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Neuroblastoma is the commonest solid tumour in children under the age of 5 years (50% of cases before 2 years, 90% before 5) and the second cause of death after accidents. Approximately one child in 10,000 develops neuroblastoma by the age of 15 years. The situation in other European and North American countries is similar to that in France. As neuroblastoma is derived from the sympathetic nervous tissues, it is associated with the production of large amounts of catecholamines and their metabolites which are excreted in the urine. Less than 5% of cases do not produce catecholamines. Vanillylmandelic acid (VMA), homovanillic acid (HVA) and dopamine (DA) are the most useful chemical markers for the diagnosis and clinical control of neuroblastoma. They are generally measured using the reliable and sensitive high pressure liquid chromatography (HPLC). Survival is related to stage (the Evan's staging protocol has been superseded by the INNS staging), and age at diagnosis. There is almost 100% survival for stages I and IIa before the age of 12 months, and less than 20% for stage IV when diagnosed after 2 years of age. Multiple copies of the N-myc oncogene, deletions of chromosome 1p, and diploidy in tumour cells are associated with poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to better evaluate the role of bone marrow purging procedures in the treatment of stage IV neuroblastoma, two similar groups of patients, prospectively treated during the same period at Léon Bérard Center, Lyon, France, and at Giannina Gaslini Institute, Genova, Italy, were reviewed. 18 children were treated in Lyon with a protocol including induction chemotherapy, surgery and a single course of high-dose chemotherapy followed by purged autologous bone marrow rescue. 21 patients were treated in Genoa with a very similar protocol which did not include purging procedures. Progression-free survival at 6 years was 12% (95% confidence interval 0-24%), without any difference between the two series of patients. The only prognostic factor for long-term survival was the persistence (or not) of bone lesions and the presence of metastatic disease (bone or bone marrow) at graft. The small numbers in the two groups and the very poor outcome make it difficult to conclude on the efficacy of purging.

Twenty-two patients with locally advanced or metastatic soft tissue sarcomas received high dose chemotherapy with autologous bone marrow graft. Eleven patients receiving melphalan also received fractionated total body irradiation. Six patients (four in CR and two in PR) were intensified after first line therapy. Thirteen patients were grafted after chemosensitive relapse: seven in second CR, one in third CR, one in first PR, three in second PR and one in fourth PR. Three patients with primary refractory disease were intensified. The overall response rate in 66% in nine evaluable patients. The overall median survival and disease-free survival were 19 and 15 months, respectively. The actuarial survival rates at 2 and 5 years were 40% and 32% respectively. There was one treatment-related death due to infection. We conclude that high dose chemotherapy is feasible and provides reasonable response rates in patients with advanced soft tissue sarcomas.

The real need for extensive staging at the time of diagnosis is discussed in regard to small cell lung carcinoma. We performed a decisional retrospective analysis on a series of 182 patients, based on three staging steps: the first step included physical examination and routine biologic tests. The second step consisted of liver ultrasonography and needle aspiration of any clinically detectable tumor mass, and the third step included bone marrow examination, radionuclide bone scan, thoracic, abdominal, and brain CT scan. A stepwise multivariate logistic regression performed on 11 variables considered in the first step shows that a four-parameter model can predict the spread of the disease (limited or extensive): weight loss, performance status, and elevated LDH or alkaline phosphatase levels. Limited disease can be predicted in two ways: (1) elevated LDH with normal alkaline phosphatases, no weight loss, and good performance status, or (2) normal LDH and alkaline phosphatases. In this series, 28 percent of patients can be predicted as having extensive disease and can be treated with chemotherapy alone without chest irradiation. After the second step, the probability of disease being extensive is only 25 percent, and only 84 (46.15 percent) patients would need to undergo the third step of staging procedures (brain CT scan, bone marrow aspiration and biopsy, radionuclide bone scan) with this method. We conclude that a multistep approach represents a simple staging method and offers the advantage of harmlessness and lower costs for patients not to be evaluated in prospective clinical trials.

