Metaiodobenzylguanidine assessment of metastatic neuroblastoma: observer dependency and chemosensitivity evaluation. The SFOP Group.

BACKGROUND: In children over 1 year of age with metastatic neuroblastoma, clearance of metaiodobenzylguanidine (MIBG) skeletal uptake after four courses of induction chemotherapy is one of the most powerful prognostic factors. How subjective is quantification of MIBG uptake, and can earlier MIBG scintigraphy separate good and bad responders? PROCEDURE: The data from 47 patients who received uniform induction therapy were reviewed. A novel scoring system of MIBG update intensity was proposed. Initial, intermediate (after two courses), and final (after four courses) intensities were scored (0 to 21 points) independently by six different observers. The initial global score and the relative score (calculated by dividing the global score after two courses by the initial score) were compared to the final score. Good responders were those who scored 0 at final MIBG. RESULTS: Between two observers, the correlation coefficient for the global score was superior to 0.80, in nine of ten comparisons established between observers 1-5. The initial score did not predict the final score insofar as only nine of fourteen patients with low initial scores were good responders. The relative score also failed to predict outcome; only six of ten patients with favorable relative score (i.e., <20%), were good responders. CONCLUSIONS: This scoring system is reliable and may be used in multicentric trials. However, both initial and relative scores failed to predict final outcome. Thus, intermediate MIBG may be omitted during induction therapy assessment.

A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma.

Standard treatment of advanced ovarian cancer is a combination of surgery and chemotherapy. Additional therapies using the i.p. route are considered as a potential means of improving the locoregional control rate. This Phase II study evaluated the efficacy of i.p. radioimmunotherapy (RIT) in patients with minimal residual ovarian adenocarcinoma after primary treatment with surgery and chemotherapy. Between February 1995 and March 1996, six patients with residual macroscopic (<5 mm) or microscopic disease as demonstrated by laparotomy and multiple biopsies received i.p. RIT. All had initial stage III epithelial carcinoma and were treated with debulking surgery and one line (four patients) or two lines (two patients) of chemotherapy. RIT was performed with 60 mg of OC 125 F(ab')2 monoclonal antibody labeled with 4.44 GBq (120 mCi) of 131I injected 5-10 days after the surgical procedure. Systematic laparoscopy or laparotomy with multiple biopsies performed 3 months after RIT in five patients (clinical progression was seen in one patient) showed no change in three patients and progression in two patients. Toxicity was mainly hematological, with grade III neutropenia and thrombocytopenia in two patients. Human antimouse antibody production was demonstrated in all six patients. This study showed little therapeutic benefit from i.p. RIT in patients with residual ovarian carcinoma.

Bone pain palliation with 85Sr therapy.

UNLABELLED: The aim of this retrospective study was to evaluate the efficacy of 85Sr in the palliation of metastatic bone pain. 85Sr decays by electron capture with a gamma emission of 514 keV and associated x-ray emissions of 10-15 keV; physical half-life is 64 d. METHODS: Between 1977 and 1992, 119 doses of 85Sr chloride (mean activity 335 MBq [9 mCi]) were intravenously administered to 108 patients with hyperalgic generalized bone metastases from prostatic carcinoma (52 patients), breast carcinoma (41) or other cancers (15). Pain, performance status, blood and urinary excretion values were investigated during follow-up, and survival time was recorded. Strontium bone scans were obtained up to 8 wk after injection to document isotope biodistribution and to estimate absorbed doses. RESULTS: At 12 wk, 72.2% of patients showed significant benefit from treatment, i.e., enhanced quality of life and pain relief; 49.1% became free of pain. These beneficial effects lasted from 1 to 36 mo (mean 4.3 mo). The best symptomatic improvement was seen in patients treated at an early stage of metastatic skeletal disease and in prostate cancer patients. No evidence of a significant dose-response relationship was found in the data analysis. The mean absorbed dose ratio of metastases to marrow was estimated at 8.2. We found no evidence that hematological toxicity was a major problem; however, all patients experienced a reduction in blood counts, especially in platelets. CONCLUSION: Systemic radionuclide therapy using 85Sr is a feasible, effective and well-tolerated palliative treatment in patients with refractory bone pain. We attained at least the same response rate as that reported with bone-seeking beta-emitting radionuclides such as 89Sr. The patients who benefited the most from 85Sr treatment were in an early stage of metastatic disease or had prostate cancer. Our clinical findings could not be linked to either the total injected activity of 85Sr or the estimated absorbed dose delivered to metastases.

