after the first-line treatment, but 2 of them recurred (1 IA, 1 IIB). A second remission was achieved in both cases. The overall survival rates were 100% at 2 years, 94% at 5 years and 89% at 10 years. The dual objective of curing the patient of her malignant disease while preserving her reproductive function was achieved in 53% of the patients.

[Cervical adenocarcinomas: diagnostic, prognostic and therapeutic aspects in a 49 case-control study]. / Aspects diagnostiques, pronostiques et thérapeutiques des adénocarcinomes du col utérin: à propos d'une série de 49 cas.

OBJECTIVES: The aim of this study was to search for potential diagnostic, therapeutic and prognosis differences between a series of 49 adenocarcinomas of the cervix and a matched series of epidermoid carcinomas. METHODS: Forty-nine adenocarcinomas were treated between 1978 and 1992 and retrospectively compared to a series of 98 paired epidermoid carcinomas. RESULTS: The adenocarcinoma incidence is 5.4%. There was no significant difference for age distribution, parity, or hormonal status. There was also no significant difference for clinical features. Stage I appeared more frequently in the adenocarcinoma group (stage I: 69.4%, stage II: 14.3%, stage III: 14.3%, stage IV: 2%). Stage I are also more frequently found in the adenocarcinoma group (69.4% versus 42. 9%, p< 0,05). Combined radio-surgical treatment was proposed more often for the adenocarcinoma group (respectively radio-surgery combination 73%, radiotherapy alone 18%, surgery 9%); in the epidermoid carcinoma group, combined radio-surgical treatment and radiotherapy were the usual treatment (46%); surgery alone appeared in third rank place (8%). Adenocarcinoma pelvic recurrences appeared more frequently (28.6% for adenocarcinoma group versus 13.3% for epidermoid group p< 0.05), while distant recurrence was the same (12. 2% for adenocarcinoma group versus 11.2% for epidermoid group, p< 0. 05). Five years overall survival rate was worse for the adenocarcinoma group (52% versus 63.7%, p< 0.05) but the difference was not significant for the disease free survival rate. Only for stage Ib, there are also more pelvic recurrences (35.4% versus 13.1%, p< 0.05), more distant recurrences (9.6% versus 2.6%, p< 0.05), and lower overall survival for adenocarcinomas (58.7% versus 88.5%, p< 0. 01). CONCLUSION: The incidence of adenocarcinomas is slightly increasing (absolute value in our experience) and the low stages seem to be more frequent in our experience probably by staging inaccuracy. Adenocarcinoma prognosis seems to be worse because of its poor radio-sensitivity. It seems necessary to optimize clinical staging and therapeutic protocols excluding radiotherapeutic approach, including surgical purposes or radio-surgical associations if unfavorable histological features or tumoral enlargement (T> 3 cm) are found.

An interpersonal analysis of Rorschach aggression variables in a normal sample.

This study investigated the relationship between Rorschach aggression variables and a self-report measure of interpersonal control and aggression (Structural Analysis of Social Behavior), rated for best and worst states, with 50 college students using forward stepwise regression analyses. Aggressive Movement (AG) was related to the report of self-attack for the best state ratings. The following findings were significant for the worst state ratings. AG was related to viewing the other as reacting as if attacked but the self as acting more affiliatively to the other. Aggressive Past (AgPast) was related to reacting to the other more submissively. A combined Aggressive Potential (AgPot)/Aggressive Content (AgC) variable was related to viewing the other as reacting less submissively and acting more dominantly. AgC was related to viewing the other as reacting less submissively. Methodological limitations are discussed, including potential problems regarding social desirability for the self-report aggression measure.

Are the MMPI subtle subscales subtle measures of their scales?

This study investigated the ability of the MMPI Wiener-Harmon subtle subscales (on scales D. Hy, Pd, Pa, and Ma) to serve as subtle or unobtrusive measures of their scales. Forty outpatients completed the MMPI under standard instructions, followed by a fake-good or fake-bad instructional set. First, we investigated the paradoxical effect found in the MMPI faking literature (in which, overall, the subtle subscale T-scores change in a direction opposite of the faking instructions) and found that not every subtle subscale shows this effect. Secondly, the subtle subscale T-scores achieved under faking conditions showed no significant relationship to their respective full-scale T-scores achieved under standard conditions. Therefore, our results do not support the Wiener-Harmon subtle subscales as subtle measures of their scales.

[Results of the surgical treatment of epidermoid carcinoma of the mobile tongue and mouth floor. Apropos of 157 patients]. / Résultat du traitement chirurgical des carcinomes épidermoïdes de la langue mobile et du plancher buccal. A propos de 157 patients.