Although the decision to continue or to stop prematurely a clinical trial is not solely based on statistical tests, they bring useful objective arguments to the data monitoring board. However, the multiple use of statistical tests leads to increase the risk of false positive conclusions in favor of one of the treatments, and several methods have been developed to address this problem. This article presents the four major strategies that are being used for monitoring clinical trials, as well as the rationale for planning and using such statistical monitoring procedures.

In order to fulfil the ethical principles linked to the protection of patients randomized in a controlled clinical trial, monitoring procedures need to be set up. In this context, a committee of experts, called the data monitoring committee is in charge of reviewing regularly unblinded data to assess the quality and the relevance of the trial, to evaluate the evidence of an emerging treatment difference and to control the rate of occurrence of serious adverse events. After each meeting, the monitoring committee reports to the steering committee its recommendation to continue or to stop the trial prematurely. Protocol modifications might be proposed as well. Illustrated with several examples, this article reviews different situations a monitoring committee might have to tackle with.

In this prospective study, an image cytometric DNA-analysis was performed in 86 women with breast neoplasms (72 primary invasive carcinomas and 14 benign lesions). Four DNA ploidy parameters were analysed: histogram type (according to AUER classification), DNA-index, tumor cells with DNA content above the 5n limit and DNA malignancy grade (DNA-MG, calculation according to Böcking). Their correlations with well established prognostic factors in breast carcinomas (tumor size, lymph node status, histologic grade, hormone receptor content) were studied. All but one benign lesions were diploid (13/14 cases), whereas the majority of the primary invasive breast carcinomas were aneuploid (58/72 cases). A predominance of carcinomas with a percentage of cells superior or equal to 1% with DNA content above the 5n limit was observed (54 cases out of 58). Most of the aneuploid tumors had a histogram type III or IV (53 cases) or a high DNA-index (50 cases). Of these 58 aneuploid cases, only 26 tumors had a DNA-MG superior to 1. Interestingly, 26 tumors had the 4 criteria of aneuploidy, 19 had 3 and 9 had 2 and only 4 tumors had one parameter. The DNA-MG was significantly related to hormonal receptors (p less than 0.001) and tumor size (p less than 0.01). The histogram types (Auer classification) and the DNA content above the 5n limit were correlated with histologic grade (SBR or SBRM) (p less than 0.02). Concerning the DNA-index no correlation was observed with well established prognostic factors. On the other hand no significant correlation was found between these new biologic variables and lymph node status.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetically guided administration of melphalan was investigated during a pilot study in patients with advanced ovarian adenocarcinoma. The schedule involved a fixed dose on day 1 (7.9 mg) followed by a second dose on day 2, calculated on the basis of pharmacokinetic data to achieve a target area under the concentration-time curve (AUC). 20 courses of intravenous melphalan were administered to 7 patients. AUC, standardised to 1 mg/m2, ranged between 4.3 and 8.9 (mg/l) min. In 12 fully evaluable courses, less than 15% deviation from the target AUC was found, showing that AUC monitoring was possible by means of the test dose. Pharmacodynamic effects showed a positive correlation with melphalan AUC. Myelosuppression appeared at 47 (mg/l) min and grade 3 or 4 haematological toxicities were observed in 4 cycles, associated with AUC values ranging between 86 and 112 (mg/l) min. Relative leucocyte decreases were well correlated with AUC values.

Among the patients showing evidence of cerebral metastases without previously known cancer history, lung cancer has been found 37 times as the primary tumor in our institution. There were 34 men and three women and all but two were heavy smokers. Only one presented at diagnosis with thoracic symptoms but the chest radiograph was abnormal in 34. The histologic type of the primary tumor was obtained in 32 cases as a result of thoracic investigations and in five cases from metastatic tumor tissue. The primary tumor appeared to be non-small cell lung carcinoma in 26 cases and small cell lung carcinoma in 11 cases. These results show that patients treated with surgery (20 cases) have a better survival (median 10 months versus 4.5) than the others, and among surgically treated patients only those treated with bifocal resection (eight patients) are long-term survivors. Also, in four of six patients, objective regression of the neurologic symptoms was seen after radiation therapy alone. Central nervous system relapse was seen in 12 patients, but in none of the patients treated with postoperative radiation therapy. Conventional chemotherapy (11 patients) induced objective responses only in the small cell type and proved to be too toxic when used simultaneously with radiation therapy in inoperable patients.

