[Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. / Thermothérapie et thermochimiothérapie au laser diode dans le traitement du rétinoblastome.

INTRODUCTION: The use of transpupillary thermotherapy alone or associated with systemic chemotherapy is a therapeutic modality of ocular retinoblastoma that allows ocular preservation without external beam irradiation of the eye. We present our experience with thermotherapy in the treatment of selected cases of retinoblastoma. MATERIAL AND METHODS: This paper reports a retrospective case series of patients treated for retinoblastoma by thermotherapy or chemothermotherapy (carboplatin IV followed by thermotherapy) in a single institution from October 1994 to December 2000. Data collected include general characteristics of the treated children, tumor characteristics, and the results of the treatments on local tumor control. Transpupillar thermotherapy was delivered with a diode laser through an operating microscope. Each tumor was treated separately and laser intensity, spot size, and duration were adapted to the size of the tumor and the clinical response. Chemothermotherapy consisted in thermotherapy delivered shortly after an intravenous injection of carboplatin (560 mg/m(2)) at day 1, followed by thermotherapy alone at day 8 if the lesion was 6mm or more in diameter. This cycle was administered every 28 days. The choice between thermotherapy and chemothermotherapy depended on the initial size of the lesions. Thermotherapy was used when the lesion measured 3mm or less. Lesions measuring more than 15 mm, or associated with substantial vitreous seeding, retinal detachment, or optic nerve head involvement are not suitable for these techniques. RESULTS: During the study period, 239 children were treated in our institution and 109 of them (147 eyes, 372 tumors) could be treated conservatively without external beam radiation. The median tumor diameter at the moment of thermotherapy or chemothermotherapy was 2mm (range, 0.2-15.0mm). One hundred and ninety-four tumors were treated by chemothermotherapy and 18 by thermotherapy alone. In 75% of the cases, the treatment was administered after two courses of chemotherapy (etoposide and carboplatin). After a mean follow-up of 55 months (range, 16-89 months), tumor control was obtained in 87.1% of lesions after chemothermotherapy and 77.8% after thermotherapy. Salvage enucleation was necessary for seven lesions (seven eyes) but none in the cases where thermotherapy was used alone. No severe systemic side effects were noted. DISCUSSION: Diode laser delivers hyperthermia on the tumor bed and its use alone or in association with systemic administration of carboplatin makes it possible to preserve the eye without external beam irradiation, with few side effects and less cumulative doses of chemotherapy. CONCLUSION: Thermotherapy and chemothermotherapy provide excellent local tumor control and eye preservation in selected cases of retinoblastoma.

Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter.

In melanoma cell lines, two different patterns of MHC class II expression have been described, either an IFN gamma-inducible expression of HLA-DR and HLA-DP, with a faint or null expression of HLA-DQ, resembling that described for melanocytes, or a constitutive expression, i.e., IFN-gamma independent, of all three HLA-D isotypes. As this latter phenotype has been associated with a more rapid progression of melanoma tumors, we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression. In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines, we have shown the constitutive expression of CIITA (class II transactivator) transcripts, CIITA being known as the master switch of MHC class II expression. Unexpectedly, these transcripts initiate from promoter III of the CIITA gene, a promoter that is mainly used constitutively in B lymphocytes. This expression was further shown to occur through factor(s) acting on the enhancer located upstream of CIITA promoter III, which was previously described in epithelioid cells as an IFN-gamma-response sequence. The hypothesis of a general abnormality of the IFN-gamma transduction pathway was dismissed. Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines, we propose the hypothesis that this phenomenon might not be a random event, but could be linked to the neoplasic state of the melanoma cells.

Uncoordinated HLA-D gene expression in a RFXANK-defective patient with MHC class II deficiency.

