Radiotherapy in the management of lung oligometastases.

In recent years, the development of both medical imaging and new systemic agents (targeted therapy and immunotherapy) have revolutionized the field of oncology, leading to a new entity: oligometastatic disease. Adding local treatment of oligometastases to systemic treatment could lead to prolonged survival with no significant impact on quality of life. Given the high prevalence of lung oligometastases and the new systemic agents coming with increased pulmonary toxicity, this article provides a comprehensive review of the current state-of-art for radiotherapy of lung oligometastases. After reviewing pretreatment workup, the authors define several radiotherapy regimen based on the localization and size of the oligometastases. A comment on the synergistic combination of medical treatment and radiotherapy is also made, projecting on future steps in this specific clinical setting.

Radiotherapy in the management of synchronous metastatic lung cancer.

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers.

[Stereotactic body radiation therapy for hepatocellular carcinoma: Results from a retrospective multicentre study]. / Radiothérapie en conditions stéréotaxiques du carcinome hépatocellulaire : résultats d'une étude rétrospective multicentrique.

PURPOSE: The purpose of this paper was to describe local control, overall survival, progression-free survival and toxicity of CyberKnife®-based stereotactic body radiation therapy of hepatocellular carcinoma. MATERIAL AND METHODS: Records of all the patients treated for hepatocellular carcinoma at the Eugene-Marquis cancer centre, Rennes and the Bretonneau hospital, Tours (France), between November 2010 and December 2016, were reviewed. Radiation therapy was performed as a salvage treatment, while awaiting liver transplantation or if no other treatment was possible. RESULTS: One hundred and thirty-six patients were consecutively included in the study. The median follow-up was 13months. Median total dose prescribed, fractionation and overall treatment time were respectively 45Gy, three fractions and 5 days. Overall survival, progression-free survival and local control rates at 1year and 2years were 79.8 % and 63.5 %, 61.3 % and 39.4 %; 94.5 % and 91 %. Two grade 3 acute toxicity events and two grade 4 late toxicity events corresponding to a duodenal ulcer have been reported. Seven patients underwent classic radiation-induced hepatitis and 13 patients showed non-classical radiation-induced hepatitis. Barcelona Clinic Liver Cancer stage, World Health Organisation grade and planning target volume were correlated with overall survival in univariate Cox analysis. CONCLUSION: Stereotactic body radiation therapy is effective and well-tolerated for inoperable hepatocellular carcinoma or as a bridge to liver transplantation. Toxicity is mainly related to cirrhotic background and requires a selection of patients and strict dose constraints.

[Chemoradiation for oesophageal cancer: A critical review of the literature]. / Chimioradiothérapie des cancers de l'œsophage : revue critique de la littérature.

Locally advanced oesophageal cancer treatment requires a multidisciplinary approach with the combination of chemotherapy and radiotherapy for preoperative and definitive strategy. Preoperative chemoradiation improves the locoregional control and overall survival after surgery for locally advanced oesophageal cancer. Definitive chemoradiation can also be proposed for non-resectable tumours or medically inoperable patients. Besides, definitive chemoradiation is considered as an alternative option to surgery for locally advanced squamous cell carcinomas. Chemotherapy regimen associated to radiotherapy consists of a combination of platinum derived drugs (cisplatinum or oxaliplatin) and 5-fluorouracil or a weekly scheme combination of carboplatin and paclitaxel according to CROSS protocol in a neoadjuvant strategy. Radiation doses vary from 41.4Gy to 45Gy for a preoperative strategy or 50 to 50.4Gy for a definitive treatment. The high risk of lymphatic spread due to anatomical features could justify the use of an elective nodal irradiation when the estimated risk of microscopic involvement is higher than 15% to 20%. An appropriate delineation of the gross tumour volume requires an exhaustive and up-to-date evaluation of the disease. Intensity-modulated radiation therapy represents a promising approach to spare organs-at-risk. This critical review of the literature underlines the roles of radiotherapy for locally advanced oesophageal cancers and describes doses, volumes of treatment, technical aspects and dose constraints to organs-at-risk.

Preoperative radiotherapy in breast cancer patients: 32 years of follow-up.