The authors reported a retrospective pathological study of 168 patients classified PT2N- treated by Patey mastectomy completed by axillary and internal mammary lymph node removal. The size of micrometastases ranged from 0.012 to 0.87 millimeters. All 2800 lymph nodes were examined, using successively HPS and IHC procedures. Detection of micrometastases has been improved by immunohistochemical staining on paraffin embedded sections using anticytokeratin MAb clone antiKL1. The 168 patients were divided into two groups. The first one included 31 patients IHC+ out of 168 (18.5%); there were 47 micrometastatic nodes with negatives nodes out of 2800 (1,67%). The second group included 137 patients (81.5%) out of 168 with negative nodes. If we consider the PT2N-clinical status, it appears a percentage of 16 to 20% of patients developing recurrence within ten years after surgical treatment. There was no significant difference concerning the disease--free survival at ten years. Variability in metastatic node involvement spread led us to distinguish 3 subgroups of uneven prognostic value. The relative risk of relapse ranged from 1 (ICH + 1) to 1.94 (ICH + 2 and 3) merged. Do PT2N- group with recurrence and ICH + group concern the same patients? We cannot statistically prove that micrometastatic nodes are a bad prognostic factor by further studies which are required.

Human gallstones were studied by visual inspection, computerized tomographic imaging, and chemical analysis to assess physicochemical characteristics that may determine the outcome of in vitro shock-wave fragmentation. Eighty-five stones (mean diameter: 13.2 +/- 5 mm) were each collected from different patients. Fifty-five (65%) calculi were angular and 30 (35%) round or oval-shaped. Three easily obtained measures were derived from each stone's optimal computerized tomographic image including the mean stone density, a measure corresponding to the standard deviation of the mean stone density value which we termed the stone density distribution index and which may reflect the physicochemical heterogeneity of a given gallstone, as well as the density range. After the administration of 2500 shock waves using an electrohydraulic generator, fragmentation was noted in 68 calculi (80%) and was satisfactory in 27 (32%) (where the largest resulting fragment diameters were all less than or equal to 5 mm). Strong determinants of satisfactory fragmentation on multivariate analysis included a stone diameter of less than or equal to 15 mm, the presence of an angular stone shape, and a stone density distribution index of greater than or equal to 60 Hounsfield units. The other parameters did not independently determine satisfactory fragmentation. Prospective clinical trials are needed to assess whether these findings result in a better prediction of the success of extracorporeal biliary lithotripsy and a broadening of its indications.

From January 1986 through December 1988, 227 patients were included in a multi-institutional pilot study for small cell lung cancer (SCLC). Out of the 211 patients who fully completed the staging procedures, 77 (35%) appeared to have SCLC limited to the thorax. All patients received combination therapy consisting of AVI (Adriamycin, VP-16 and Ifosfamide), except during radiotherapy when the Adriamycin was omitted, plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP-16 and Ifosfamide), completed by 2 courses of initial chemotherapy (AVI). Radiotherapy consisted of 1.5 Gy/fraction, 2 fractions/day, 5 days/week in the first course, and 1.8 Gy/fraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 51 Gy, felt to be equivalent to 60 Gy at normal fractionation. CT treatment planning was employed to design a treatment consisting of multiport radiotherapy, using AP-PA and laterals or obliques beams. During the first course, the homolateral hemithorax received 9 Gy total dose on days 1, 3, 5. During the third course, 360 degrees arctherapy was generally used to boost the reduced tumor volume to a 51 Gy. Besides chest X ray and CT scan, staging and restaging procedures included fiberoptic bronchoscopy. Response rate after irradiation is 61%, with 46% complete responders and 51% local control. The median survival is 14 months, and disease-free survival 42% at 1 year. Complications consisted of cardiac toxicity in 2 patients, 1 death of acute pulmonary toxicity, and 4 instances of moderate chronic radiation pneumonitis. Thus, high doses of radiation can be delivered combined with chemotherapy using this protocol, with an acceptable toxicity and encouraging results in response rate and local control. A longer follow-up is needed to evaluate the impact of these results on survival.

