Bulletin du Cancer

Biomedical advances to further the quality of life (QL) of cancer patients must nowadays be complemented by psycho-social evaluation and intervention. The challenge is to quantify the qualitative and to objectivate the subjective. To evaluate QL during treatment of individual patients, open interviews are unsurpassed. However, to measure QL of patient groups, questionnaires are necessary. Some examples from the QL literature illustrate the main drawbacks of questionnaires: lack of sensitivity, specificity, and iterative applicability. To circumvent these problems, it is suggested to add a global self-assessment of QL to questionnaires. Such an instrument, Anamnestic Comparative Self-Assessment is briefly described.

We evaluated the contribution of an epirubicin-based adjuvant chemotherapy on disease-free survival (DFS) in poor prognosis, node-negative breast cancer (BC) patients. Poor prognostic factors were defined as: pathologic tumor size >or= 4 cm, estrogen-receptor negative, and progesterone-receptor negative. Scarff-Bloom Richardson grade 2 tumors must have two of these factors, and only one in case of grade 3. Between 1988 and 1994, 328 patients were randomized to receive either no systemic treatment (control, n = 161), or fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2), 6 cycles every 21 days (FEC50, n = 167), without any hormonal treatment. The median follow up was 114 months. The 10-year DFS rates were 64 and 71%, respectively (p = 0.23). In the Cox regression model, independent prognostic factors of relapse were the number of nodes examined < 10 (p = 0.002), BCS (p = 0.01), and premenopausal status (p = 0.04). In this model, the relative risk of relapse was 1.46 (CI95 %: 1.05-1.87) in favor of FEC50. In patients who underwent BCS, 21 % developed a local relapse (24 versus 18 %, respectively). The 10-year local DFS was 70.5 and 79.3 %, respectively (p = 0.27). The 10-year overall survival was not different (74.1 versus 70.7 %, p = 0.82). After 10 years of follow-up, the FEC50 regimen reduced the risk of relapse in poor-prognosis node-negative BC patients. The incidence of local relapse was high, and probably related to inclusion criteria. Epirubicin was probably underdosed in such patients, and ongoing studies using 100 mg/m(2) of epirubicin will give us the answer in a near future.

Rubidazone is a semisynthetic antibiomitotic close to daunorubicin and doxorubicin. Fifty two patients with various advanced cancers received rubidazone intravenously at the initial unitary dose of 200 mg/m2 in a single injection at three week intervals; this base line dosage had been adapted in function of leuko-platelet variations observed between the injections. An objective improvement was noted in 18 patients out of 51 evaluable patients (34% of the cases), 6 times the regression of tumoral volume was greater than 50 per cent but not complete (3 breast adenocarcinomas and 3 lymphomas). Manifestations of intolerance-toxicity were minor on the haematologic side (32%); however, they were relatively frequent from the digestive (63%) and general (82%) point of view; symptoms of cardiac disturbances (21%), responsible for the discontinuation of the chemotherapy, necessitate careful attention in the management of the treatment. The comparison of the results of this trial with those obtained by trials using other drugs belonging to the same chemical family don't show, for solid tumors, any difference in efficacy between rubidazone, daunorubicin or duborimycin; however, the difference is very striking with doxorubicin which showed more efficacy (6.5% as 29% of regression greater than 50%). Owing to the conditions of admission and the very strict criteria of analysis in this study, it would seem useful to go into details regarding the interest of rubidazone in lymphomas (only one failure has been recorded out of 6 treated cases).

Pigmented melanomas were induced in the Syrian golden hamster by oral administration of 9, 10-dimethyl 1,2-benzanthracene. The primary tumors were grafted into new animals to obtain a series of transplantable tumors. The grafted tumors show the malignant characters which are not present in the primary tumors. These were studied clinically, histologically and ultrastructurally. We believe that this transformation occured perhaps as a consequence of the selection of cells which have a more prominent tendency toward malignancy. This selection could be explained by a greater resistance of lesser pigmented melanocytes or by their weak immunologic capacity. The malignant potential of these cells could eventually be correlated with the presence of viral particles which act as cocarcinogens.

We have studied and compared the 1,25-dihydroxyvitamin D3 receptor (RD3) content of 154 human digestive carcinoma with the normal mucosa one, removed at distance from the same surgical specimen. The distribution of biopsies is as follows: 5 oesophagus, 10 stomach, 6 small bowel, 35 right colon, 47 left colon, 40 rectum and 11 pancreas. RD3 were measured by the Dextran Coated Charcoal method and characterized by sucrose gradient ultracentrifugation. One single class of high affinity binding sites (kD = 1.5 +/- 0.7 x 10(-10) M) was defined, with a sedimentation coefficient of approximately 3.4 S. The RD3 was present in the 6 samples of small bowel and in 82% of whole normal mucosa, whatever their localization along the digestive tract and pancreas, while in the tumoral tissue, the RD3 was positive in only 32% of the cases. In these tumor specimens the incidence decreases from 64% in the right colon to 27% in the left colon and only 15% in the rectum (P less than 0.001). RD3 rates vary slightly with the localization and are of the same level in normal tissues and in tumors: 10-314 (median = 59) vs 13-175 (median = 64) (P greater than 0.005) respectively. No significative variations relating to age or sex of patients were found. However, all RD3 positive tumors from left colon and rectum were well differentiated histologically. These results show that the normal colonic mucosa is a potential target for 1,25-dihydroxyvitamin D3, which can play a role in the metabolism of calcium and other ions. They also suggest that vitamin D3 could be a modulator of colorectal cell growth and differentiation and its receptor is frequently lost during malignant transformation.