[Standards, options and recommendations (SOR) for diagnosis, treatment and follow-up of osteosarcoma. Groupe de travail SOR]. / Standard, Options et recommandations (SOR) pour le diagnostic, le traitement et la surveillance de l'ostéosarcome.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. For pediatric issues, this project is a collaboration between the FNCLCC and the French Society of Pediatric Oncology (SFOP). The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the clinical care of osteosarcoma in children and adult. METHODS: Data have been identified by literature search using Medline (1985-december 1998) and the expert groups personal reference lists. The main criteria considered were incidence, risk factors, prognostic factors and efficacy of treatment. Once the guidelines were defined, the document was submitted for review to 27 national and international independent reviewers, and to the medical committees of the 20 French Cancer Centres and, in particular, the 4 which have particular expertise in pediatric cancer management. RESULTS: The main recommendations for osteosarcoma management are that: 1) the clinical diagnosis is based on appropriate clinical and radiological findings; 2) the final diagnosis is pathological and the biopsy should be performed by the surgeon who will subsequently perform the definitive surgery; 3) surgical biopsy must be of adequate size and performed by an experienced surgeon; 4) the therapeutic strategy for osteosarcoma is based on surgery with neoadjuvant and adjuvant chemotherapy given in experienced centres. Inclusion of high dose methotrexate is recommended for children, and the dose of methotrexate must be adapted for adults. Inclusion of children in SFOP protocols and adults in EORTC and FNCLCC clinical trials is recommended; 5) treatment of metastatic osteosarcoma is based on chemotherapy and surgery to lung metastases which may be curative. Amputation is rarely appropriate. Inclusion of children in SFOP and of adult in EORTC and FNCLCC clinical trials for metastatic osteosarcoma is recommended; 6) at the present time, there are no clear data on which to base guidelines for timing and duration of follow-up studies in this condition.

Screening for neuroblastoma in France: methodological aspects and preliminary observations.

A pilot study of neuroblastoma mass screening was initiated in January 1990 in the Rhône French district. The expected number of births per year is 26,000. The study is designed for a 5-year period with three major goals: 1) measurement of the compliance rate of a voluntary test at 4 months of age; 2) evaluation of the technical value of high-pressure liquid chromatography (HPLC) as a screening method; and 3) detailed biological characterization of all detected tumors. 61,551 children were screened between May 1, 1990 and December 31, 1993. Participation was 69% in 1990, 81.5% in 1991, and over 83% in 1992. HPLC was a satisfactory assay method. The number of clinical examinations required for positive tests as defined in the protocol is 1 per 3,621 tests. The false positive rate is 1 per 3,583 tests. Eight neuroblastomas were discovered by-screening (one stage I, three stage II, one stage III, three stage IVs). All are alive and well but were good prognosis cases according to the main prognostic factors. Five patients were discovered before screening (so called Halo effect): one stage I, one stage III, three stage IVs. One died of disease and four are alive in complete remission after treatment. Two patients were false negative (one stage III with N-myc amplification, one stage IV with bad prognosis features) and three cases of neuroblastoma were missed because of noncompliance with the screening program. This pilot study concludes on the feasibility of a mass screening program in France. The estimated cumulative incidence of neuroblastoma at 3 years is 1 per 4,375 living births and overdiagnosis is probable. All the detected cases were of good prognosis and the false negative ones were poor prognosis cases.

[Developments in the treatment of osteosarcoma since 1979. Report of the statistics at the Centre Léon-Bérard]. / [Evolution du traitement de l'ostéosarcome depuis 1979. A propos de la statistique du Centre Léon-Bérard.