Small-cell lung carcinoma can be distinguished from other histological types of lung cancer because of its high metastatic potential. Initial staging procedures divide the patients into two main prognostic groups: the so-called "limited" (to the thorax) and the extensive disease patients. Based on the results of a prospective pilot study involving 182 patients and on a review of the literature, the authors discuss the usefulness of initial staging in increasing the number of detectable metastases, assessing tumour burden, evaluating treatment results and identifying prognostic factors. Complete tumour staging at the time of diagnosis appears to be very helpful for a better knowledge of the disease and better therapeutic decisions.

Over a 5 month period, a study of the incidence of nosocomial infections (NI) was carried out in the Léon Bérard Oncology Center (Lyons). It comprised 1,551 patients classified in groups according to the site of origin of the underlying malignancy. The respective frequency of the different types of nosocomial infections and the responsible agents was evaluated in each group and the incidence was calculated per day of hospitalization. The overall incidence of NI was 11.29 per 1,000 patient-days, with a maximal value of 20.04 for patients suffering from lymphomas. The most frequently encountered infections were bacteremias (22.7%), followed by urinary tract infections (20.8%) and wound infections (20.5%). The most frequent causative agents of NI were Escherichia coli (25.8%), Pseudomonas aeruginosa (13.9%), Staphylococcus aureus (9.8%) and Staphylococcus epidermidis (9.8%). The latter micro-organism together with Escherichia coli were the most frequent causative agents of bacteremias. Even though cancer patients are particularly prone to developing infections, the incidence of NI could be reduced thanks to a program of control and surveillance of infectious episodes during hospitalization.

Anthracyclines containing regimen are widely used in advanced breast cancer. The response to first line chemotherapy varies according to many individual factors and the theoretical response to a given protocol cannot predict the response of a patient. A randomized clinical trial (ERASME) was initiated in order to evaluate the more appropriate first line chemotherapy scheme in advanced breast cancer. Prognostic factors were included in a multiple logistic regression to explain the response after the first 3 chemotherapy courses (monthly FEC). Three factors were found to be statistically significant: adjuvant hormonotherapy, loco-regional metastases, adjuvant adriamycin containing regimen (pejorative prognostic factor). By combining these factors, this statistical model enables us to predict a response rate to a first line chemotherapy from 27 to 87%. Such a model can be taken into account in a decision-making procedure of first line chemotherapy in advanced breast cancer.

An epidemiological study of neuroblastoma in the Rhône-Alpes area was carried out over a 5 year period. The aim was to set up a background for a screening program in order to increase the number of neuroblastoma diagnosed in children before age 1, and decrease or eliminate advanced stage neuroblastomas.

A number of prognostic factors have emerged from a retrospective study of 83 patients with breast cancer associated with a solid intracerebral tumour (59%), or meningeal invasion (33%) or both (8%). The median survival was 4 months without significant difference between breast tumours and meningeal carcinomatosis. Women in pre-menopause at the initial diagnosis of breast cancer (P less than or equal to 0.05) or who were 50 years of age when the cerebral metastasis occurred (P less than or equal to 0.05) or who had only one metastasis (P less than or equal to 0.02) had a better prognosis. During meningeal carcinomatosis, CSF protein and carcinoembryonic antigen levels have no prognostic value. All patients with intracerebral tumour had been irradiated (40 Gy over 4 weeks). The tumour was removed whenever possible. Intrathecal or systemic chemotherapy and hormone therapy seem to be favourable prognostic factors. This would suggest that chemotherapy may increase the survival of patients with this type of breast cancer, but only randomized studies will demonstrate its true effectiveness.