Résumé De mars 2003 à avril 2004, 1 289 patientes ayant un carcinome canalaire in situ (CCIS) du sein ont été colligées au cours d’une enquête nationale multicentrique prospective. Pour chaque cas, les données clinicoradiologiques, histopathologiques et les modalités de traitement ont été recueillies. L’âge médian était de 56 ans. Le diagnostic a été réalisé par mammographie dans 87,6 % des cas. Les patientes ont eu une mastectomie (M), une chirurgie conservatrice (CC) exclusive et une CC avec radiothérapie (RT) dans 30,5, 7,8 et 61,7 % des cas. Un prélèvement du ganglion sentinelle (GAS) et un curage ont été réalisés dans 21,3 et 10,4 % des cas et une hormonothérapie délivrée chez 13,4 % des patientes. Le grade nucléaire était bas, intermédiaire et élevé dans 21, 38,5 et 40,5 % des cas. L’exérèse a été considérée complète dans 92 et 88,3 % des cas (groupe CC et CC + RT). On note d’importantes variations régionales dans les traitements, avec des taux de M entre 20 et 37 % des taux de RT après CC entre 84 et 96 % et une hormonothérapie entre 6 et 34 % des cas. Cette étude a permis une évaluation des modalités de prise en charge des CCIS en France, avec des corrélations précises entre les facteurs histopathologiques et les traitements ; elle montre une variabilité interrégionale, comme dans les pays anglo-saxons.

We report our experience of CBDCA-CPM combination chemotherapy as first line therapy in 101 ovarian cancers. The therapeutic scheme was: initial cytoreductive surgery followed by six chemotherapy cycles (CBDCA 400 mg/m2/d IV dl, CPM 600 mg/m2/d IV dl, dl = d21) and second-look laparotomy. The initial stages were four Ic, three IIa, four IIb, four IIc, 15 IIIa, 28 IIIb, 23 IIIc and 20 IV. After initial surgery, there were 39 macroscopic residual diseases superior to 2 cm, 26 macroscopic residual diseases inferior or equal to 2 cm, four microscopic diseases and no residual disease in 30 cases (unknown in two cases). The overall response rate to chemotherapy was 83% with 56% histologic complete response rate. The main toxicity was haematological with 60% of leucopenia grade III-IV, 52% of thrombopenia grade III-IV. Age at diagnosis, residual disease after first look surgery and length of CA 125 normalization were significant prognostic factors for survival in this series.

Between 1994 and 2004, 104 patients with epithelial advanced ovarian cancer were treated in the central region of Tunisia (81 stage III and 23 stage IV). Average age of patients was 54 years. Primary surgery was optimal (residue < 2 cm) in 40 cases (38,5 % of patients). Fifty nine patients were treated with neo adjuvant chemotherapy based on platinum, associated to paclitaxel in 19 % of cases. Interval debulking surgery interested 30 patients and was optimal in 66,7 % of cases. Global survive was 57 % at 2 years and 27 % at 5 years. Survival rate for patients treated with optimal debulking surgery was similar to that of those treated with initial optimal surgery. Prognostic factors for a better survive were : age < 40 years (p < 0,05), stage III (p < 0,01), a normal level of CA125 after surgery (p < 0,01), primary optimal initial surgery (p < 0,02) and response to neoadjuvant chemotherapy (p < 0,01). Prognosis of ovarian carcinoma is worse in Tunisia as like as in the world. In case of extensive tumor, the neoadjuvant chemotherapy before interval debulking surgery permits to improve survive and quality of life in some patients.

To evaluate the role of adjuvant therapy in survival and to identify important prognostic factors in uterine sarcoma. One hundred five patients with uterine sarcoma have been retrospectively researched to evaluate the results in this tumor group. 43.8% had leiomyosarcoma, 28.6% had endometrial stromal sarcoma and 27.6% had a malign Mullarian mixed tumor while the distribution according to the histological subgroups were found to be 42.6,16.2 and 41.2% in grade I, II and III tumors respectively. 38.1% of the patients had Radiotherapy, 18.1% had chemotherapy and 12.4% had chemoradiotherapy in addition to surgery. The distant metastases rate is 30% and the local recurrence is 16.2%. All the local recurrences and 90% of the distant metastases have occurred within the first two years. The disease free survival and overall survival rates at 3rd and 5th years are 54.46, 49.88, 54.63 and 51.09% all respectively. In our series, univariate analysis for overall survival demonstrated statistical significance for radical surgery, grade, stage, age, menopausal status and presence of RT in treatment modality, but; histology, number of mitosis, tumor size demonstrated no significance. Our data favors treatment for uterine sarcoma with radical surgery plus radiotherapy alone over 54 Gy or with chemotherapy.

