Metatarsal giant cell tumors and giant cell reparative granuloma are similar entities.

Light and electron microscopic investigations and studies of the resorption ability in vitro of giant cells were done in two patients with giant cell osteolytic lesions of metatarsal bone. Giant cells harvested from both patients were similar in morphologic features and ability to resorb dentin. After other diagnoses of osteolytic lesions of metatarsal bone were ruled out, one lesion was considered a giant cell reparative granuloma and the other a true giant cell tumor of bone. Clinical, radiologic, ultrastructural, functional studies, and data in the literature, indicated that giant cell reparative granuloma only can be differentiated from giant cell tumor by younger age at diagnosis and the occurrence of giant cell clusters. All other features (cortical erosion, high rate of recurrence, hemorrhage areas, predominant intercellular collagenous substance) are characteristic of both lesions. If these two giant cell lesions are different entities, more accurate means are needed to distinguish them.

Bone remodelling and tumour grade modifications induced by interactions between bone and swarm rat chondrosarcoma.

Chondrosarcoma is currently defined as a malignant cartilage tumour arising de novo or within a pre-existing benign cartilage tumour. Chondrosarcoma can be surgically resected, but all grades have significant rates of local recurrence. The purpose of the present study was to develop an animal intraosseous chondrosarcoma model simulating the progression of human chondrosarcoma and elucidating its behaviour and biology. An intraosseous Swarm rat model was designed to assess interactions between bone and chondrosarcoma. A comparison of tumour grading was carried out according to transplantation site. The effects of chondrosarcoma cells (SRC cells) on the mineralisation capacities of osteoblasts and on osteoclast differentiation were studied in relation to modifications observed in vivo at the cellular level. Transplantation of Swarm rat chondrosarcoma within bone marrow or contiguous to induced periosteal lesions led to extensive bone remodelling with trabecular bone rarefaction and periosteal apposition. Transplantation in close contact to bone but without any periosteal lesion had no effect on bone, suggesting that bone healing factors interact with tumour development. With the intramedullary model, the development of tumours of different grade confirms that bone environment is an important factor in malignancy. A decrease of bone nodule formation was noted after cocultures of SRC cells with rat bone marrow, but there was no modification of osteoclast differentiation after cultures of total rabbit bone cells with SRC cells. These data reveal the importance of interactions between bone environment and tumour in inducing bone remodelling and variations in tumour malignancy.

Leukaemia inhibitory factor (lif) is expressed in hypertrophic chondrocytes and vascular sprouts during osteogenesis.

Avascular cartilage is replaced by highly vascularized bone tissue during endochondral ossification, a process involving capillary invasion of calcified hypertrophic cartilage in association with apoptosis of hypertrophic chondrocytes, degradation of cartilage matrix and deposition of bone matrix. All of these events are closely controlled, especially by cytokines and growth factors. Leukaemia inhibitory factor (LIF), a member of the gp130 cytokine family, is involved in osteoarticular tissue metabolism and might participate in osteogenesis. Immunohistochemical staining showed that LIF is expressed in hypertrophic chondrocytes and vascular sprouts of cartilage and bone during rat and human osteogenesis. LIF is also present in osteoblasts but not in osteoclasts. Observations in a rat endochondral ossification model were confirmed by studies of human cartilage biopsies from foetuses with osteogenesis imperfecta. LIF was never detected in adult articular chondrocytes and bone-marrow mesenchymal cells. These results and other data in the literature suggest that LIF is involved in the delicate balance between the rate of formation of calcified cartilage and its vascularization for bone development.

Potential synergies between matrix proteins and soluble factors on resorption and proteinase activities of rabbit bone cells.

Human growth hormone (GH) has recently been found to stimulate osteoclastic resorption, cysteine-proteinase and metalloproteinase activities (MMP-2 and MMP-9) in vitro via insulin-like growth factor-I (IGF-I) produced by stromal cells. The present study investigated the effects of two extracellular matrix components (vitronectin and type-I collagen) on hGH- and hIGF-1-stimulated osteoclastic resorption and proteinase activities in a rabbit bone cell model. After 4 days of rabbit bone cell culture on dentin slices with vitronectin coating, hGH and hIGF-1 stimulated bone resorption and hIGF-1 upmodulated cysteine-proteinase activities. MMP-2 expression (but not resorption, cathepsin or MMP-9 activities) was upmodulated by hGH and hIGF-1 on dentin slices coated with type I collagen as compared to those without coating. Then, vitronectin was synergistic with hIGF-1 in the regulation of cysteine-proteinase production whereas collagen showed synergy with hGH and hIGF-1 in the regulation of MMP-2 production. Anti-alphavbeta3 totally abolished the effects of hGH and hIGF-1 on metalloproteinase release, but had no influence on cathepsin release. The results suggest that cysteine-proteinase modulation is not mediated by alphavbeta3 integrin (strongly expressed on osteoclastic surface) whereas the resorption process and metalloproteinase modulation are clearly mediated by this integrin. Our finding about the collagen coating also suggests that hGH- and hIGF-1-stimulated MMP-2 activity are mediated, along with alphavbeta3 integrin, by another adhesion molecule.