One hundred and ninety six patients underwent brain irradiation for metastases between 1973 and 1981. Complete follow-up was possible in 180 cases. CT appeared to be the best diagnostic tool. Whatever the type of the tumor, irradiation improved symptoms and signs in 65.3 p. 100 of cases and neurological status in 37 p. 100 of cases. The median survival was 4.2 months, the mean survival 6.6 months, the percent survival at 1 year 11 p. 100. It is necessary to irradiate the whole brain with doses of 40-45 Gy in 4.5 weeks. Shorter periods of irradiation allows a short inhospital stay but implies anti-oedematous treatment. Chemotherapy did not improve the results. Excision surgery had limited indications: isolated metastases, accessible site in zones with no functional importance, good performance status, local control obtained for primary tumor, no extra-cerebral metastases. Surgery must be followed by whole brain irradiation. Derivation is necessary when increased intracranial pressure and treatment resistance are present. Irradiation indications are large. The results were palliative but valuable: irradiation was always indicated except when disorders of consciousness were present. Tolerance was usually good.

Adult patients with advanced non-Hodgkin's lymphoma in whom conventional chemotherapy has failed are seldom cured thereafter. We studied 100 such patients with intermediate-grade or high-grade non-Hodgkin's lymphoma who were subsequently treated with high-dose chemotherapy (61 patients) or high-dose chemotherapy plus total-body irradiation (39 patients), with bone marrow transplantation used for hematologic support. Thirty-four patients had disease that had been refractory to primary chemotherapy, and 66 patients had had a complete remission with primary chemotherapy but later relapsed. Before autologous bone marrow transplantation and high-dose chemotherapy, the 66 relapsed patients had also received conventional salvage chemotherapy; 22 had had no response or had had disease progression (a response termed "resistant relapse"), and 44 patients had responded partially or completely (a response termed "sensitive relapse"). After high-dose therapy and bone marrow transplantation, the actuarial three-year disease-free survival was zero in the refractory group, 14 percent in the resistant-relapse group, and 36 percent in the sensitive-relapse group. Patients who had had a complete remission in response to initial chemotherapy had a higher disease-free survival rate than those who had not (P less than 0.001), and patients with sensitive relapse had a higher disease-free survival rate than those with resistant relapse (P less than 0.003). These results should be considered in the planning or interpretation of trials of salvage chemotherapy in adults with non-Hodgkin's lymphoma.

Electric birefringence has been used to examine the states of association of tubulin in phosphocellulose-purified tubulin or depolymerized microtubule protein solutions at low temperature. In a high electric field (1000-4000 V/cm), tubulin could be orientated (owing to the existence of a permanent and/or induced dipole) and exhibited a positive birefringence (delta n), related to its intrinsic optical anisotropy. The analysis of the relaxation process (depending on hydrodynamic properties of molecules), by measurement of the time decay of delta n, revealed the existence of a multicomponent or polydisperse system, whatever the tubulin solution. Two relaxation times, representative of the smallest and the largest orientated species, were obtained by computer-fitting analysis. The mean values of relaxation time for phosphocellulose-purified tubulin were 0.8 and 8 microseconds. In microtubule protein solutions, large-sized macromolecular species with relaxation time up to 450 microseconds were detected. The largest species (relaxation times ranging from 50 to 450 microseconds) could be eliminated by centrifugation at 3000000 X g for 1 h. Addition of microtubule-associated protein to either pure tubulin or high-speed centrifuged microtubule protein led to a rapid formation of large species analogous to those present in microtubule protein. Molecular dimensions of the relaxing structures were estimated using simple hydrodynamic models and values of rotational diffusion constants calculated from the relaxation times, and compared to those of the structures described in the literature. In conclusion, we have found that (a) phosphocellulose-purified tubulin is not only composed of elementary species (dimers) but also contains tubulin-associated forms of limited size (up to 7-10 dimers), (b) depolymerized microtubule protein solutions contain ring oligomers and structures very much larger, the formation of which is dependent on the presence of microtubule-associated protein.