One hundred and six patients with stage Ic to IV ovarian carcinoma were treated by a protocol consisting of optimal debulking surgery followed by 9 cycles of CHAP chemotherapy. Clinical response was confirmed by a second-look procedure. Sixty-nine patients (65%) responded with 54 histological complete remissions (50.8%). Nineteen patients did not receive any complementary treatment due to a negative reaction, or prolonged neutropenia. Seven patients received maintenance chemotherapy, 10 an abdominal radiotherapy, 22 intraperitoneal chemotherapy and 11 autologous bone marrow transplantation. The 5-year survival rate was 32.5% and disease-free survival rate was 39.7%. Prognostic-factor analysis showed that age, initial staging, residual disease and cytological grading were significant. The authors propose a classification based on the risk of relapse, and different therapeutic indications for improving response rate and patient survival.

pS2 protein assay was performed with Elsa-pS2 kit (CIS-Biointernational) on a group of 1,065 patients with operable breast cancer who underwent breast surgery in the years 1982 through 1990. The median follow-up was 57 months. This group included exclusively infiltrating ductal carcinoma with primary surgery. Age mean was 58 yr; T0-T1, 33.6%; T2-T4, 66.4%; Differentiation grade I, 29%; node negative, 53%; estrogen receptor (ER) positive, 62.4%; progesterone receptor (PR) positive, 55.2%; mean tumor size, 2.4 cm; local recurrence, 5.2%; metastasis, 17.5%. pS2 values varied from 0.1 to 707 ng/mg of cytosol protein (median, 5.6; mean 24.5; 95th percentile 112 ng/mg p). There was no significant relationship between the mean level of pS2 and age, tumor size, nodal status, whereas pS2 was related to histological grade (P < 10(-3)), ER (P < 10(-5)), and PR (P < 10(-5)). By using 2 ng/mg p as pS2 cutoff, 77/391 (19.7%) of ER+PR+ tumors were pS2-, and 122/345 (35.4%) of ER-PR-tumors were pS2+; with this cutoff, a strong relationship existed between pS2 and overall survival, but not between pS2 and relapse-free survival. With Cox multivariate analysis, pS2 protein was classified after lymph node status, histological size, ER, differentiation grade, age, clinical stage, PR. In patients with axillary lymph node involvement (N+), pS2 status could discriminate between good and bad prognosis, specially for patients with small tumors (< 2 cm) and with less than seven invaded nodes. This study showed that pS2 protein was a poor prognostic factor in comparison with classical factors.

One hundred and eight patients with residual epithelial ovarian cancer at second laparotomy, after first line plastine-based chemotherapy were treated with intraperitoneal rHU-interferon-gamma at a dose of 20 x 10(6) U/m2, twice a week for 3-4 months. 86% of the patients had residual macroscopic tumors and 33% bulky tumors (> 2 cm). From the 99 evaluable patients, 62 had an evaluative third laparotomy and nine additional patients a laparotomy. Complete pathologic and global response rates to interferon-gamma were 23 and 32% respectively. Age and tumor size were independently correlated with treatment response. Patients (n = 41) under the age of 60 with a tumor size less than 2 cm had a complete and global response rate of 42 and 54% respectively. Interferon-gamma was equally effective in chemo-resistant and chemosensitive tumors. Median duration of response was 21 months and median survival of responder patients was 86% at 2 years. In multivariate analysis, response to interferon-gamma was the most prominent prognostic factor of this population of patients with residual ovarian cancer.

One hundred and nine patients with limited small cell lung carcinoma were entered in a phase II study alternating six cycles of combination chemotherapy and three courses of mediastinal radiotherapy. Chemotherapy consisted of doxorubicin 40 mg/m2 day 1, etoposide 75 mg/m2 days 1, 2, 3, cyclophosphamide 300 mg/m2 days 3, 4, 5, 6, and methotrexate 400 mg/m2 day 2 (+folinic acid rescue) or cisplatin 100 mg/m2 day 2. The total mediastinal radiation dose was 45 or 55 Gy. A 6 to 8 cycle maintenance chemotherapy followed this induction protocol. The complete remission rate at the end of the induction therapy was 79%. The local recurrence rate was 25% and the distant metastases rate was 52%. Median survival is 17.2 +/- 1.2 months and survival rate at 3 years is 26%. Lethal toxicity occurred in 3% of patients during induction therapy, and long term survivors are being evaluated. Our results justify further investigations with this alternating schedule.

Topoisomerase I inhibitors are a new therapeutic class whose clinical evaluation began a few years ago; Irinotecan (CPT-11) gave interesting results in colon cancer; side effects were neutropenia, diarrhea, vomiting and a cholinergic syndrome. Topotecan was useful in lung and ovarian cancer; side effects were mostly hematologic. Undergoing studies concern dose optimization, mode of administration and therapeutic associations.