This study evaluates the long-term outcomes of a retrospective cohort of breast cancer (BC) patients who had received curatively intended premastectomy radiation therapy (RT). We analysed locoregional control, disease-free survival (DFS) and overall survival (OS), pathological complete remission (pCR), predictors thereof, and immediate safety. The series consisted of 187 patients with a median age of 49 years [43-60] and T2-T4 or N2 tumours. Between 1970 and 1984, they had received slightly hypofractionated RT to the whole breast, ipsilateral supraclavicular fossa and axilla ± the internal mammary chain (45-55 Gy/18 fractions of 2.5 Gy/34 days) systematically followed by a modified radical mastectomy with an axillary dissection. No other preoperative treatment was given. Among the 166 centrally reviewed tumour biopsy specimens, 22% had a triple-negative (TN) phenotype, 17% were HER2 3 + or amplified and 61% were ER+. The median follow-up was 32 years [23-35]. The 25-year locoregional control rate was 89% [93%-82%] and the 25-year DFS and OS rates were identical, 30% [24%-37%]. A pCR in the tumour and lymph nodes had been achieved in 18 among all patients (10%), but in 26% with TN disease. In the multivariate analysis, the TN status was the only predictive factor of pCR (OR = 5.49, 95% confidence interval [CI] 1.87-16.1, p = 0.002). Also, the pN status (HR = 1.69, [1.28-2.22], p = 0.0002) and TN subtype (HR = 1.80, [1.00-3.26], p = 0.05) exerted a significant prognostic impact on OS. The postoperative complication rate (grade >2) was 19% with 4.3% of localized skin necrosis. Preoperative RT followed by radical surgery is feasible and associated with good long-term locoregional control.

[Chordoma]. / Les chordomes.

PURPOSES: To review in the literature, all the epidemiological, clinical, radiological, histological and therapeutic data regarding chordomas as well as various notochordal entities: ecchordosis physaliphora, intradural and intraparenchymatous chordomas, benign notochordal cell tumors, parachordomas and extra-axial chordomas. To identify different types of chordomas, including familial forms, associations with tuberous sclerosis, Ollier's disease and Maffucci's syndrome, forms with metastasis and seeding. To assess the recent data regarding molecular biology and progress in targeted therapy. To compare the different types of radiotherapy, especially protontherapy and their therapeutic effects. To review the largest series of chordomas in their different localizations (skull base, sacrum and mobile spine) from the literature. MATERIALS: The series of 136 chordomas treated and followed up over 20 years (1972-2012) in the department of neurosurgery at Lariboisière hospital is reviewed. It includes: 58 chordomas of the skull base, 47 of the craniocervical junction, 23 of the cervical spine and 8 from the lombosacral region. Similarly, 31 chordomas in children (less than 18 years of age), observed in the departments of neurosurgery of les Enfants-Malades and Lariboisière hospitals, are presented. They were observed between 1976 and 2010 and were located intracranially (n=22 including 13 with cervical extension), 4 at the craniocervical junction level and 5 in the cervical spine. METHODS: In the entire Lariboisière series and in the different groups of localization, different parameters were analyzed: the delay of diagnosis, of follow-up, of occurrence of metastasis, recurrence and death, the number of primary patients and patients referred to us after progression or recurrence and the number of deaths, recurrences and metastases. The influence of the quality of resection (total, subtotal and partial) on the prognosis is also presented. Kaplan-Meier actuarial curves of overall survival and disease free survival were performed in the entire series, including the different groups of localization based on the following 4 parameters: age, primary and secondary patients, quality of resection and protontherapy. In the pediatric series, a similar analysis was carried-out but was limited by the small number of patients in the subgroups. RESULTS: In the Lariboisière series, the mean delay of diagnosis is 10 months and the mean follow-up is 80 months in each group. The delay before recurrence, metastasis and death is always better for the skull base chordomas and worse for those of the craniocervical junction, which have similar results to those of the cervical spine. Similar figures were observed as regards the number of deaths, metastases and recurrences. Quality of resection is the major factor of prognosis with 20.5 % of deaths and 28 % of recurrences after total resection as compared to 52.5 % and 47.5 % after subtotal resection. This is still more obvious in the group of skull base chordomas. Adding protontherapy to a total resection can still improve the results but there is no change after subtotal resection. The actuarial curve of overall survival shows a clear cut in the slope with some chordomas having a fast evolution towards recurrence and death in less than 4 years and others having a long survival of sometimes more than 20 years. Also, age has no influence on the prognosis. In primary patients, disease free survival is better than in secondary patients but not in overall survival. Protontherapy only improves the overall survival in the entire series and in the skull base group. Total resection improves both the overall and disease free survival in each group. Finally, the adjunct of protontherapy after total resection is clearly demonstrated. In the pediatric series, the median follow-up is 5.7 years. Overall survival and disease free survival are respectively 63 % and 54.3 %. Factors of prognosis are the histological type (atypical forms), localization (worse for the cervical spine and better for the clivus) and again it will depend on the quality of resection. CONCLUSIONS: Many different pathologies derived from the notochord can be observed: some are remnants, some may be precursors of chordomas and some have similar features but are probably not genuine chordomas. To-day, immuno-histological studies should permit to differentiate them from real chordomas. Improving knowledge of molecular biology raises hopes for complementary treatments but to date the quality of surgical resection is still the main factor of prognosis. Complementary protontherapy seems useful, especially in skull base chordomas, which have better overall results than those of the craniocervical junction and of the cervical spine. However, we are still lacking an intrinsic marker of evolution to differentiate the slow growing chordomas with an indolent evolution from aggressive types leading rapidly to recurrence and death on which more aggressive treatments should be applied.