Recent experiments show that membrane ATPases are capable of absorbing free energy from an applied oscillating electric field and converting it to chemical bond energy of ATP or chemical potential energy of concentration gradients. Presumably these enzymes would also respond to endogenous transmembrane electric fields of similar intensity and waveform. A mechanism is proposed in which energy coupling is achieved via Coulombic interaction of an electric field and the conformational equilibria of an ATPase. Analysis indicates that only an oscillating or fluctuating electric field can be used by an enzyme to drive a chemical reaction away from equilibrium. In vivo, the stationary transmembrane potential of a cell must be modulated to become "locally" oscillatory if it is to derive energy and signal transduction processes.

Seventeen patients received high-dose therapy with autologous bone marrow transplantation (ABMT) when in partial response after induction therapy. There were 11 children and six adults between 3 and 57 years old. Twelve patients were determined to have high-grade lymphoma (ten Burkitt's and two lymphoblastic), and five had intermediate-grade diffuse lymphoma. Ten patients had surgically proven active disease in the abdomen, two had active disease in the bone marrow, and five persistent neurological symptoms. The time interval between diagnosis and ABMT was 2-10 months (median 4 months). Two patients died of progressive disease and two others died while in complete remission (CR) because of toxicity. Thirteen of 17 are still alive and disease free with a median observation time of 2 years. Morbidity was high with 6/17 life threatening reversible complications but overall survival is 75% at 24 months in a group of patients clearly defined as having a very bad prognosis in previous studies.

Using experimental modes with normal allogeneic bone marrow (BM) contaminated with Burkitt or neuroblastoma cell lines, and a liquid culture assay, we demonstrated that, when used in optimal conditions, the immunomagnetic depletion technique permitted a reproducible elimination of 3-4 log malignant cells. Results were very similar to those obtained with the complement lysis procedure in Burkitt lymphoma. This immunomagnetic procedure was used in 123 cases of autologous bone marrow transplantation (ABMT) in children with neuroblastoma. The analysis of the cases demonstrated, first, that the procedure induced a significant loss of mononuclear cells but was not toxic for BM precursors. Delays to engraftment observed in a few patients were probably due to the combination of pejorative factors, especially the damage caused to the micro-environment by previous heavy and prolonged chemotherapy or the double ABMT programme. Second, patients presented with profound T-cell defect with undetectable IL2 secretion up to 1 year post-graft but they all had normal NK functions from the first month post-graft, these functions exceeding normal values on the second and third months post-graft. Finally, in 20 cases, dual-immunofluorescence staining permitted the demonstration that the autograft contained malignant cells before purging that were eliminated by the immunomagnetic depletion.

Between 1981 and 1985, 50 patients, mainly children and adolescents, with advanced B-cell lymphoma were entered on a protocol comprising eight drugs: cyclophosphamide, vincristine, prednisolone, high dose methotrexate, adriamycin, BCNU, cytosine arabinoside and thioguanine. Treatment to the central nervous system consisted of intrathecal methotrexate and cytosine-arabinoside in association with high dose methotrexate without irradiation. Data was collected prospectively with regard to response rate, treatment related complications and survival. Histology was reviewed in all referred cases and in 21 there was supportive evidence from immunological and cytogenetic studies. The overall complete response rate was 86%: 31/36 stage III and 12/14 stage IV. There were four treatment related deaths. The overall disease-free survival is 75% with a median follow up of 32 months. In the group of stage IV patients 5/7 with only marrow involvement, 2/4 with isolated CNS involvement and 1/3 with combined CNS and marrow infiltration survive. All the patients with CNS involvement at presentation underwent consolidation treatment with high dose chemotherapy and bone marrow transplant. These results demonstrate the very high curability of B-cell lymphoma using intensive multiagent therapy even with advanced abdominal disease. Bone marrow infiltration does not appear to be an adverse prognostic factor in isolation from bulk disease or CNS involvement. There remain, however, two groups of patients in whom further intensification of therapy is indicated, namely, those with initial CNS involvement, especially in combination with marrow infiltration, and those with extensive multiorgan involvement at presentation who fail to achieve remission with initial therapy. For the other patients, the large majority, a reduction in the intensity and duration of therapy is currently under study.

