[Pharmacokinetic profile of high-dose doxorubicin administered during a 6 h intravenous infusion in breast cancer patients]. / Profil pharmacocinétique de la doxorubicine administrée à haute dose en perfusion de 6 h chez des patientes atteintes d'un cancer du sein.

The purpose of our investigation was to evaluate the pharmacokinetic profile of doxorubicin administered by a new schedule. Nine non-pretreated young women with high risk breast cancer (mean age: 38, range: 29-45) entered this trial and received, cyclophosphamide (600 mg/m2) given as a 30-min infusion followed by doxorubicin (120 mg/m2) as a continuous infusion over 6 h. Chemotherapy was combined with hematopoietic factor support (G-CSF or GM-CSF). Blood was sampled over the 0-54 h period and 14 cycles were studied for pharmacokinetics. Doxorubicin as well as its major metabolite doxorubicinol were assayed in plasma specimen by high performance liquid chromatography. Mean doxorubicin plasma concentration peak was 42.6 ng/ml (standard deviation (SD): 13.3). The mean terminal half-lives were 32.6 h (SD: 22.0) and 39.2 h (SD: 21.6) for doxorubicin and doxorubicinol, respectively. Mean areas under the plasma concentration-time curve (AUC) were 413 ng/h-1 ml (SD: 103) and 1,707 ng/h-1 ml (SD: 815) for doxorubicin and doxorubicinol respectively. Consequently, the ratio of the AUC of doxorubicinol to that of doxorubicin was high (mean: 4.1 (SD: 1.6)) contrasting with previous studies reporting ratios less than 1 in patients with normal liver function. The systemic clearance of doxorubicin was 5.23 l/min/m2 (SD: 1.91). The inter- and intra-patient variability for AUC was low for both drugs. Hence the coefficients of variation were 24.6% for doxorubicin, 26.2% for doxorubicinol (inter-individual variation) and less than 10% for both compounds (intra-individual variation). In conclusion, the pharmacokinetic profile of doxorubicin (120 mg/m2) administered as a 6 h-continuous infusion is characterized by a greater exposure to doxorubicinol. This could be explained by a saturation in the biliary excretion process during the period following the end of the infusion.

Amplification of 11q13 DNA markers in head and neck squamous cell carcinomas: correlation with clinical outcome.

This study was performed on 282 patients with primary head and neck squamous cell carcinomas to evaluate the prognostic importance of 11q13 amplification. Amplification of the 11q13 DNA markers, HST-1/FGF-4 and BCL-1, evaluated by Southern and slot blot hybridisation, was detected in 52% of tumours. 11q13 amplification was associated with tumour site since this alteration occurred in 76% of tumours arising in the hypopharynx, versus 40% in the other sites (P = 0.0007). 11q13 amplification was also significantly related to the presence of involved neck lymph nodes (P = 0.013). The relationship between 11q13 amplification and risk of progression was studied in two subgroups of head and neck cancer patients with regard to treatment modalities. The presence of 11q13 amplification in the tumour was not significantly associated with a shorter event-free survival (P = 0.82) and crude survival (P = 0.61) of the 201 patients treated by surgery and postoperative radiotherapy. Similarly, absence of a relationship was observed for the group of 79 patients treated by surgery alone. These results confirm that 11q13 amplification is a prominent event in head and neck squamous cell carcinoma, indicating that it may be a common genetic event in the development of these neoplasms, but is not a reliable prognostic marker.

Rflp analysis of the L-myc oncogene in head and neck-cancer - relationship study with susceptibility and disease progression.