[Radiotherapy in central neurocytoma and review of literature]. / Place de la radiothérapie dans les neurocytomes centraux et revue de la littérature.

Central neurocytoma is a rare primary central nervous system tumour of young adults with good prognosis. Typical and atypical forms are described according to various histologic and histopathologic parameters. Central neurocytoma develops in the periventricular areas and is revealed by increased intracranial pressure. The tumour exhibits typical characteristics on CT scan and MRI and a characteristic peak of glycine on spectroscopy-MRI. The main treatment is total resection, which is achievable only in half of the cases. External beam therapy improves local control of partially resected and/or atypical central neurocytoma. Many studies show that stereotactic radiotherapy can be used in the therapeutic management as exclusive treatment, in postoperatives residues and in case of distant recurrence. Chemotherapy is the last line of treatment in refractory forms, especially in the forms with extracranial and/or neuromeningeal spread and in recurrent forms after treatment with surgery and/or radiotherapy.

[Radiation therapy of sinonasal natural killer/T-cell lymphoma]. / Radiothérapie des lymphomes NK/T localisés aux fosses nasales.

Natural killer (NK)/T-cell lymphoma are part of lymphoproliferative diseases, they are rare in Europe and the United States but relatively common in Asia and South America. Natural killer (NK)/T-cell lymphoma present clinically as destructive lesions of the upper aerodigestive tract with perforation of deep structures of the face, destruction of the palate or an invasion of orbits. Treatment modalities of these lymphomas are still discussed because of the lack of available studies and the rarity of this disease. Radiotherapy provides a rapid control of the disease and is positioned as a major treatment of localized stages of NK/T-cell lymphoma of the nasal cavity. We therefore studied the different forms of radiation therapy in the early stages of nasal NK/T-cell lymphoma.

How infections with non-retroviral RNA viruses may be involved in the development of neoplasia.

There have been reports of associations of infections with non-retroviral RNA viruses and tumour development. A hypothesis is proposed as to how non-retroviral RNA viruses may play a role in the development of neoplasia. It is based on a recent report of the detection of complementary DNA (cDNA) of the RNA virus lymphocytic choriomeningitis virus in mouse and hamster cells. This lends credence to the claim made in 1975 of the detection of cDNA copies of genomic DNA of three non-retroviral RNA viruses integrated into the DNA of host cells. Briefly, the hypothesis proposes that at least one cDNA fragment of a non-retroviral RNA virus is synthesized and integrated into the genome of the host cell in a way that could lead or contribute to tumour development. General approaches for testing the hypothesis are outlined.

Experience with high dose dexamethasone in the treatment of chronic symptomatic immune thrombocytopaenia.