Seventy-two patients with a localized osteosarcoma were treated between September 1979 and December 1987 by neoadjuvant chemotherapy, local surgery and post-operative chemotherapy. Chemotherapy regimens varied throughout the years but always comprised high dose methotrexate with leucovorin rescue and adriamycin pre-operatively for children under the age of 15, and ifosfamid and cis platinum in adults. Post-operative chemotherapy for bad responders (greater than 10% of residual malignant cells), was at first an association of adriamycin and cis platinum, and later of holoxan and cis platinum. Surgery changed from amputation to local conservative surgery (graft or prosthesis) which is now the most frequent surgery--61% of the patients are alive and disease-free at 5 years. Good responders to pre-operative chemotherapy have a much better prognosis (81% at 5 years) than bad responders (45%). There is no significant difference according to age or pre-operative chemotherapy regimen.

[Massive bone grafts in children (apropos of 10 cases)]. / Greffes osseuses massives chez l'enfant (à propos de 10 cas).

We studied 10 massive - 70 degrees C frozen dried allografts (7 terminal intermediate) in children between the ages of 9 and 16 with malignant tumors (8 primary osteogenic sarcomas and 2 Ewing sarcomas). A good response to chemotherapy was observed. The average follow-up is 2 years (7-36 months). Results showed 4 mechanical complications (2 plate failures, 2 graft fractures) and no deaths. The surgical procedure and postoperative management are discussed and compared to prosthetic reconstruction.

Gallium-67 scanning in the staging of cryptogenetic fibrosing alveolitis and hypersensitivity pneumonitis.

Gallium-67 citrate is known to localize within inflammatory sites. Gallium-67 scanning is used for the evaluation of lung inflammation (i.e. alveolitis) during interstitial lung diseases. We investigated 27 patients with cryptogenetic fibrosing alveolitis (n = 17) and hypersensitivity pneumonitis (n = 10) using gallium-67 lung scanning and lung function tests (forced vital capacity, diffusing capacity, resting and exercise blood gases). Investigations were performed before and after one year of methylprednisolone treatment. None of eight healthy volunteers had any abnormal gallium-67 uptake. In all patients with cryptogenetic fibrosing alveolitis an initial abnormal gallium-67 uptake was observed (mean fixation index: 163 +/- 18). In addition, analysis of lung function tests a year after initial evaluation showed that unchanged or improving patients presented initially with a lower gallium-67 index than patients with evidence of deterioration (153.9 +/- 23.7 vs 251.0 +/- 23.3.; p less than 0.01). Similarly, among patients with hypersensitivity pneumonitis the index was lower in unchanged or improving patients than in those with deterioration (74.9 +/- 22 vs 226.7 +/- 4.9; p less than 0.05). Thus gallium-67 scanning is useful in the management of cryptogenetic fibrosing alveolitis and hypersensitivity pneumonitis.

Pitfalls and solutions in neuroblastoma diagnosis using radioiodine MIBG: our experience about 50 cases.

We have been among the first authors to point out that false negative cases could be observed with 131I-MIBG scintigraphy for neuroblastoma. We have observed until now ten of such false negative cases, 7 with primary tumor and 3 with bone metastases. Fifty 131I-MIBG scans were performed in 35 children with histologically proven neuroblastoma (24 grade IV) and compared to bone scans, CT and NMR images, ultrasound and clinical results. The visualization of the primary tumor shows a higher sensitivity with MIBG (79%) than with bone scans (47%) and a 100% specificity with each method. MIBG and bone scans, for bone metastases, are similar in the sensitivity (87.5%) but MIBG is much more specific (100%) than bone scan (81%). These results clearly confirm the superiority of MIBG scan for detection of primary tumor as well as bone metastases. However, MIBG is not always the most appropriate investigation, as shown by 11 observed pitfalls. Ten false negative cases have been observed and must be considered: in five out of 10 cases, bone scans performed with 99m Tc-HMDP made the diagnosis (3/7 cases of primary tumor and 2/3 cases of bone metastases). Moreover, one case was not usable due to a large digestive uptake. Our aim is to understand the reasons of the false negative by a meticulous analysis of every single case. The optimal procedure for neuroblastoma diagnosis, extent and follow up clearly seems to be the following strategy: MIBG scan must be firstly performed; in case of non-demonstrative scan the bone scan, which is complementary, will greatly contribute to the diagnosis.