The L-myc DNA restriction fragment length polymorphism (RFLF), revealed by EcoRI digestion, has been evaluated in a case-control study including 161 head and neck cancer (HNSCC) patients and 160 normal healthy individuals with similar smoking and alcohol habits. No significant difference in the distribution of L-myc genotypes (LL, LS or SS) was found between the two populations implying thus no predisposition to head and neck tumour by either allele. There was no significant association between L-myc genotypes and the usual clinicopathological features such as T staging, differentiation status and lymph node involvement. Moreover, follow-up data from 154 patients was obtained and correlated with the L-myc pattern. No significant difference was observed in metastasis occurrence, multiple cancer incidence and survival data in the patients classified according to the L-myc genotypes; only a trend to preferentially develop metastasis in lung for patients with S allele was noted. In conclusion, our data shows that the L-myc typing does not contribute to HNSCC risk or prognosis assessment. A review of L-myc RFLP published studies shows contradictory results even on the same type of tumour and emphasizes the lacunae in understanding the biological role of L-myc for valid interpretation of L-myc allelic associations with cancer susceptibility or prognosis.

Alteration of the C-met oncogene locus in human head and neck-carcinoma.

The c-met proto-oncogene encodes the receptor for the hepatocyte growth factor/scatter factor (HGF/SF) which induces eel proliferation and motility. We have analysed the genetic alteration involving the c-met locus on chromosome 7q31 using the pMet H polymorphic probe, in tumor and normal DNA from 87 patients with head and neck squamous cell carcinomas (HNSCC). We report the observation of loss of heterozygosity (LOH) at this locus in 23% of informative cases, contrasting with the previously reported 40% LOH detected in breast cancer. Further, gain of genetic material was also observed in 13% of the HNSCCs. The alterations of c-met gene were not significantly associated with standard pronostic features including tumor size and lymph node status. Involvement of the c-met locus in allelic imbalance, either loss or gain of genetic material, is relatively consistent with complex karyotype patterns detected in head and neck squamous cell carcinomas through previous cytogenetic studies.

[Therapy by neutron capture of ocular melanoma: dosimetry and microdosimetry]. / Thérapie par capture de neutrons des mélanomes oculaires: approches dosimétrique et microdosimétrique.

Neutron capture therapy (NCT) aims at destroying cancerous cells with the alpha and 7Li particles produced by the neutron capture reaction on 10B. This note reports on the study of the boron distribution in tissues on an animal model (nude mice) xenografted with a human ocular melanoma after an i.p.injection of 2g/kg of 10B-BPA and in cells cultured in the presence of 530 mumol/l of 10B-BPA. A concentration of 64 ppm of 10B in the active part of the tumour with a ratio of concentrations versus the skin of 3.7 are observed. Investigations on cells reveal the presence of boron in the cytoplasm. The biological, dosimetric and microdosimetric consequences of these findings are discussed.

Frequent amplification of 11q13 DNA markers is associated with lymph node involvement in human head and neck squamous cell carcinomas.

Amplification of 11q13 DNA markers, particularly hst-1/FGF4 oncogene and the bcl-1 locus, was evaluated in 178 head and neck squamous cell carcinomas (SCCs) by Southern blot and slot blot hybridisation. Coamplification of hst-1/FGF4 and bcl-1 genes was found in 57% of primary tumours and in 60% of the 89 metastatic lymph nodes tested. The pattern of amplification was significantly similar in matched sets of primary SCCs and metastatic lymph nodes. Levels of amplification, quantified by densitometric analysis of slot blots, ranged from 2 to 18-fold normal gene dosage. Also, c-myc oncogene (8q24) was found amplified less frequently, since 7% of 169 SCCs tested contained amplification of this gene, the level of which ranged from 2 to 8-fold. Hst-1/bcl-1 gene amplification was observed more frequently in the tumours arising from the hypopharynx. Coamplification of hst-1 and bcl-1 genes was significantly positively associated with tumours with nodal involvement (P = 0.001). Incidence of hst-1/bcl-1 gene amplification is higher in the tumours with a clinical stage III or IV. Hst-1/bcl-1 gene amplification was not related to tumour differentiation or local invasiveness. This prospective study shows that amplification of 11q13 DNA markers is a prominent event occurring in head and neck SCC and may contribute to the pathogenesis and evolution of a subset of patients bearing this type of cancer.

Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas.