OBJECTIVE: To evaluate the efficacy of high dose dexamethasone (HDD) as treatment for symptomatic chronic immune thrombocytopaenia (ITP). DESIGN: A non-randomised intervention study with final evaluation one year after treatment, comparing findings before and after intervention. SETTING: Tygerberg University Hospital, South Africa. PARTICIPANTS: A consecutive sample of six children with chronic (duration more than six months) ITP. The diagnosis of ITP was based on a platelet count of < 100 x 10(9)/1 together with appropriate clinical, laboratory and bone marrow findings. INTERVENTIONS: All children treated with dexamethasone 0.5 mg/kg/day intravenously for four days every 28 days for a total of six cycles. MAIN OUTCOME MEASURES: A rise in platelet count maintained for a least one year associated with the disappearance of symptoms due to thrombocytopaenia. RESULTS: Treatment was easy to administer and well tolerated with transient side effects in only two children. Three patients had a rise in platelet count of > 50 x 10(9)/1 during treatment and three had platelet counts of > 30 x 10(9)/1 after completion of therapy but only one at one month and one at six months after completion of the six courses respectively. None of the patients showed a sustained rise in platelet count during and after HDD treatment. CONCLUSION: HDD did not cause a significant sustained rise in the platelet count in children with chronic symptomatic ITP. If high dose prednisone and IVIG fail, a splenectomy should be considered in children over five years of age.

Bone mineral density in long-term survivors of childhood cancer.

Bone mineral density (BMD) of the lumbar spine was measured in 97 long-term survivors of childhood cancer 5-23 years after diagnosis using dual-energy X-ray absorptiometry (DXA). They had been treated for acute leukemia (n = 22), brain tumors (n = 16), lymphomas (n = 16), Wilms' tumor (n = 10), neuroblastoma (n = 7) and other cancers (n = 26). The correlations between BMD and the Z-scores for weight for height, height for age and weight for age at diagnosis and follow-up were evaluated with stepwise multiple regression. Correlations with cumulative corticosteroid and radiation dose were examined with Spearman's correlation coefficient. The number of nature of fractures were noted. A BMD Z-score of below -2 was present in 13 and a BMD Z-score of -1 to -2 in 31 children. In total, a low BMD was observed in 45% of children. Height for age at follow-up correlated significantly with BMD Z-score. Increasing doses of cranial irradiation (18-54 Gy) were associated with lower BMD (p = 0.001, Spearman). This was true also for 22 children with acute lymphoblastic leukemia (ALL) who had received 18-24 Gy cranial irradiation (p = 0.04, Spearman). Fractures occurred in 14 children following trauma. The difference in BMD Z-scores of children with and without fractures did not achieve statistical significance although the majority of the children with fractures had low BMD Z-scores. The significant inverse correlation between height for age at follow-up and BMD must be interpreted with the realization that DXA is not a volumetric measurement of BMD and that short stature is associated with a smaller skeletal mass.

Hodgkin's disease in children in southern Africa: epidemiological characteristics, morbidity and long-term outcome.

We reviewed 39 children < 15 years of age treated for Hodgkin's disease (HD) from 1973 to 1996. There were seven black, 12 white and 20 coloured children (of mixed ethnic origin). The M:F ratio was 2.9:1 and the median ages 147, 124 and 119 months in white, coloured and black children, respectively. Coloured and black children came mainly from a poor socio-economic background. Cervical lymphadenopathy was present in 74% and systemic symptoms in 51% of cases. Five per cent had clinical stage I, 41% stage II, 28% stage III and 26% stage IV disease. Two children underwent a staging splenectomy. The majority of white children presented with stages I and II and the majority of black and coloured children with stages III and IV HD. Nodular sclerosing (59%), mixed cellularity (40%) and lymphocyte-depleted (43%) were the most common histological subtypes in white, coloured and black children, respectively. Epidemiologically, white children fitted the criteria for HD type I and coloured and black children the criteria for HD type III. Nineteen children were treated with ChlVPP (chlorambucil, vinblastine, prednisone, procarbazine) and 20 with MOPP (mustine, Oncovin, procarbazine, prednisone) and/or ABVD (Adriamycin, bleomycin, vinblastine, DTIC) with involved field radiotherapy to bulky mediastinal disease. The projected 10-year survival after ChlVPP or MOPP/ABVD therapy was similar at 52%. In stages I and II, HD projected survival at 5 and 10 years was 85%, and in stages III and IV it was 82% at 5 and 48% at 10 years. The relapse rate was 47% in stage II, 45% in stage III and 44% in stage IV. Tuberculosis was suspected and treated in five children at the time of, and in seven children (three confirmed) subsequent to, the diagnosis of HD. Varicella developed in six and herpes zoster in five children. Five treatment-related deaths were due to septicaemia following splenectomy (two), marrow failure, corpulmonale and secondary leukaemia.