Hodgkin's disease (HD) in children of 4 years of age or younger is seldom reported. It seems more frequent in developing countries. We report on 11 cases out of 115 cases of HD in patients of 15 years of age or younger observed between 1980 and 1991. The youngest patient was 29 months old and the median age was 2 years 11/12. The male/female ratio was 2.6. Mixed cellularity was found in six cases, lymphocytic predominance in two cases and nodular sclerosis in two cases. B symptoms were observed in four cases. Four patients had stage II, three stage III and four stage IV disease. Chemotherapy consisted of MOPP/ABVD in all cases. One patient received mantle field radiation therapy. Of ten evaluable patients, seven achieved complete remission, three patients were lost to follow-up in partial remission before achieving the treatment program. There were no relapses so far and no death attributable to toxicity. The follow-up ranges from 2 to 8 years. These data indicate the high frequency of HD in very young patients and suggest that chemotherapy alone is very efficient in this subset of patients.

Epithelial mesenchymal transition (EMT) is a fundamental mechanism controlling multiple events during embryonic development. Mesenchymal cells appear transiently in some diploblasts, the most primitive species characterized by two epithelial layers. Since almost 800 million years, EMT has been conserved throughout evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Most interestingly, specific molecular pathways have been conserved in many different species to drive EMT. In the animal kingdom, a recurrent theme is that EMT controls the intercellular adhesion machinery and the dynamics of its associated cytoskeleton. EMT pathways are also tightly connected to determination and differentiation programs, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is now shown to operate during the early stages of carcinoma invasion leading to blood or lymph vessel intravasation of malignant cells. The converse mechanism - mesenchymal-epithelial transition (MET) - then operates at distant sites from the primary tumor to form macrometastases from isolated micrometastatic cells. The mesenchymal-like state of carcinoma confers stemness, protection from cell death, escape from immune response and, most importantly, resistance to conventional and targeted therapies. Our laboratory has designed an EMT high-throughput screen of small molecular weight compounds and biologics in order to establish new therapeutic approaches that interfere with the plasticity of carcinoma cells. New therapeutic interventions are envisioned to delay tumor recurrence.

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.

Following surgery for epithelial carcinoma of the ovary, FIGO stages IIc, III and IV, 110 patients received chemotherapy in one of four treatment regimens (Melphalan; Cyclophosphamide-Methotrexate-Fluoro uracil; Cyclophosphamide-Cisplatinum; Cyclophosphamide-Cisplatinum-Fluoro-uracil). Melphalan alone was as effective as combination chemotherapy and less toxic. The study confirms that the survival duration is inversely correlated to the stage of the disease and to the amount of residual disease following surgery. It also confirms the role of the "second look" surgery in the evaluation of the response to chemotherapy, and in the overall management of the disease.

Anaemia is one of the most dreaded complications among patients with malignant pathologies. Its causes can be varied and whatever its severity, the impact on the quality of life of the patient remains essential. However, the epidemiologic data concerning anaemia are very few in the literature. This is why we carried out a large national survey about the prevalence and the management of anaemia among patients with malignant diseases. The F-ACT (French Anaemia Cancer Treatment) study is a retrospective observational multicentric study conducted with 178 experts practicing in 112 centers or units treating patients with solid tumours and/or malignant haematological diseases. Control over one day standard of consultation for each questioned expert, 2 782 patients were enrolled, including 1 892 (68%) patient with solid tumour and 890 (27%) patient with malignant haematological disease. The median age was 61 years (range : 18-93 years) including 1 335 women (48%) and 1 447 men (52%). A the date of enrollment, the median level of haemoglobin (Hb) was 11,6 g/dl (range: 5,2-18,5 g/dl) and 44% of patient had a level of Hb < 11 g/dl. An anaemia was found in all the cancer localizations and whatever the stage or the therapeutic status of the disease. Approximately 2/3 of the anaemic patients received treatment by erythropoiesis stimulating agent (ESA) and approximately 17% of them did not receive any specific treatment for this anaemia. The median level of Hb at the introduction of the ESA was 10 g/dl. These results, compared with those reported in study ECAS (European Cancer Anaemia Survey) in 2001, seem to show an improvement in the management of anaemia and the use of the ESA, in particular an earlier introduction of this type of treatment since the appearance of anaemia.

One thousand two hundred and twenty-five partial breast resections, examined in serial gross sections have been retrospectively reviewed. The percentage of benign lesions in comparison with malignant lesions is 70 per cent-30 per cent. The percentage of malignant lesions is maximum (43%) in clustered microcalcifications which are so the best criteria of malignancy. A diagnosis of non infiltrating carcinoma has been misdiagnosed at the first examination in 6 per cent of cases. This misdiagnosis is partially explained by very small foci of carcinoma and recent recognition of certain histological types of early carcinoma. It must be noticed the unsuspected frequence of carcinoma (17%) detected by random in ipsilateral breast tissue from plastic surgery, after controlateral reconstruction for carcinoma. The analysis of benign lesions associated with carcinoma shows a significative frequent association with carcinoma in two types of lesion: radial scar and late phase of blunt duct adenosis.