Matrix metalloproteinases are believed to play an important role in tumor invasion and metastasis. To examine the expression of the stromelysin 3 (ST3) gene, a new member of the matrix metalloproteinase gene family, 111 head and neck squamous cell carcinomas and 21 metastatic lymph nodes were analyzed by Northern blot. ST3 gene expression was observed in 106 carcinomas and 19 metastatic nodes, but in only 2 of 60 samples of corresponding normal tissue tested in parallel. ST3 RNA, by in situ hybridization, and ST3 protein, by immunohistochemical analysis, were specifically detected in fibroblastic cells immediately surrounding invasive cancer cells. This fibroblastic expression of the ST3 gene is characteristic among the matrix metalloproteinase genes known to be overexpressed in head and neck carcinomas, since stromelysin 2 transcripts were specifically detected in neoplastic cells, and type I collagenase transcripts in both neoplastic cells and stromal fibroblasts. Furthermore, there was a highly significant positive correlation (P < 0.0001) between ST3 RNA levels and local invasiveness by the cancer cells, suggesting that enhanced expression of the ST3 gene may contribute to the neoplastic phenotype in head and neck carcinomas.

[Thyroid function after thyroidectomy for benign goiter. 200 cases explored by ultrasensitive TSH]. / Fonction thyroïdienne après thyroïdectomie pour goître bénin. A propos de 200 cas explorés par TSH ultrasensible.

Based on a retrospective study of a series of 200 thyroidectomies for benign goitre and a mean follow up period of 12 Months, the authors analysed post-operative thyroid function and correlated it with the degree of surgical excision (47 unilateral lobectomies, 91 classical subtotal bilateral lobectomies and 62 extended bilateral subtotal lobectomies). After a presentation of the results in comparison with data from the literature, the timing and threshold for the institution of replacement therapy are examined and the need for prolonged clinical and laboratory monitoring is also stressed. In terms of changes in laboratory criteria only monitoring of spontaneous changes in US TSH allows opotherapy to be avoided or conversely to accurately define the conditions for institution of definitive replacement therapy. The justification of total thyroidectomy in the treatment of multihetoronodular goitres almost totally involving the glandular parenchyma is acknowledged.

[Gastric teratoma in newborn children]. / Les tératomes gastriques du nouveau-né.

In neonates, teratomas infrequently involve the abdomen: among 51 known cases, 39 were gastric teratomas, which account for less than 2% of all germ cell tumors in the neonatal period. Associated malformations are minor, located in the region of the tumor, and apparently less frequent than in other sites. Malignancy is exceedingly rare (a single case) and well controlled as a result of the anti-tumor processes specific to the neonatal period. Gastric teratomas are diagnosed early and can be cured by tumorectomy removing a thin ring of the surrounding stomach wall.

[Thyroid microcarcinoma with a fatal outcome and 34 other unusually aggressive cases reported in the literature]. / Microcarcinome thyroïdien d'évolution fatale et trente-quatre autres cas inhabituellement agressifs rapportés dans la littérature.

A follicular thyroid microcarcinoma was revealed by scapular metastases. Despite treatment, other metastases were the cause of death after a course of 14 years. In the medical literature there are at least thirty-four other examples of follicular or papillary carcinoma of less than 15 mm (previously called occult) that have either given rise to blood-born metastases or have been the cause of death. Present data from light and electron microscopy, immunohistochemistry and microspectrophotometry cannot differentiate between small and large carcinomas. Microcarcinomas (particularly papillary ones) are frequent in the general population and are found in 5% of thyroids. They are usually not aggressive. Those which show vascular or capsular invasion, a lack of lymphoid infiltrate and large cervical lymph node metastases are more likely to have an unfavorable course. The discovery of a microcarcinoma in a thyroid cells for an extended follow-up.

[Therapeutic results in a series of 73 cases of nasopharyngeal carcinoma]. / Résultats thérapeutiques d'une série de 73 cas de carcinome naso-pharyngé.