The Tygerberg Hospital Children's Tumour Registry 1983-1993.

This study records the disease profile and outcome of all 492 children with confirmed cancer below the age of 15 who were admitted to Tygerberg Hospital, South Africa, from 1983 to 1993. The black (48.3%), so-called coloured (30.3%) and caucasian (21.3%) children did not represent a confined geographical area. Leukaemia (22.8%), brain tumours (20.5%), lymphomas (15.2%), nephroblastomas (10%), neuroblastomas (8.5%) and retinoblastomas (5.7%) were the most common tumours. All children were treated with standard protocols and included in the Kaplan-Meier survival analyses. 14 patients were lost to follow-up. Projected survival in (acute lymphoblastic leukaemia) ALL was 63% in white children, but only 17% in black children. Survival was 65% in stage 1 and 2 Wilms' tumour, and exceeded 50% in medulloblastoma and astrocytoma. So-called African Burkitt's lymphoma occurred in all population groups. Overall, 5-year survival in Hodgkin's disease was 70%. Black and coloured children with neuroblastoma presented mainly with stage 3 and 4 disease. All 26 black and coloured children with retinoblastoma had a negative family history and advanced disease which needed enucleation.

Increased peripheral lymphocytes, lymphoid hepatitis and anaemia in African vervet monkeys seropositive to retroviruses.

Wild-caught African Vervet monkeys are commonly infected by Simian T-lymphotropic virus I (STLV1) and Simian immunodeficiency virus (SIV), yet the natural histories of these infections are largely unknown. Seropositivity was associated with increased total, T and atypical lymphocytes. In seropositive females there was mild, normocytic, normochromic anaemia. Lymphoid hepatitis was present in seven seropositive cases. African Vervets used in biomedical research, vaccine production and organ transplantation research are often infected by exogenous retroviruses which can be oncogenic and immunosuppressive in captive monkeys. Elimination of these infections may be possible by breeding Vervets in captivity.

Activation and demethylation of the intracisternal A particle genes by 5-azacytidine.

Treatment of C3H 10T1/2 mouse embryo fibroblasts with the cytidine analogues 5-azacytidine and 5-aza-2-deoxycytidine causes altered gene expression and results in the manifestation of phenotypic changes and altered cell morphology. This includes the conversion of these cells to adipocytes, chondrocytes and myotubes. The effects of these analogues on intracisternal A particle (IAP) gene expression in mouse C3H 10T1/2 cells have been examined. Treatment with either 3 microM 5-azacytidine or 0.3 microM 5-aza-2-deoxycytidine for 24 h was associated with an immediate increase in IAP gene transcription, and with the subsequent appearance of IAPs in the cisternae of the cells 24 h after removal of the drug. Control cells contained no, or very few, IAPs and IAP mRNA. Analysis of the methylation status of the IAP genes, using the restriction endonucleases HpaII, MspI and HhaI, showed that these genes were already demethylated at the end of the 24-h treatment period. IAP gene transcripts were detectable even after a 16-h drug treatment period, at which stage the genes were not yet fully demethylated. After further growth in fresh medium for 90 h, the levels of IAP RNA started to decline, but the demethylated CpG sites were not yet remethylated. These results suggest the involvement of other factors, in addition to methylation, in the regulation of IAP gene expression. These drugs were found to have no stimulatory effect on several oncogenes examined in this study.

The morphology of human immunodeficiency virus particles by negative staining electron microscopy.

Negative staining electron microscopy was used to examine culture fluids from the H9/HTLV-III cell line after concentration by centrifugation. Characteristic retrovirus-like particles bearing distinctive envelope projections were seen. The virion envelope was frequently extended in the form of a bleb or a tail. These particles were morphologically virtually indistinguishable from similar preparations of Friend murine leukaemia virus. H9/HTLV-III culture fluids contained, in addition, numerous comet-shaped particles with a dense head and flared tail. These particles were clumped by the addition of anti-HTLV-III-positive serum suggesting that they may represent intermediate forms of the virus.