In about 50% of patients with stage IV neuroblastoma, micrometastases are present in the bone marrow when it is harvested for an autograft to follow induction therapy, and the risk of graft contamination by neuroblastoma cells has been the rationale for the use of a purging procedure. However, bone marrow metastases are detected with trephine biopsies which only explore the sites biopsied and do not reflect potential contamination of the pooled marrow harvested for autograft. A two-colour fluorochrome labelling method is described which permits as few as 1 neuroblastoma cell in 100,000 normal bone marrow cells from the autograft to be detected. Three monoclonal antibodies (UJ13A, H11 and 11.14) which react with neuroblastoma cells are used as single reagent in combination with a fourth anti-panleucocyte antibody. This method requires only 2 h for the analysis of three million marrow cells from the autograft, and is more effective than alkaline phosphatase staining with the same monoclonal antibodies. Results were compared with conventional techniques (four biopsies and four aspirates) carried out at the same time in 34 consecutive patients. Of 18 cases with negative aspirates and biopsies, neuroblastoma cells were detected in two autografts by the immunological method. Of 16 cases with positive aspirates and/or biopsies, 10 autografts were positive by the immunological method and six were negative. Thus, marrow micrometastases were detected in 16 of the 34 patients, but the autograft contained malignant cells in only 12 of these patients and the immunological analysis demonstrated that the use of a purging procedure allowed the elimination of neuroblastoma cells from the autograft before its reinjection to the patients.

In 1977, the authors described the grid method, a topographic technique for mapping the microscopic spread of breast cancer. The current report describes the relapse-free survival of a series of 203 patients with T2 N- mammary cancer (T2 N0 N1 ab N-) who were treated by mastectomy and regional lymph node dissection and have been followed since 1974. A good prognosis did not prevent relapse in 15% to 20% of patients within the first 5 years. To determine whether the grid method can identify patients at high risk within this group, disease-free survival and survival were compared in two subsets, a "limited" group (L) and a "diffuse" group (D). The difference between the two groups was statistically significant for both parameters (88%) versus 77% and 93% versus 85% after 5 years) (P less than 0.01 and P less than 0.02). Other prognostic measures were uniformative. Thus, the grid method has a good prognostic score when compared with the factors usually measured--menopausal status, estrogen receptors, histologic type--and could be used to select appropriate adjuvant therapy in breast cancer.

Metastatic breast adenocarcinoma is a very chemosensitive tumor. Polychemotherapy (CT) is more active than mono-CT inducing a 50-60% response rate in naive chemotherapy patients. The response rate is increased by adding hormonotherapy (HT) to CT in hormone-receptors positive patients. Whether or not HT and CT should be concomitant or consecutive is still questionable. The overall survival remains poor (22-30 months) and no improvement happened during the last decades. A hope for the future is possible from 2 different concepts: high dose chemotherapy or intermittent CT with successive short inductions treatment and no maintenance therapy.

The importance of assessing the quality of life is more and more emphasized when therapeutic effects are to be studied. However, if its theoretical bases appeared as rather well established, they are not yet effectively translated into the presently available instruments: there is not yet any "gold exchange standard" in this field. This fact is the result of the difficulty of this translation and of the medical tendency to reduce the assessment of the quality of life to the assessment of the health. The second part of this paper is thus devoted to the presentation of a new instrument ("PQVS" in french, or "QLPI" for "Quality of Life Profile Inventory"). It was devised for applying the theoretical bases of the study of the quality of life. It thus allows for the assessment: 1) of the quality of the global life, 2) of the quality of what is experienced in several dimensions of the life, and 3) of the individual structure of the quality of life.