From 1975 to 1982, 73 cases of nasopharyngeal carcinoma were treated in Strasbourg (Centre Paul Strauss) and Metz (CHR Bon Secours). 34.1% of the patients were of maghrebine origin, the others were europeans. Two histological types were studied: undifferentiated carcinomas of UCNT type, spinocellulars carcinomas of CS type. 60.3% of the patients had T3 and T4 stages, and only 27.4% of the patients had no pathological nodal. As to treatment, radiotherapy is the best choice, because of the deep situation and the frequent involvement of nodals in the nasopharyngeal carcinoma. Taking into account the level of radiation doses, complications remain acceptable. The rate of overall failure is 51.3% at 3 years. The prognostic factors are essentially linked with sex, age, tumor site, site, histological type, T stage of UICC classification and TNM of the same classification, N stage of HO classification, and evaluation of treatment response realised at 4 months. The crude overall survival rate is 52% for patients of the serie.

[Gastroesophageal reflux in asthmatic and chronic bronchitis patients]. / Reflux gastro-oesphagien chez les asthmatiques et les bronchitiques chroniques.

To determine the relationship between gastroesophageal (GE) reflux and pulmonary disease, we studied 21 asthmatics, 30 chronic bronchitics, 6 patients with GE reflux and no pulmonary symptoms, and 10 control subjects; GE reflux was diagnosed by pH monitoring and GE scintiscanning. Frequency of GE reflux in the asthmatics was 57%; in chronic bronchitis it was 56%. Pulmonary function tests did not show any differences between patients with or without reflux. The GE reflux episodes were more numerous but shorter in asthmatics than in chronic bronchitis. Patients with digestive symptoms alone were no different from chronic bronchitis with respect to reflux. The mechanism whereby reflux triggers pulmonary problems was investigated using the following 2 tests: scintiscan for pulmonary aspiration, and esophageal acid infusion (0.1N HCI). Six pulmonary aspirations were detected. Only asthmatics, with or without reflux, showed any significant variations in maximal expiratory flow at 50% and 25% of VC after HCI infusion. Thus, our results show that asthmatics differ from bronchitis patients by the characteristics of their reflux.

[190 cancers of the thyroid with a follow-up of more than 5 years]. / 190 cancers de la thyroïde. Avec plus de 5 ans de recul.

Outcome in 190 patients operated upon by first intention for thyroid cancer is analyzed after follow up over more than 5 years. No deaths due to cancer occurred in 57 cases of papillary cancer, but 7 cases presented pulmonary metastases, while the global-5-year survival rate in 63 cases of vesicular cancer (including 25% with preoperative metastases) was 60%. In the absence of preoperative metastases, ans if well differentiated forms are separated from moderately differentiated forms, the respective 5-year survivals were 88 and 45%. The 1-year survival rate for the 42 cases of anaplastic cancer was 15%, while the 5-year rate for 15 cases of medullary cancer was 80%.

Quantitative bone scintigraphy: usefulness in the survey of patients treated for bone metastasis of prostatic cancer.

The purpose of this study was to develop a quantitative bone scintigraphy (QBS) method in order to evaluate the evolution of bone metastases in patients treated for disseminated prostatic cancer. Data obtained by whole body scintigraphy after injection of 99mTc-methylene diphosphonate enabled us to define three indexes, GR, R1 and R2. They respectively represent the amount of activity retained in the bones, in the metastatic sites and in pathological sites related to the global activity of the skeleton. Repeated QBSs have been performed on 59 patients with prostatic carcinoma treated for bone metastasis with hormonal therapy. Results of QBS are well correlated to clinical findings, particularly pain evolution. In addition, the calculated indexes of QBS made it possible to distinguish three groups of patients according to regression, stabilization or evolution of their lesions under hormonal therapy. QBS seems to be a sensitive and useful test for the evaluation of the therapeutic efficiency on bone metastases from prostatic carcinoma.

Gastroesophageal reflux in patients with asthma and chronic bronchitis.