We describe the analysis of a patient, JER, presenting classical immunological features of MHC class II deficiency. Unexpectedly, some HLA transcripts (HLA-DRA, HLA-DQA, and HLA-DMA) were found to be expressed in the JER cell line at nearly wild-type levels, while HLA-DPA and the HLA-D beta-chain transcripts were not detected. Gene reporter experiments confirmed the differential transcriptional activities driven by the HLA-D promoters in the JER cells. A defect in RFXANK was first suggested by genetic complementation analyses, then assessed with the demonstration of a homozygous mutation affecting a splice donor site downstream exon 4 of RFXANK. Because the severe deletion of the resulting protein cannot account for the expression of certain HLA-D genes, minor alternative transcripts of the RFXANK gene were analyzed. We thereby showed the existence of a transcript lacking exon 4, encoding a 28-aa-deleted protein that retains a transcriptional activity. Altogether, we characterize a new type of mutation in the RFXANK gene in a MHC class II-defective patient leading to an uncoordinated expression of the HLA-D genes, and propose that this phenotype is ensured by severely limited amounts of an active, although truncated RFXANK protein.

Positive effect of regional analgesia (RA) in terminal stage paediatric chondrosarcoma: a case report and the review of the literature.

A 10-year-old girl was treated for progressive left pelvic chondrosarcoma and severe local pain radiating to the ipsilateral lower extremity. Despite high doses of opioids, pain was poorly controlled and treatment resulted in urine retention and constipation. Positive effect on pain (143 out of 181 days) was obtained by regional analgesia. Continuous lumbar epidural opioid infusion led to pain relief and disappearance of symptoms. Port-catheter dysfunction necessitated a change of epidural catheter and the patient was treated that with morphine, bupivacaine and clonidine plus clonazepam which resulted in relief of constipation and restoration of urinary function. The patient subsequently developed an abscess required or subarachoid infusion (morphine associated with clonazepam, clomipramine and corticosteroids). Later bilateral controlateral cordotomy was performed due to absence of analgesia and the patient subsequently died of tumour progression.

[Infectious sequellae of 913 central catheters in oncology]. / Suivi infectieux de 913 cathéters centraux en cancérologie.

Infections associated with central catheters are a significant source of morbidity in cancer patients. The first evaluation done as part of a continuous catheter surveillance program included the 913 central catheters inserted in 1995. Three of these catheters are still in place. All were tunneled subcutaneously, and most were inserted via the subclavian route. There were 839 simple silicone catheters and 74 catheters with a cuff. Two groups were defined based on whether the central catheter was inserted for administering inpatient or outpatient chemotherapy (n = 704) or for another reason (perioperative care, symptomatic or palliative therapy; n = 209). Catheter-related infection was defined as an infection at the catheter site or as septicemia retrospectively shown to be related to the catheter. The risk of catheter-related infection was expressed as the number of cases per 1000 days of catheterization. Reasons for catheter removal were distributed in table I.

HLA class II-mediated death is induced via Fas/Fas ligand interactions in human splenic B lymphocytes.

HLA class II molecules, expressed on the surface of antigen-presenting cells, are responsible for the presentation of antigen-derived peptides to CD4+ helper T lymphocytes. Signaling via these molecules initiates the generation of second messengers leading to programed cell death (PCD) of activated B lymphocytes. The present study examined the mechanism of HLA class II-mediated apoptosis and describes the essential role of the molecule Fas and its ligand (FasL). FasL was expressed in B lymphocytes after stimulation via HLA class II or with phorbol esters. Expression of FasL protein was significantly increased in 50% of B lymphocytes after stimulation via HLA class II, and the level of FasL mRNA was also increased either by activation with phorbol esters and ionomycin or by signaling via HLA class II. Although HLA class II signaling did not change the expression of the Fas molecule, it did lead to increased sensitivity to Fas-mediated apoptosis. The crucial role of Fas/FasL interactions was confirmed by the absence of cell death via HLA class II in B cells lacking Fas expression, and by the significant inhibition of HLA class II-mediated apoptosis in the presence of either an antagonistic anti-Fas or anti-FasL antibody. These data demonstrate FasL expression on activated human B lymphocytes and support the idea that antigen presentation could contribute to the regulation of lymphocyte populations via Fas and FasL interactions.

Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line.

The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

IL2 triggers a tumor progression process in a melanoma cell line MELP derived from a patient whose metastasis increased in size during IL2/INFalpha biotherapy.