Effects of ionic strength and proteolytic digestion on the conformation of chromatin fibers were studied by electric birefringence and relaxation measurements. The results confirm that at low ionic strength chromatin presents structural features reflecting those observed in the presence of cations. Soluble chromatin prepared from rat liver nuclei by brief nuclease digestion exhibits a positive birefringence. As the salt concentration is increased, the transition to a compact solenoidal structure is deduced from changes in electro-optical properties: the positive birefringence gradually decreases and the observed reduction in 40 mM NaCl is nearly 95%; the relaxation time decreases dramatically and the character of the kinetic changes since the decay of birefringence described initially by a spectrum of relaxation times becomes monoexponential. On digestion with proteases at low ionic strength we observe at first a rapid increase of the positive birefringence concomitant with an increase of the relaxation time. Then the birefringence decreases and becomes negative. Chromatin undergoes two successive transitions: the first transition is explained by a lengthening of nucleosomal chains without modification of the orientation of nucleosomes within the superstructure and the second one by the unwinding of the DNA tails and internucleosomal segments. When chromatin is digested at 30 mM NaCl we find a single unfolding transition characterized by the decrease of birefringence and a slight increase in the relaxation time. The results imply that the positive birefringence of chromatin does not depend on the presence of whole histone H1 and that a salt concentration of 30 mM NaCl is sufficient to modify the initial site or/and the effects of proteolytic attack.

1. A type 2 therapeutic trial consisting of the administration of monthly cycles of chemohormonotherapy, each cycle combining weekly sequences of mephalan, prednisone, cyclophosphamide, and prednisone, has been achieved in 20 stage II or III myeloma patients. Tolerance of this regimen in treated out-patients was found to be excellent. Preliminary data indicate that the better survival rate in patients treated by this regimen is still not reached at a 30-month follow-up examination by three other nonrandomized control groups of patients receiving continuous therapy with prednisone alone, prednisone + cyclophosphamide, or prednisone + melphalan. 2. Analysis of the main prognostic factors of the four trials indicates that a) IgG-type myelomas are associated with a better prognosis than IgA type; nonexcreting myelomas are associated with the best prognosis, while Bence Jones myelomas are associated with a prognosis as poor as that of the IgA type; b) tumor volume as well as renal insufficiency, at the time of diagnosis, are also prognosis factors; this study confirms the prognostic value of the recently proposed clinical staging system based on these parameters but outlines that 10% of the patients died from a cause not directly related to myeloma plasmocyte proliferation. 3. In conclusion, these results point out: a) the possible advantage of using two alkylating agents instead of one at the beginning of the disease; b) the need to classify multiple myeloma according to prognosis before attempting therapeutic trials.

Sixty-five patients more than one year of age at diagnosis with stage IV neuroblastoma were prospectively treated since january 1983. Seventeen per cent were not consolidated with massive therapy and ABMT (progression: 3 cases; died at induction: 4 cases; died at surgery: 1 case; parental refusal: 2 cases) and all died. Among 49 evaluable cases, 31 were grafted in PR and 18 in CR or VGPR. Actuarial progression free survival at 35 months is 33% for the grafted group and 24% for the whole group. These results are better than previous experience of this group (8% at 30 months).

The activity of gamma-glutamyltranspeptidase (gamma GT) (EC 2.3.2.2) was examined by histoenzymatic labelling on frozen sections derived from normal breast tissue, benign lesions and carcinomas. In biopsies from normal tissue and benign lesions, labelling was very intense in lumina and in the apical pole of the cells lining the lumina whilst in the cytoplasm it was slightly positive. In 34 out of 70 carcinomas, gamma GT activity was either undetectable or slightly positive while in the remaining 36 there was intense activity. Statistical examination of the results revealed no obvious correlation of gamma GT activity with histological grade of the tumour, progesterone receptor content or classification of patients by pre- or postmenopausal status. A good correlation between gamma GT activity and the following unfavourable prognostic signs: lymph node metastases and absence of oestradiol receptors. Patients with gamma GT-negative tumours may have a more favourable prognosis than those with gamma GT-positive tumours.