Unlabelled: The aim of this study was to identify clinical, biological or morphological prognostic factors in 113 patients with HCC in terms of survival. All patients (100 men, aged 65 [28-85], 95% cirrhosis) were diagnosed between 1982-1990. Mean survival time was 21 +/- 3 weeks. Eleven (over 25) variables were isolated by univariate analysis. A multivariate survival analysis (Cox regression model) disclosed that serum creatinine (p = 0.0002), alkaline phosphatase (p = 0.02) and Okuda's stage (p = 0.025) were independent predictors of survival. Comparison of survival curves for different values of these prognostic variables allows division of patients in three groups of prognostic significance in terms of survival (p < 0.05). Conclusion: these results facilitate stratification of patients with HCC to design and evaluate future controlled trials.

In a population of 2,372 consecutive cases of breast carcinomas, 114 cases of clinically occult non palpable breast lesions have been diagnosed (4.8%). 51% of them can be considered as minimal breast carcinomas (MBC) by Gallager's definition and 72% by that of the American College of Surgeons; whatever the definition this category has an excellent prognosis with 11% of axillary invasion for the infiltrating tumors under 5 mm and 7% for these under 10 mm and 100% 5-year survival rate in both cases. The category of infiltrating tumors of over 5 mm and 10 mm also has a good prognosis with 21% and 26% of axillary lymph node invasion respectively, with a survival rate of 83.82% and 77.92%. The comparative histological analysis shows at this stage an increase in the intraductal carcinomas (IC) (35% instead of 6% for the palpable carcinomas), the infiltrating ductal carcinomas with predominant intraductal component (IDCPIC) (19% instead of 12%) and the tubular carcinomas (11% instead of 3%). The study of the peritumoral and environmental mastopathy and the histological repartition, confirms the classical histogenetic arguments regarding breast carcinomas.

Seventy children (3.7 +/- 3.3 y) with definitely confirmed diagnosis of neuroblastoma had 115 whole body scans carried out 24 h after injection of 3.7 MBq/kg of I-123 mIBG (83 scans) or 0.7 MBq/kg of I-131 mIBG (17 scans) or 0.9 to 4.5 GBq of I-131 mIBG (15 post-therapeutic scans). The scans were interpreted as positive in the presence of any non-physiological uptake area or of any bone uptake of the tracer, even at the level of the metaphyseal complex. For the primary tumour, the sensitivity of mIBG scans was 73%. Ten false negative patients had an overlap of the tumour with the bladder or heart images (4 cases) or with positive metastatic images (6 cases: liver, spine). Three false negative patients had neuroblastomas which did not secrete catecholamines. The specificity of mIBG was 94%. In our opinion, mIBG scans have a complementary role to assess the activity of post-therapeutic remnants. For the detection of hepatic and lymph node metastases, the sensitivity was about 50% and the specificity was 100%. The standard used for the detection of bone marrow metastases was the cytological and histological examination of 10 bone marrow aspirations and one or more biopsies (CHBMS). The sensitivity of mIBG scans was 90% and the specificity 68%. However, reviewing the data from the 16 false positive scans, we found 11 definitely proven bone metastases, 3 biological relapses and 2 cases of delayed abnormal CHBMS supporting the positivity of the mIBG scans, raising the specificity to 100%. Tc-99m diphosphonate bone scans had a sensitivity of 78% and a specificity of 51%. We suggest that positive mIBG scans may save other procedures since our data do not support false positive detection of bone or bone marrow metastases. In contrast, patients with negative mIBG findings should be further explored.

Between 1976 and 1986, we have treated 115 patients with base of the tongue carcinomas. The mean age was 53.8 years. Staging system used was the UICC TNM classification of 1979. 70% of the tumors were T3 or T4 and 42% had N2 or N3 lymph nodes. Loco-regional treatment was irradiation alone (98/115) or surgery and post-operative radiotherapy (17/115). 67 patients received an induction chemotherapy. 3 and 5 years actuarial survival was 25% and 23%, and 42, 48, 20 and 17% at 3 years for T1, T2, T3 and T4 lesions respectively. Local control rate at the primary sites was 55%, local control rate in the neck was 78%. Distant metastases occurred for 10% and 8% had a second primary. Nodal status was the only other prognostic factor. Local control rate obtained with irradiation alone was not good. For limited tumors T1 and T2, a better local control rate can be obtained with interstitial therapy or surgery.

Breast cancer specimens from 115 patients were assayed for the presence of estrogen receptors (ER) using a monoclonal antibody (H222 SP gamma) and an immuno-histochemical method ER-ICA. The specific ER immuno-staining was observed in cell nuclei. The intensity of the immuno-staining level (ISL) and the percentage of positive cells (PC) variable within tumors tissue, were graded (from 0 to 3): intensity level (IL) and percentage of positive cells (PC). (IL + PC) were correlated to biochemical ER assay using radiolabeled ligands ER - RLA. Both ER - ICA and ER - RLA were correlated in 87.9% of the cases. Discrepancies between both assays appeared mainly due to heterogeneity of the tissue samples. From this study it is concluded that ER - ICA is a reliable histochemical method since well correlated with biochemical assay, easily and rapidly performable, and constitutes a new approach method for ER detection in tissue, particularly valuable in minimal breast cancer, and precancerous lesions.