Cysteine protease production by human osteosarcoma cells (MG63, SAOS2) and its modulation by soluble factors.

The production of cysteine protease by two human osteosarcoma cell lines (MG-63 and SaOS2) was analyzed, as well as their modulation by interleukin 1beta (hIL-1 beta), interleukin 6 (hIL-6), insulin growth factor-1 (hIGF-1), oncostatin M (hOSM), leukemia inhibitory factor (hLIF) and growth hormone (hGH). Cysteine protease activities were detected using a synthetic substrate. The protease activities (especially cathepsin L activity) of both cell lines were increased significantly in the presence of hIL-1 beta, hIL-6 and hOSM. In contrast, hIGF-1 and hGH decreased these activities, and no effect was detectable in the presence of hLIF. The addition of antibodies against the gp-130 chain of the hIL-6 and hOSM receptors totally inhibited the stimulating effect of these two cytokines on cysteine protease activities. In increasing collagen type I degradation, hIL-1beta, hIL-6 and hOSM could be involved in bone resorption, whereas the inhibitory action of hIGF-1 and hGH on collagen type I degradation suggest that this factor could play a role in bone formation.

Thyroid carcinomas after irradiation for a first cancer during childhood.

BACKGROUND: The thyroid gland is among the most radiosensitive organs. However, little is known about the long-term risk of developing a thyroid tumor after fractionated external radiotherapy for cancer during childhood. OBJECTIVE: To study the long-term risk of developing a thyroid tumor in 4096 three-year survivors of childhood cancer treated between May 1942 and December 1985 in 8 centers in France and the United Kingdom, 2827 of whom had received external radiotherapy. METHODS: A wide range of radiation doses were given to the thyroid: 1164 children received less than 0.5 Gy and 812 received more than 5.0 Gy, the average dose being 7.0 Gy. RESULTS: After mean follow-up of 15 years (range, 3-45 years), 14 patients-all of whom had received radiotherapy-developed a clinical thyroid carcinoma. Within the cohort, the relation between radiation dose to the thyroid and risk of thyroid carcinoma and adenoma was similar to that observed in patients who received radiotherapy during childhood for other reasons, such as an excess relative risk per gray of 4 to 8, up to a few gray. In contrast, compared with thyroid cancer incidence in the general population, the standardized incidence of thyroid carcinoma was much higher than expected from the dose-response relationship estimated within the cohort and from patients who received radiotherapy during childhood for other reasons: a dose of 0.5 Gy was associated with a standardized incidence ratio of 35 (90% confidence interval, 10-87) and a dose of 3.6 Gy with a standardized incidence ratio of 73 (90% confidence interval, 28-153). We did not show a reduction in excess relative risk per gray with use of an increasing number of fractions. CONCLUSION: Although we cannot estimate the exact proportion, it is probable that some or all children who are treated for cancer are predisposed to developing a thyroid carcinoma.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Risks of brain tumour following treatment for cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy.

A cohort of 4,400 persons treated for various cancers of childhood in France and the UK was followed up over an extended period to assess risks of subsequent brain tumour in relation to the radiotherapy and chemotherapy that the children received for their first cancer. Elevated risks of subsequent brain tumours were associated with first central nervous system (CNS) tumour (two-sided p = 0.0002) and neurofibromatosis (two-sided p = 0.001). There was also elevated brain tumour risk (two-sided p = 0.003) associated with ionising radiation exposure, the risk being concentrated among benign and unspecified brain tumours. The radiation-related risk of benign and unspecified brain tumours was significantly higher than that of malignant brain tumours (two-sided p< or =0.05); there was no significant change of malignant brain tumour risk with ionising radiation dose (two-sided p > 0.2). In general, there were no strong associations between alkylating agent dose and brain tumour risk. The only significant association between brain tumour risk and alkylating agent dose was in relation to compounds used (bleomycin, chloraminophen) that are thought not to deliver substantial doses to the brain; the statistical significance of the trend with dose depended on a single case, and thus must be considered a weak result.

Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood.

Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.

Dose distribution throughout the body from radiotherapy for Hodgkin's disease in childhood.

BACKGROUND AND PURPOSE: The individual dosimetry performed for a multicentre European cohort study of second malignant neoplasm following radiotherapy for a solid cancer in childhood demonstrated a large variation in the radiation doses estimated to any site. MATERIALS AND METHODS: From this study we have extracted the present work, i.e. estimation of doses for patients who underwent radiotherapy for Hodgkin's disease in their childhood. These patients were treated using high energy X-rays from linear accelerators (MV group), gamma-radiation from Cobalt machines (Cobalt group), soft X-rays from orthovoltage machines (kV group) and electron beams from accelerators (MeV group) at six French and UK centres. All patients started their radiotherapy between 1955 and 1985 and about 12% of them received more than one beam quality. Most of the patients were irradiated with large mantle AP/PA or partial mantle fields. Patients with transdiaphragmatic extension were also irradiated using inverted-Y paraaortic fields. The absorbed doses at the 91 skeleton points are used to calculate the mean dose to the active bone marrow. RESULTS: Estimates of the median and mean doses, standard deviations and ranges to 13 specific sites of the body and to the active bone marrow are reported. Depending upon the size and sex of patients, target volume and position and radiotherapy techniques, the estimated doses are highly spread, attaining 0.19-106.07% of the target dose. This study underscores the need for individual dosimetry in epidemiological studies. Comparison with the available measured and calculated doses to the ovary and testis shows good agreement. CONCLUSION: This study underscores the need for individual dosimetry in epidemiological studies.

Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood.

BACKGROUND: Radiotherapy and chemotherapy are associated with an increased risk of second malignant neoplasm (SMN). An association between SMN and familial aggregation has also been shown. The aim of this study was to investigate the role of familial factors in the risk of SMN and their potential interaction with the effect of treatment. METHODS: We devised a case-control study of 25 children with SMN (cases) and 96 children with no SMN after a cancer treatment (controls), taken from a cohort of 649 children treated at our institution between 1953 and 1985. A complete family history was obtained for patients and controls and a familial index defined to evaluate the degree of familial aggregation. The radiation dose given at 151 sites in the body was estimated for each radiotherapy course for each child. FINDINGS: Among family members of the 25 SMN cases, there were ten with early-onset (< or = 45 years) cancer, compared with eight among relatives of the 96 controls. Compared with patients who had no family history of early-onset cancer, those with one or more affected family members had an odds ratio for SMN of 4.7 (95% CI 1.3-17.1; p = 0.02). Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausen's disease) did not affect this risk substantially. INTERPRETATION: Both genetic factors and exposure to ionising radiation have independent effects on the risk of SMN. Follow-up of children treated for cancer should be especially vigilant when there is a family history of early-onset cancer.

Estimation of the radiation dose delivered to any point outside the target volume per patient treated with external beam radiotherapy.

The methodology we have developed to study dose distribution outside the target volume during external beam radiotherapy allows us to determine the dose received by the patient arising from leakage radiation and scattered radiation from both the head of the treatment machine and from the treatment room. It also allows us to evaluate the dose due to photon scattering in the patient by means of a dedicated 3-D algorithm permitting computations for the whole body of the patient and taking into account height, sex and anatomical data at the time of the treatment, dosimetric data and lung heterogeneity parameters. This methodology offers solid criteria for recommendations concerning radiation protection.

Solid malignant neoplasms after childhood irradiation: decrease of the relative risk with time after irradiation.

The pattern of the temporal distribution of solid cancer incidence after irradiation in childhood is not well known, although, its importance in radioprotection is well known. We studied a cohort of 1,055 children from 8 European cancer centres, who received radiotherapy between 1942 and 1985 for a first cancer in childhood. After a mean follow-up of 19 years, 26 children developed a solid second malignant neoplasm (SMN), as compared to 5.6 expected from general population rates. Both the excess relative risk and the excess of absolute risk of solid SMN were higher among children who were younger at time of the irradiation. After reaching a maximum 15 to 20 years after irradiation, the excess relative risk of SMN decreased with time after irradiation, when controlling for age at irradiation and sex. The analysis of the risk of thyroid, brain and breast cancer together, as a function of the dose averaged on these 3 organs lead to similar results.

Class I and II HLA typing after a 10 Gy-4 hour therapeutic total body irradiation.