Human melanomas may express both in vivo and in vitro functional IL-Rs and may be expected to directly respond to injected IL2. This may generate biological situations which may be favourable for the patient, but also for tumor progression. Here, we analyse the latter hypothesis. MELP is a melanoma cell line derived from a patient whose metastasis increased in size during IL2/IFN alpha biotherapy [correction of biotheraphy]. These cells have been characterized in vitro for their phenotype and for their sensitivity to IL2. In vitro MELP cells express an IL2-R alpha(+) beta(+) gamma(-) phenotype and IL2 treatment induces the acquisition of new functional characteristics represented (i) by the increased surface expression of two markers of metastatic evolution (ICAM-1 and CD44); (ii) by the stable induction of the IL2-R gamma with the appearance of functional IL2-R beta complex, which are also recognized by GM-CSF; (iii) by the inhibition of transcription of a regulatory cytokine such as IL6; (iv) by a differential effect of IL6 on CD44 surface expression in MELP cells treated or not with IL2 (MILG cells); (v) by the acquisition of faster growth rates and appearance of piling up and multilayer cellular organization; (vi) by the development of rapidly growing tumors in nude mice. IL2 induces in MELP cells a tumor progression process that could mimic the metastatic evolution observed in vivo during biotherapy. Therefore, MELP phenotype may help to define a subset of patients in which IL2 therapy may trigger unfavourable evolution.

[Neonatal cholestatic lithiasis associated with E. coli infection]. / Lithiase cholestatique néonatale associée à une infection à colibacilles.

BACKGROUND: Cholestasis associated with gallbladder lithiasis is quite uncommon in the neonate. We report such a case possibly due to a bacterial infection. CASE REPORT: A 25 day-old neonate was admitted because he suffered from cholestatic jaundice associated with biological findings of inflammation. Hepatic cellular function and transaminases were normal. Ultrasonography showed hepatomegaly and a 10 mm diameter gallstone with sludge into the gallbladder. The patient was given cefotaxime plus netilmicine. Soluble antigenes for E coli were positive in the urine. Jaundice and inflammatory findings returned to normal within 10 days and ultrasonography was normal at the age of 20 months. CONCLUSION: Neonatal E coli infection could be responsible for gallstone formation since E coli endotoxin may induce biliary stasis and favours lithogenous action of bacterial glycoproteins.

[Serum marker of the functional hepatic mass after extensive hepatectomy. The branched/aromatic amino acid ratio. Experimental and clinical studies]. / Un marqueur sérique de la masse hépatique fonctionelle après hépatectomie élargie. Le rapport des acides aminés ramifiés (AAR) sur les aromatiques (AAA). Etudes expérimentales et cliniques.

During severe hepatic insufficiency, serum amino acid profile is modified with an increase of aromatic amino acids (AAA) (Tyrosine and Phenylalanine) and methionine concentrations and a decreased value of 3 branched chain amino acids (BCAA) (leucine, isoleucine and valine). These observations have been confirmed after hepatic surgery in experimental and clinical studies. In experimental models, after 10, 32, 68, 77 or 90% hepatectomy in Wistar rats, the BCAA/AAA ratio (R) is correlated with the extent of hepatectomy: r = 0.74, p < 0.001; with the post-operative interval time (8, 24, 32, 48, 168 or 240 hours): r = 0.60, p < 0.001 and with the liver weight when animals are sacrificed: r = 0.64, p < 0.001. In clinical studies, 26 patients have undergone 60 to 80% hepatectomy for primary or secondary tumors of the liver and R is determined on the immediate post-operative day and every day during the first post-operative week. Liver regeneration is followed by single photon emission computerized tomoscintigraphy on days 0, 7 and 30 with assessment of hepatic growth index (HGI) estimated by the ratio: liver mass on day 7 or 30/remnant liver mass on day 0. On post-operative day 7, R is 1.61 +/- 0.3 (normal: 3.5 +/- 0.51). Mean liver volume is 60 +/- 11% and HGI is 1.9 +/- 0.3. On this day, a correlation is found between R and HGI (r = 0.76). On post-operative day 30, HGI is 2.34 +/- 0.50, mean liver volume is 89.6 +/- 0.9% and R is 2.02 +/- 0.65.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapeutic strategy in 46 cases of radiation injury of the intestine]. / Stratégie thérapeutique dans 46 cas d'intestin radique.