Pilot study of combined radiosurgical treatment of carcinoma of the rectum. 116 patients underwent surgical excision of a carcinoma of the rectum after concentrated preoperative irradiation giving 40 grays in 18 sessions over the pelvic tumour volume. The operation in 79 cases consisted of abdomino-perineal excision and in 37 cases of anterior resection. The node involvement noticed on the resected volume is of 16,4 per cent. The operative mortality is of 7,7 per cent and the complications due to radiotherapy itself mainly a delay in cicatrisation. Survival rate at five years is of 60 per cent. Preoperative irradiation seems to be realy a benefit in the treatment of rectal carcinoma.

Among 120 cases of cerebral metastases, 62 primary sites were found. The diagnosis of the primary site was confirmed: --after the first investigations in 48 cases (in 90% of cases by anamnestic inquiry, clinical examination or chest X ray); --by the evolution of the disease in 5 cases; --by autopsy in 9 cases. The most frequent primary sites were lung (45%), digestive tract (17.7%), melanoma (8%) and ovary (6.5%). Among the identified cases, 25 received treatment for their primary cancer, but only 4 had a surgical resection. There was no significant difference in mean survival between the 2 groups (defined as primary site known or unknown); over all mean survival was 8 months. The early discovery of cerebral metastases suggests the advanced state of the disease. Therefore, investigations which cause the patient to suffer do not seem justified merely for research purposes.

Therapeutic monitoring of 120 hours continuous 5-fluorouracil associated with cisplatin. For 31 patients treated by continuous 5-fluorouracil with cisplatin, a therapeutic monitoring of 5-fluorouracil is performed, based on the 48 first hours area under the curve (AUC) and the total AUC. The 5-fluorouracile taylorization allows to reduce some toxicity's while preserving an efficiency (objective responses 42%). Many patients are considered with potentially low 5-fluorouracile clearance. Dose reductions of 5-fluorouracile are frequent, reach 50% during the third cure and allow the achievement of targeted AUC. The role of cisplatin in this necessary reduction of dose is unknown.

Male breast cancer is rare compared to its female counterpart representing less than 1% of cancer in men. The objective of our retrospective study is to report the epidemiologic and clinical profile and to analyse the therapeutic results and prognostic factors in a Tunisian population collected during a period of 20 years at a single institution. We collected from 1979 to 1999, all the histological confirmed male breast cancers treated at our institution. We analyse the following data: age, clinical presentation and features, therapeutic protocol, results and prognostic factors. Survival was done with the Kaplan-Meier method and comparison with the log-rank test. 123 cases of male breast carcinoma were collected with a median age of 65 years. Most patients (62.2%) have an advanced T4 disease with bilateral lesions in 4 cases. Infiltrating ductal carcinoma represent 91% of all tumours. 85% of tumours expressed hormonal receptor. The treatment consisted in a radical mastectomy in 93 cases (84%) followed by radiotherapy, chemotherapy and in many cases by hormonotherapy. After a median follow up of 26 month, 22 patients presented loco regional recurrence and 41 metastases. Estimated 5-year survival rate was 62%. The presence of metastasis, nodal involvement, advanced disease, and grade affected survival. Male breast cancer represent at our institution 1 % of the male cancers treated comparable to the literature data. T4 tumours represent a higher rate, the treatment approach is the standard applicable in breast cancer; prognostic factors are the classical one like breast cancer in women.

Multidrug resistance (MDR) is characterized by the overexpression of P-glycoprotein (Pgp), which is responsible for decreasing drug uptake and/or increasing drug efflux in resistant cells. Although Pgp has a broad-spectrum specificity, this protein seems to react preferentially with amphiphilic and cationic molecules. Rhodamine 123 (R123) is widely used as a marker for mitochondria in living cells and its uptake is dependent on plasma and mitochondrial membrane potential. More recently, cross-resistance to R123 in cells resistant to adriamycin has been demonstrated and a correlation between expression of Pgp and reduced intracellular accumulation of R123 has been shown. The measurement of R123 uptake or efflux allows the characterization of cells displaying a MDR phenotype with overexpression of Pgp, even with low levels of resistance. Other proteins have now been identified which play a role in resistance and in drug transport, including MRP. For this reason we need to determine if R123 is transported only by Pgp or if R123 is a substrate for transport by other drug resistance proteins as well. We also discuss the possibilities of using several techniques based on fluorescence with R123 in order to fully characterize cells by measuring both Pgp activity and its presence/localization.