Squamous cell carcinomas of the oral cavity were treated in 157 patients by surgery as first-line (104) or salvage (53) treatment. Postoperative irradiation delivered either for locally advanced tumors (stade III-IV) or for unfavorable histological data (nodal or surgical margins involvement). The retrospective study with a mean time of follow-up of 2.5 years shows a loco-regional control rate of 75% statistically influenced by histological nodal status (p < 0.01). Cumulative and cause specific survival rates at 5 years are 41.1% and 57.2% respectively. T stage was found to be a prognostic factor of survival (p < 0.01) as bone involvement (p < 0.05). Surgical margins are influent on local control and survival only in absence of radiation.

Instructed faking and MMPI-2 response latencies: the potential for assessing response validity.

Differences in Minnesota Multiphasic Personality Inventory-2 (MMPI-2) response latencies between groups instructed to respond honestly or fake were explored. There were 120 undergraduate students who completed a computer administered MMPI-2 with instructions to either respond honestly, to underreport psychopathology, or to overreport psychopathology. Results showed that subjects required significantly more time to respond in a manner that was inconsistent with their response set when pattern of endorsement (acceptance vs. rejection) was considered and less time when pattern of endorsement was not considered. The differential response of subjects across groups suggests that response latencies are related to response styles and that future research may indicate a methodology for utilizing response latencies in assessing response validity.

Potential prognostic value in human breast cancer of cytosolic Nme1 protein detection using an original hen specific antibody.

The metastasis-suppressor nme gene (also called nm23), first identified in murine melanoma cells, exists as two forms in human: nme1 and nme2. However, only the lack of expression of nme1 has been related to distant metastasis appearance in human breast cancer. The aim of this work was first to raise specific antibodies to allow the analysis of Nme1 and then, with this specific tool, to evaluate the predictive value of Nme1 detection in cytosolic extracts of human breast tumours. We obtained a hen antibody that specifically reacts with Nme1 without any cross-reaction with Nme2. We analysed the expression of the protein in 59 human breast tumours and found a significant relationship between this expression and oestrogen receptor status (P<0.001). Moreover, Nme1 expression is related to metastasis-free survival (P<0.001) and survival of patients (P<0.001). The determination of Nme1 expression in primary tumours using our antibody should be an interesting predictive test of the metastasis for clinical investigations.

Relation between unbound plasma concentrations and toxicity in a prolonged oral etoposide schedule.

OBJECTIVE: This study was undertaken in order to evaluate the impact of pharmacokinetics on the toxicity of oral etoposide administered daily for 21 days. METHODS: The daily dose was 50 mg/m2. Thirty-two patients 24 males and eight females, 36 76 years old, treated for various tumour types), were evaluated. Blood samples were obtained on day 1 for all patients, and on day 21 for 16 patients. Plasma etoposide concentrations were determined by high-performance liquid chromatography, and etoposide plasma protein binding by equilibrium dialysis. RESULTS: On day 1, the mean value (with coefficient of variation for interindividual variability) for the unbound fraction (fu), area under the concentration versus time curve (AUC), and unbound AUC was 9.8% (59%), 34 mg x h/l (39%), and 3.5 mg x h/l (92%), respectively. The ratio between AUC on day 1 and day 21 ranged between 0.5 and 1.8 (mean 0.9, with CV 33%). The plasma trough unbound concentrations and the unbound AUCs both corresponding to the first administration were significantly higher in the 11 patients who had a severe neutropenia than in the 21 patients who had no or moderate toxicity. However, total etoposide concentrations did not differ between these two groups. A limited sampling strategy using the NONMEM program and a database of 89 patients previously studied was performed. The optimal sampling schedule (i.e. 1, 4, and 24 h after oral etoposide administration) allowed to obtain the AUC accurately on day 1. CONCLUSION: Individual adjustment of oral etoposide based on unbound pharmacokinetics after the first administration appears relevant and feasible.

Isolated clustered microcalcifications: diagnostic value of mammography--series of 400 cases with surgical verification.

PURPOSE: To determine the diagnostic value of mammographic criteria in cases of isolated clustered microcalcifications. MATERIALS AND METHODS: Four hundred mammographic studies of isolated clustered microcalcifications for which surgical verification was available were reviewed. A descriptive statistical study was performed to evaluate the distribution of each criterion relative to histopathologic results, followed by a multivariate study to determine statistically significant criteria. Seven breast specialists gave a consensus opinion on the need for surgery. RESULTS: There were 302 benign lesions and 98 cancers. The most useful criteria were vermicular form, linear/branching shape, and irregular size of microcalcification. The number of biopsies recommended with use of these three criteria was 177 instead of the 172 recommended by the experts. CONCLUSION: Use of these three preoperative criteria permits correct diagnosis of most such malignancies (90% in our series vs 67% diagnosed by the experts).