Our expérience in the treatment of 46 cases with radiation enteritis (RE) permitted to summarize 5 key points in the Surgical Strategy: laparotomy incision, enterolysis technique, small bowel and colon preservation, anastomosis technic and parenteral nutritional support. Surgery is imposed most of the time in digestive and nutritional Insufficiencies due to radiation enteritis. 46 patients aged to 33-81 years (mean age = 59) were included for possible surgery. The first clinical digestive symptoms were occlusion (n = 39) and/or digestive fistula (n = 7) and/or perforation (n = 3). These abnormalities were often associated with severe malnutrition (weight loss > or = 20% of usual weight) inducing surgery preparation with pre-operative parenteral nutrition (8 to 350 days). 3 patients were not operated because of general problems and lived 1 to 7 months after the beginning of parenteral nutrition. For operated patients (n = 43), 12 underwent 2 operations (resection and/or enteral liberation) and one patient underwent 4 surgical interventions because of digestive fistula. In 35 cases, small bowel resection was performed leaving 135.4 +/- 62.6 cm of intestine (0 to 225 cm of jejunum and/or ileum) and in 13 cases, complete enterolysis was achieved. All the patients received a post-operative parenteral nutrition during 1 to 23 months (median = 6.2 +/- 5.3 months). 31 patients received home parenteral nutrition during the pre and/or post-operative phase for a median duration of 6.3 +/- 3.2 months (range: 1-23 months). 4 patients died during the immediate post-operative phase and among them, 3 died after the second surgery. 12 deaths were observed due to the primary cancer and 6 due to the evolution of radiation lesions. Median survival of patients without cancer evolution reach 180 months with a 5-year survival rate of 94% (Kaplan-Meier method). In patients with radiation enteritis, the pre and post-operative nutritional support associated with radical surgery allows to obtain prolonged survival in non cancer patients.

[Therapeutic strategy for large cervical, mediastinal metastatic mature teratomas and large retro- and intraperitoneal lesions]. / Stratégie thérapeutique devant de volumineuses métastases tératomateuses matures cervicales, médiastinales et d'énormes lésions rétro et intra-péritonéales.

A 27 years old man was treated after surgery and classic chemotherapy for a right testicular teratoma (stage IV). Two months after the end of chemotherapy the patient developed "a Growing Teratoma Syndrome" with left subclavian and mediastinal nodes enlargement and bulky abdominal cystic masses with vena cava compression, collateral circulation and oedema of inferior members. Four debulking surgical approaches: cervical, thoracic and abdominal were performed and permitted complete functional recovery.

Central nervous system lesions in hypomelanosis of Ito: an MRI and pathological study.

A severe form of hypomelanosis of Ito is reported, which presented as fetal macrocephaly and neonatal epileptic encephalopathy. Lymphocyte karyotypes were normal. MRI showed an absence of delineation between cortical grey matter and white matter. The prominent neuropathological finding was an abnormal cortical morphogenesis, with the co-existence of cells migrating normally and cells exhibiting arrêt en route or even the complete absence of migration. Intense astrocytic reaction with moderate dystrophic features was present. Juxtaposition of two migration behaviours in the neural cells paralleled the cutaneous findings and reinforced the hypothesis of a genetic chimerism.

[Chronic pain of cancers. How to update and promote the subcutaneous administration of morphine]. / Les douleurs chroniques des cancers. Comment réactualiser et promouvoir l'administration de morphine par la voie souscutanée?

In order to treat the cancer chronic pains, the morphine is the most relevant analgesic, since it has rapid, powerful and multiples possibilities of administration. The subcutaneous Administration should be proposed in case of impossibility to act orally. It is a simple and efficient choice, which requires to be organised outside the specialised centers, i.e. at the patient's home. Today, the arrival of news materials allows a continuous and ambulatory injection linked to a better efficiency and acceptance (less side effects). The "P.C.A. methods" allows self administration, which meets the needs.

A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain.

This study compared the efficacy and the adverse effects of controlled-release morphine (CRM) suspension (SAR 213) and CRM tablets (Moscontin) in the treatment of cancer pain. This multicenter, randomized, double-blind, double-dummy, crossover study was carried out on 52 patients. Each patient received both study treatments given at an equivalent dosage of morphine during each of two 7-day periods. The primary outcome variable was the severity of pain assessed three times daily by means of a visual analogue scale. Secondary criteria of efficacy were the severity of pain assessed by verbal rating scale, the need for "rescue" doses of immediate-release morphine, treatment preference, and indices of quality of life (activity, mood, sleep). There were no statistically significant differences in the parameters assessed when comparing the two groups. This study shows that, when prescribed at the same doses, CRM suspension and CRM tablets have similar efficacy and adverse effects, as well as the same duration of action. The results of this first clinical study carried out on CRM suspension are especially relevant for patients with cancer pain who have difficulty swallowing.