The neoplasias resistance to chemotherapy is mainly due to multidrug resistance phenomenon (MDR) mediated by an ATP-dependent efflux pump called P-glycoprotein. This function can be reversed by many multidrug reversing agents so numerous chemotherapy regimens have been initiated in malignancies. To make sure the success of these protocols it is necessary to detect as soon and as certain as possible the presence of resistant cells among malignant population. We have chosen to evaluate functional test using rhodamine 123 in this aim in view. We have made various mixtures of resistant ans sensitive cells of three cell lines. Rhodamine 123 allows to detect 1% of resistant cells among sensitive cells. Influence of dead cells on the interpretation is discussed.

The value of early CA 125 assays and analysis of its diminution kinetics during chemotherapy have been the subject of numerous studies. In contrast, routine utilization of CA 125 assays in clinical practice remains controversial or at best difficult to apply because the definitions and prognostic values associated with CA 125 assays vary greatly from one study to the next. This study was designed to determine whether serial CA 125 assays during induction chemotherapy for ovarian carcinoma, using simple evaluation criteria directly applicable in routine clinical practice such as early normalization (level < 35 UI/ml) are predictive of response to treatment or improved survival. This retrospective longitudinal analysis concerned a historical population of 140 patients with ovarian carcinoma stages III and IV treated at the Antoine-Lacassagne Cancer Center between 1978 and 1993. All the patients were treated by chemotherapy based on platinum salts every 21 days. Serum CA 125 assays were performed both before and after surgery and during each chemotherapy cycle. Eighty-four patients had a pre-operative CA 125 assay. No difference is observed in survival as a function of their preoperative CA 125 concentration (p = 0.4). Sixty-seven patients had a CA 125 assay the 6th week after initiation of chemotherapy, 62 the 9th week and 47 the 18th week. Normalization of CA 125 the 6th week (p = 0.0001), the 9th week (p = 0.0008) and the 18th week (p = 0.03) after the initiation of the chemotherapy cycle are correlated with survival. The median survival in our study is 42 months if the CA 125 is below 35 UI/ml the 6th week versus 13 months if the level of CA 125 remains more than 35 UI/ml. In all, 66 of the 105 FIGO stage III patients underwent second-look surgery. Normalization of CA 125 levels is correlated with the absence of any gross residual tumor at the second-look procedure, the 6th week of chemotherapy (p = 0.0019), the 9th week of chemotherapy (p = 0.0003) and the 18th week of chemotherapy (p = 0.0015). This correlation is not confirmed when the presence of histologic residual tumor in biopsy specimens obtained during second-look surgery is taken into consideration. Overall, 88% of patients whose CA 125 levels failed to normalize during evaluation at the second cycle of chemotherapy have residual tumor at second-look surgery. Outside of clinical trials, repeated early CA 125 assays to determine the chemosensitivity and the prognosis of patients with ovarian carcinoma are of little interest compared to a single CA 125 assay at the 6th week after initiation of chemotherapy. This approach seems to be a good compromise between the information sought and its practical use. However the interest of early modification of chemotherapy regimen after 2 cycles, if the level of CA 125 remains more than 35 UI/ml, will have to be showed.

CA-125, a serum marker of epithelial ovarian cancer, was studied by a radioimmunometric method: the sensitivity and specificity of the assay was studied in 260 patients with non ovarian carcinomas and 120 patients with non malignant diseases. The ideal threshold value has been discussed. Levels higher than 20 UI/ml (cut-off value) have been found in 53% of cases. Sensitivity falls to 25% if the cut-off value is 65 UI/ml. The serum levels correlated well with the existence of a metastatic disease (P less than 0.001). A second assay allowed to study in 163 cases the correlation between the variations of the serum level and the clinical evolution; a good correlation was found except in case of stable disease. High levels have also been found in patients with benign diseases, most of all in cases of pneumonia and severe liver cirrhosis.

The prognostic value of CA 125 initial half-life in serum (Tb) during the first cycles of first-line chemotherapy was studied in 62 patients with stage III or IV ovarian cancer. The half-life was strongly correlated; 1) with the rate of biological remission (P < 0.001). This one was respectively equal to 94.7% when Tb was lower than 20 days, 66.6% when Tb was between 20 and 40 days and 7.7% when Tb was higher than 40 days; 2) with the rate of histological remission (P < 0.001) which was equal to 66.6% when Tb was lower than 13 days; 3) with the speed of recurrence growth measured by the doubling time (dT) of CA 125. The median of dT was equal to 182 days when Tb was lower than 13 days, 63 days when Tb was between 13 and 20 days (P < 0.02) and 38 days when Tb was higher than 20 days (P < 0.001); 4) with the duration of disease-free survival (DFS) (P < 0.001): the medians were equal to 23.9 months, 18.0 months, 12.0 months, and 5.5 months, respectively, when Tb was lower than 13 days, between 13 and 20 days; 20 and 40 days, and higher than 40 days; and 5) with the duration of overall survival (OS). The probability of survival at five years was equal to 48% when Tb was lower than 13 days. This probability falled to 13%, 12%, and 8%, when Tb was respectively between 13 and 20 days, 20 and 40 days and higher than 40 days. Multiple regression analysis showed that CA 125 half-life was the most important prognostic factor for DFS and OS. Analysis of correlation allowed to identify a relation between: 1) dT and Tb [dT = Tb/[-0.305 + (0.0388)(Tb)]; P < 10(-4)]; 2) the slope of CA 125 initial regression (P) and DFS [DFS = 201.9e (-16.64*P); P < 10(-8)]; 3) P and OS [OS = 285.0e(-17.00*P); P < 10(-7)]. The initial CA 125 half-life measured during the first cycles of first time chemotherapy seemed to be a critical predictor of response to therapy.