To determine the relationship between gastroesophageal (GE) reflux and pulmonary disease, we studied 21 asthmatics, 30 chronic bronchitics, 6 patients with GE reflux and no pulmonary symptoms, and 10 control subjects; GE reflux was diagnosed by pH monitoring and GE scintiscanning. Frequency of GE reflux in the asthmatics was 57%; in the chronic bronchitics it was 56%. Pulmonary function tests did not show any differences between patients with or without reflux. The GE reflux episodes were more numerous but shorter in asthmatics than in chronic bronchitics. Patients with digestive symptoms alone were no different from chronic bronchitics with respect to reflux. The mechanism whereby reflux triggers pulmonary problems was investigated using the following 2 tests: scintiscan for pulmonary aspiration, and esophageal acid infusion (0.1N HCl). Six pulmonary aspirations were detected. Only asthmatics, with or without reflux, showed any significant variations in maximal expiratory flow at 50% and 25% of VC after HCl infusion. Thus, our results show that asthmatics differ from chronic bronchitics by the characteristics of their reflux.

[Thyroid carcinoma in an adult cystic teratoma of the ovary with bony metastases]. / Carcinome thyroïdien sur tératome kystique adulte de l'ovaire avec métastases osseuses.

An oophorectomy specimen in a patient aged 36 showed a dermoid cyst with a struma ovarii and what was considered to be a folliculo-trabecular adenoma. Two osseous metastases appeared 4 and 8 years later respectively. The follow-up so far is 15 years. This is the twentieth reported case of mature cystic teratoma of the ovary containing metastating thyroid carcinoma.

Characterization of cell types in human breast tumor primary cultures.

Primary cultures of cells from breast carcinomas were attempted in 74 cases. Growth was observed in 46 cases. Using immunochemical demonstration of keratin proteins (KER), epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), three morphologically distinct cell populations were characterized and described. Two cell types (E- and E'-cells) were identified as epithelial by their positive staining for KER and EMA. The third type (F cells) displayed a negative staining for these two epithelial markers; they were considered as stromal cells (fibroblasts). More than 50% of the cultures consisted of pure epithelial cells. Positive CEA staining was observed only in KER- and EMA-positive cells. Out of the 30 cultures, 15 displayed positive staining for CEA. In 7 of these, 30-50% of cells displayed positive, diffuse staining for CEA. The other 8 cultures consisted of more than 50% CEA-positive cells. Strong and homogeneous positivity was restricted to the E-cells, while in the same cultures, E'-cells displayed heterogeneous and diffuse staining. Efficiency and value of this cell culture system are discussed, in comparison with other human breast tumor cell (HBTC) culture techniques. Identification of growing cells and cellular composition of primary cultures are emphasized.

[Circulating immune complexes in breast cancer]. / Complexes immuns circulants dans le cancer du sein.

The occurrence of circulating immune complexes (CIC) was investigated in serum samples from 139 patients with breast cancer, using the 125I-C1q binding test. In the 85 cases of regional forms, the level of Clq binding activity did not appear to be correlated with the clinical TN stage, nor with the local treatment of the tumor. Conversely it was clearly elevated in the 13 cases of inflammatory breast tumors, and the decrease of CIC at the post-chemotherapy, but pre-surgical stage may involve the inflammatory signs in this augmentation of CIC. Frequency of occurrence and levels of CIC were slightly increased in the 41 metastatic breast cancer patients when compared to the cases of local breast carcinoma. In the disseminated forms, increase, no change, or decrease of CIC levels showed a poor correlation to progression, stabilisation, or improvement of the disease. CIC seems to be of slight prognostic value in breast cancer with local forms, but regarding progression of the disease, metastatic breast cancer patients with elevated CIC did not prove to be unfavorable group. So far, CIC did not appear to be a tumor marker or an evident prognostic factor of clinical relevance in breast cancer. Assays for antigen-specific CIC might be of greater clinical significance, in breast cancer, than the antigen non specific assays available at present.