[Analysis by broncho-alveolar lavage of the pulmonary uptake of gallium 67 in idiopathic diffuse interstitial fibrosis and sarcoidosis]. / Analyse par lavage broncho-alvéolaire de la fixation pulmonaire du gallium 67 au cours des fibroses interstitielles diffuses idiopathiques et des sarcoïdoses.

The pulmonary fixation of Gallium 67 has been studied by broncho-alveolar lavage (LBA) in a group of 10 cases of stage II pulmonary sarcoid, proven histologically, and in a group of 11 cases of idiopathic diffuse interstitial fibrosis (FID). The pulmonary activity of Gallium 67 was measured in vitro in a quantitative manner on a centrifuged clump and a supernatant of LBA as well as on the serum and in vivo in a semi-quantitative manner by the Line index. The alveolar Gallium activity has been correlated with different cytological and biochemical parameters of the lavage liquid. There was a narrow correlation in the serum between the Gallium 67 activity and the level of circulating transferrin. The fixation of Gallium in the cellular clump of LBA depends on the number of macrophages present in the clump and the total available radioactivity. The macrophages of the sarcoid and fibrosis cases picked up the gallium in a similar fashion, with an affinity all the more important as the total available radioactivity was weak. The radioactivity of the supernatant of the lavage liquid was quantitatively important and narrowly tied to the diffusible proteins present in the lavage. There was no correlation between the semi-quantitative Line index and the cytological or biochemical data in the fibrosis cases. In the sarcoid cases there was an inverse correlation with the polymorphonuclear leukocyte count. The semi-quantitative index was only correlated with alveolar gallium fixation level in the fibrosis group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Bone angiomatoses in children. Apropos of 3 personal cases]. / Les angiomatoses osseuses de l'enfant. A propos de 3 observations personnelles.

Three observations of skeletal angiomatosis are reported: one diffuse and two focal forms (Gorham's disease). The analysis of these cases and a review of the literature enhance the clinical and radiological presentation of this uncommon disease. The authors point out the interest of indirect lymphoscintigraphy and dwell on the gravity of its course, in spite of therapeutic attempts.

The hyperactive halo as a sign of renal graft death in 99mTc-DTPA studies.

In scintigraphic studies of renal transplants the absence of renal perfusion and clearance have been demonstrated to have many possible pathologic etiologies, vascular obstructions, and rejections. Increased perinephric activity was suggested as a sign of renal infarction and its absence may indicate potential renal viability. A case is presented in which a hyperactive halo was seen when the graft was dying.

[Negative bone scintigraphy in osteomyelitis in children. Difficulties in interpretation]. / La scintigraphie osseuse négative dans l'ostéomyélite de l'enfant. Difficulté d'interprétation.

The authors relate 7 cases of hematogenous osteomyelitis in children where skeletal scintigraphy with TC 99m diphosphonate was said as normal. They analyse the lack of positive radionuclide findings; misinterpretation, abnormal tracer accumulation which probably relates to regional hyperemia, transient area of discreased uptake of the tracer in the early phase of the disease and real negative bone scan; these cases are rare; when there is a high suspicion of osteomyelitis in spite of a normal bone scan Gallium imaging may be helpful.

[Endolymphatic curietherapy by lymphography with labelled lipiodol in Hodgkin's disease. A report on 408 cases (author's transl)]. / La curiethérapie endolymphatique par lymphographie au lipiodol marqué dans la maladie de Hodgkin. 408 observations.

The results of 373 lymphography examinations with radioactive lipiodol, conducted in 408 patients with Hodgkin's disease for diagnostic and prophylactic therapeutic purposes, during investigations carried out from 1966 to 1973 are analyzed. Tolerance was always excellent, especially from the hematological point of view. The efficacy of the procedure can be assessed by the fact that there were only 6% of failures (21/373) in glandular regions irradiated in this way for prophylactic purposes. Relapses occur more frequently in the inguino-iliac and lumbo-aortic regions than in the pelvic chains which were perfectly protected. This technique also enables both pelvic irradiation and ovarian protection in young women without any risk of failure. The procedure is particularly indicated in the following cases: supradiaphragmatic stages I and II, whatever the sex, and stage III especially in women. In sub-diaphragmatic stages I and II, it allows, in favourable cases, the ovarian function in women to remain intact by limiting external irradiation to invaded regions only.