The prognosis of locally advanced cancers of the head and the neck is pejorative, particularly when nodal involvement is present. In order to improve local control and to reduce distant failures, we have treated stages III and IV patients with induction chemotherapy. From May 1986 to November 1992, 125 patients with squamous cell carcinoma of the head and neck were treated by induction chemotherapy: cisplatine (100 mg/m2 at J1) and 5FU (1 g/m2 from J1 to J5 in continuous infusion) every 21 days subsequent local therapy consisted of surgery for patients with resectable disease, and/or radiotherapy. One hundred and nineteen patients were assessable (110 men and 9 women) with a median age of 57 years (range: 36-78). All patients had performance status inferior or equal to 2. According to the TNM of UICC classification 50 patients were stage IV (42%), 61 stage III (51%), 7 stage II (6%) and a stage I (1%). One hundred (84%) patients have received at least 3 cycles of chemotherapy. Seventy-four patients (62%, IC: 60.4-63.5) had clinical objective response (complete response (CR) or partial response (PR)) with 24 patients (20%) CR and 50 patients (42%) PR. Local therapy included surgery in 81 patients (68%) and radiotherapy alone in 42 patients (35%). Overall, 103 patients (87%) were rendered clinically disease-free by treatment on this protocol. The toxicities of cisplatine and 5-FU chemotherapy consisted predominantly of myelosuppression (5%) and renal toxicities (4%) and were moderate as described for this combination. At a median follow-up of 32 months, the median survival is 38 months (CI 95%, 18-54 months), and the median time to progression is 62 months. The oropharynx localization reached statistical significance for survival rates (Log-rank test, p = 0.02).

Although the range of applications for antisense oligonucleotides is vast, current research concentrates mainly on virology and oncology. We have conducted in vivo and in vitro investigations of radiolabelling and biodistribution of a 22-mer phosphodiester oligonucleotide injected in athymic mice bearing xenograft of human mammary tumor (coculture: MCF7 and fibroblasts strain AF-11). Tumor/healthy tissue ratio of the 22-mer phosphodiester oligonucleotide fixation is high during the 24 hours after injection instead of fast elimination.

These studies reaffirm the previously suggested immunochemical differences between CEA and CEA S, and suggest that the differences result from intrinsic heterogeneity of glycoproteins within given tumors rather than only differences between tumors. The present study does however suggest that differences may also exist between CEA S from different tumors; and the development and optimal application of CEA assays to the immunodiagnosis of cancer may require specific evaluation of the immunodiagnostic characteristics of preparations of CEA related glycoproteins.

The authors report a retrospective study of 129 children with retinoblastoma treated from 1963 to 1977 at the Institut Curie by enucleation of the worst eye and conservative irradiation of the other eye; this irradiation was performed either with Stallard plaque (19 cases) or with electrons (110 cases). In 8 familial cases, no enucleation has been performed. T.E.M. was used from 1964 to 1973 and iterative photocoagulation since 1968. With a 5 years follow up, 88 children (68%) are living NED, 6 are lost. There was 34 treatment failures (26%) and 1 death from second malignant tumor. At 10 and 15 years, the results are stable despite the occurrence of two other second primary tumors. Irradiation preserved 73/94 (78%) of the irradiated eyes. The technical aspects of the radiotherapy with electrons and both ocular and vital prognostic factors are discussed.

The authors report a retrospective study of 129 children with retino-blastoma treated from 1963 to 1977 at the Institute Curie by enucleation of the worst eye and conservative irradiation of the other eye; this irradiation was performed either with Stallard plaque (19 cases) or with electrons (110 cases). In 8 familial cases no enucleation was performed. T.E.M. was used from 1964 to 1973 and iterative photocoagulation has been performed since 1968. Five years absolute NED survival rate was 68% (88/129 children). In these 88 children, 94 eyes were irradiated. Ophthalmological results were as follows: 21 eyes were enucleate secondarily (20/21 were tumoral); the attempt of ocular conservation was succeeded in 78% of the cases: 73 of the 94 irradiated eyes were cured; among these 73 cured eyes, 4 had complications and 15 had sequelae; the others 54 eyes were normal; only 5 eyes escaped ophthalmological survey; for the other 68 eyes vision was evaluated: 2 eyes (3%) were functional but vision could not be measured; 10 (14%) had less than 1/10 of visual acuity; 14 (19%) had vision at least equal to 1/10 but less than 5/10; 42 (57%) had 5/10 or more. 62% of all irradiated eyes (58/94) and 79% of conservated eyes (58/73) had "useful vision". Results are discussed and compared with these published by other teams; the authors try to determine elements of visual prognosis.