Class I and II HLA typing was investigated before and at various intervals after a 10 Gy total body irradiation delivered over 4 h, prior to allogeneic bone marrow graft for various hematological malignancies, in 14 patients. A reliable class I HLA typing appeared to be possible in almost all cases 6-8 hours after the start of irradiation but was only possible in 5 patients after 24 h. Preliminary results with class II antigens might suggest a more marked "fragility" of this antigen class after irradiation. These results encourage the drawing of blood samples for HLA grouping as soon as possible after accidental whole-body irradiation.

Prospective study of the clinical symptoms of therapeutic whole body irradiation.

Thirty-one selected patients with various haematological malignancies who received a 10 Gy-4 h total body irradiation (TBI) at the Institut Gustave Roussy 24 h before high dose cyclophosphamide for bone marrow transplantation, were prospectively evaluated for gastrointestinal symptoms, body temperature, consciousness, headache, xerostomia, parotiditis, ocular symptoms, blood pressure, and respiratory and cutaneous signs for 24 h. In spite of prophylactic administration of various anti-emetic agents, 90% of the patients experienced nausea and 80% experienced vomiting. An almost constant body temperature peak--up to 40.8 degrees C--was registered 6 h after the start of irradiation. No drowsiness was reported since the introduction of the new anti-emetic agent Ondansetron. Nearly half the patients (42%) complained of headache. The proportion of patients experiencing early (during TBI) xerostomia was 61%. 74% of patients complained of parotiditis in the first 24 h. Although this low dose rate whole body irradiation is not likely to be exactly replicated in many accidental human exposures, the incidence rate and the time-course of the observed prodromal phase symptoms may prove helpful for early triage in the case of accidental irradiation.

Long-term effects on the thyroid of irradiation for skin angiomas in childhood.

Thyroid morphological and functional tests were carried out on 396 patients who were recalled because their thyroid gland had been exposed during hemangioma irradiation in childhood 11-43 years before (median, 22 years). The irradiations have been classified into two categories based on their duration: short duration, from a few seconds to a few minutes (90S and X rays), and long duration, from 30 min to several hours (336Ra, 192Ir, and 32P). The risk of a thyroid nodule increased significantly with the total dose received by the thyroid; it was linked to the dose delivered in the short duration (excess relative risk per Gy = 10), but not to that delivered in the long duration. The risk of a simple diffuse goiter, which also increased with the dose received by the thyroid, did not depend on the duration of the irradiation. In conclusion, this study emphasizes the role of the dose rate in the risk of thyroid nodule, the detection of which does not appear to be improved by plasma thyroid marker determination.

Epidemiological evidence for a common mechanism for neuroblastoma and differentiated thyroid tumour.

Because genetic predisposition probably plays an important role in the aetiology of most of childhood cancers, studies of second primaries occurring after these cancers may be particularly informative about possible common genetic mechanisms in both of these cancers. We have studied the incidence of thyroid tumours occurring after cancer in childhood in a cohort of 592 children treated before 1970. Among these children, six later developed a thyroid carcinoma, and 18 developed a thyroid adenoma. Radiation doses received to the thyroid by each of the irradiated children have been estimated using individual radiotherapeutic technical records. Thyroid carcinomas and thyroid adenomas were five times more frequent after irradiation for neuroblastoma than after irradiation for any other first cancer. This ratio did not depend on sex, nor on time elapsed since irradiation, nor on dose of radiation received for the thyroid gland. This result suggests that there is a common mechanism for the occurrence of neuroblastoma and of differentiated thyroid tumour.

[Influence of the distribution of the dose on carcinogenic effects of ionizing radiations of low lineal energy transfer on the thyroid tissue]. / Influence de l'étalement de la dose sur les effets cancérigènes des radiations ionisantes à faible transfert linéique d'énergie sur le tissu thyroïdien.

The frequency of thyroid nodules has been studied among 396 children irradiated for a hemangioma, from 1946 to 1973. 226Ra, 192Ir, 90Y, 32P, 90Sr, as well as X-rays had been used for treatments. The doses of radiation received by the thyroid of each child have been estimated retrospectively. The irradiations have been classified in two categories based on their duration: less than 30 min., and more than 30 min. The doses received with each of these two types of irradiation were summed for each patient. The risk of thyroid nodule increased as a function of the dose to thyroid only for the dose delivered with the short duration. This study emphases the importance of the role of the dose rate in the risk of radio-induced tumour.

Breast cancer treatment: which inhomogeneities have to be taken into account?

A true three-dimensional algorithm has been developed at the Gustave Roussy Institute, which can evaluate the dose distribution in inhomogeneous media. In this paper, an explanation is given that, in our view, problems of inhomogeneity cannot be solved without accounting for the third dimension and its contribution to scattered dose calculation.