[Prevention by naloxone of adverse effects of epidural morphine analgesia for cancer pain]. / Prévention par la naloxone des effets secondaires de l'analgésie péridurale par morphine pour douleur cancéreuse.

Forty cancer patients were randomly assigned to two groups (n = 20). All had incapacitating pain unresponsive to the usual non opioid analgesic drugs. An epidural catheter was set up at the level of the most painful metamere, and made to pass subcutaneously so as to exit either in the supraclacicular fossa, or on the patient's flank. At T0, the patients were given 4 mg morphine hydrochloride diluted in 10 ml normal saline. Thirty min later, patients in the naloxone group (group N) were given a 0.4 mg bolus, followed by a constant rate infusion of 5 micrograms.kg-1.h-1, of naloxone hydrochloride during 18 h. Patients in group P (placebo) were given normal saline instead. The degree of pain was studied with a visual analogue scale and analgesia was assessed by a clinician on a five point scale. These two parameters were obtained half an hour after the injection of morphine and 2, 4, 6 and 24 hours later. At the same time, the patients were questioned about adverse side-effects: nausea, vomiting, pruritus, dysuria, urinary retention. Respiratory depression was assessed clinically and biologically (blood gas measurements at the afore mentioned times). Heart rate, systolic and diastolic blood pressure were also measured. There was no statistically significant difference between the groups in quality and duration of analgesia. Pain reached its lowest level 4 h after the injection of morphine, returning to half its original value at the 24th h. This was also true for the incidence of nausea (11 in group N, 5 in group P), vomiting (3 in both groups), and urinary retention (6 in group P, 5 in group N).(ABSTRACT TRUNCATED AT 250 WORDS)

[Metastatic breast cancer. Chemotherapy with adriamycin, vindesine, cyclophosphamide and 5 FU. Value of continuous 5 FU perfusion. Results of controlled trials]. / Cancer du sein métastase. Chimiothérapie par adriamycine, vindésine, cyclophosphamide et 5 FU. Intérêt de la perfusion continue de 5 FU. Résultats d'un essai contrôlé.

Ninety-four patients with metastatic breast cancer were entered in a prospective randomised trial comparing 2 schedules of the same combination chemotherapy. Group I consisted of 46 patients, treated in a monthly three day course with adriamycin (ADM), cyclophosphamide (CPM), vindesine (VDS) and 5 fluoro-uracil (5 FU). Group II included 48 patients who received the same total monthly doses in 4 injections of ADM, CPM, VDS on days 2, 5, 16, 19 of each month together with a continuous infusion of 5 FU over a total of 10 days (days 1-5 and 15 and 19). Patient characteristics in the 2 groups as regards essential prognostic parameters were identical. We observed no difference in myelosuppression between the 2 groups. There were fewer gastrointestinal side effects in group II. Whereas complete alopecia occurred in 100% of patients in group I, only 33% of patients with the fractionated schedule totally lost their hair. The objective response rates at 8 months were 75 and 74% respectively, but the complete response rates (17.5 versus 28%) showed an advantage for group II. This advantage was not statistically significant. Durations of response were 15 months (group I) and 18 months (group II) and the median survival was 27 months in both. We conclude that prolonged low dose and fractionated administration of chemotherapy over 2 five day courses per month improves the therapeutic index and diminishes side effects.

[A cry of alarm from non-university hospital pediatric departments. What future?]. / Cri d'alarme des services de pédiatrie des hôpitaux non universitaires. Quel avenir?

A survey by questionnaire was carried out among pediatricians of the departments of pediatrics of the non university hospitals in France in order to know the activity and the conditions of work of these departments. Responses were obtained from 84 of the 140 departments of pediatrics. The results emphasized the important activity of these departments contrasting with frequent insufficiencies of the medical staff and equipment. Solutions are proposed in order to avoid an aggravation of the actual situation.