Phase II trials of fosquidone (GR63178A) in carcinoma of the breast, head and neck, ovary and melanoma.

A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.     

A phase II trial of 10-ethyl-10-deaza-aminopterin, a novel antifolate, in patients with advanced and/or recurrent squamous cell carcinoma of the head and neck. The EORTC Head and Neck Cancer Cooperative Group.

Forty-seven patients with advanced and/or recurrent squamous cell carcinoma of the head and neck were treated with 10-ethyl-10-deaza-aminopterin (10-EdAM), a new analogue of methotrexate. The drug was given as a weekly i.v. bolus injection, starting at 80 mg/m2 with two dose increments of 10% if no toxicity was observed after two weeks. Only patients with tumors of the larynx, oral cavity, oropharynx and hypopharynx were included in the trial. Eighty-two percent of the patients had had prior surgery and/or radiotherapy. Forty-four patients were evaluable for response and toxicity. Five CR (12%) and five PR were obtained, yielding a response rate of 24% (CR+PR). The toxicity was similar to that usually seen with methotrexate; stomatitis and skin toxicity were rather pronounced. The data suggest that 10-EdAM has activity similar to that of methotrexate in patients with head and neck cancer.     

Ecological association between indoor radon concentration and childhood leukaemia incidence in France, 1990-1998.

The objective of this study was to evaluate the ecological association between indoor radon concentration and acute leukaemia incidence among children under 15 years of age in the 348 geographical units (zones d'emploi, ZE) of France between 1990 and 1998. During that period, 4015 cases were registered by the French National Registry of Childhood Leukaemia and Lymphoma. Exposure assessment was based on a campaign of 13 240 measurements covering the whole country. The arithmetic mean radon concentration was 85 Bq/m (range, 15-387 Bq/m) and the geometric mean, 59 Bq/m (range: 13-228 Bq/m). A positive ecological association, on the borderline of statistical significance (P=0.053), was observed between indoor radon concentration and childhood leukaemia incidence. The association was highly significant for acute myeloid leukaemia (AML) (P=0.004) but not for acute lymphocytic leukaemia (ALL) (P=0.49). The standardized incidence ratio (SIR) increased by 7, 3 and 24% for all acute leukaemia, ALL and AML, respectively, when radon concentration increased by 100 Bq/m. In conclusion, the present ecological study supports the hypothesis of a moderate association between indoor radon concentration and childhood acute myeloid leukaemia. It is consistent with most previous ecological studies. Since the association is moderate, this result does not appear inconsistent with the five published case-control studies, most of which found no significant association.     

Lipid peroxidation and free radicals. Role in cellular biology and pathology

Membrane phospholipids attack by oxygen free radicals, i.e. lipidoperoxidation, occurs in normal cellular life. This free radicals attack is controlled by a protective system, both enzymatic (superoxide dismutase, catalase, glutahione peroxidase) and non enzymatic (vitamine E). Imbalance between attack and defense can explain many pathological events. In these events, the oxidation products of unsaturated fatty acids are of fundamental importance, in particular those derived from arachidonic acid (prostaglandins, prostacyclins, thromboxanes and leukotrienes).     

The expression of Rho proteins decreases with human brain tumor progression: Potential tumor markers

Astrocytic tumors are the most common human brain tumors. Establishment of tumor grade is a key determinant both in the choice of a therapeutic approach and in the prognosis. The diagnosis of astrocytic tumors is currently determined following histopathological analysis. The identification of molecular markers would offer a complementary tool for characterizing tumors with respect to their clinical behavior. In this study we determined the expression levels of 3 small GTP binding proteins (RhoA, RhoB and Rac1), of their inhibitor RhoGDI and of caveolin-1 in 24 human astrocytic tumors of grades I to IV. Our results demonstrated that the expression of RhoA and RhoB decreased significantly in all brain tumors studied and was inversely related with tumor of grade II to IV malignancy. The amount of caveolin-1 immunodetected was not significantly different from normal brain samples while the Rac1 expression level was diminished in astrocytic tumors of grades III and IV. Our finding that RhoA and RhoB expression levels are correlated to tumor malignancy suggests that they may serve as novel and efficient diagnostic markers for astrocytic brain tumors of histological grade II to IV and complement currently applied histopathological analysis.     

Combination of dacarbazine and mitomycin in advanced colorectal cancer

Summary Twenty evaluable patients with advanced measurable colorectal cancer received 3-week courses of a combination of IV dacarbazine 300 mg/m²/day from day 1 to day 5 and IV mitomycin 2 mg/m²/day from day 1 to day 5. Fourteen of these patients had had no prior chemotherapy and received two or more courses of this two-drug regimen. None of the patients achieved complete or partial response. Severe to life-threatening myelosuppression, was encountered in patients with prior radiotherapy and or prior chemotherapy, and/or in patients with a Karnofsky score 70. Hematologic toxicity was mild in the other patients. Nonhematologic toxic effects were generally mild to moderate and consisted essentially in nausea and vomiting. It is concluded that in our hands the regimen selected for this trial has no significant antitumor activity in advanced colorectal cancer.     

Juxta-articular bone cysts (intra-osseous ganglia): a clinicopathological study of eighty-eight cases.

The clinical, radiographic and pathological features of eighty-eight cases of histologically verified intra-osseous ganglia in eighty-three patients are described. All were located in the subchondral bone adjacent to a joint and most frequently involved the hip, the ankle (medial malleolus), the knee and the carpal bones. Forty-seven of the eighty-three patients were male and all the patients were between fourteen and seventy-three years of age, with an average age of forty-one years. There are two fundamental types of intra-osseous ganglia, one apparently arising by penetration of juxta-osseous ganglion into the underlying bone, a mechanism proved in fourteen of our eighty-eight cases (16 per cent); in the remaining seventy-four cases, the ganglion cyst was primarily intra-osseous ("idiopathic"). The initial cause of the intramedullary mucoid degeneration is discussed. We believe that mechanical stress and repeated minor trauma near the surface of the bone may lead to intramedullary vascular disturbance with consequent foci of aseptic bone necrosis. The revitalisation of these areas causes fibroblastic proliferation, followed by mucoid degeneration of the connective tissue, possibly due to some unknown local factor. Curettage or excision is usually effective, and recurrence (only four cases) is exceptional.     

Family history of autoimmune thyroid disease and childhood acute leukemia.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.     

Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.     

Personalized Massive Open Online Course for Childhood Cancer Survivors: Behind the Scenes

Background  Today, in France, it is estimated that 1 in 850 people aged between 20 and 45 years has been treated for childhood cancer, which equals 40,000 to 50,000 people. As late effects of the cancer and its treatment affect a large number of childhood cancer survivors (CCS) and only 30% of them benefit from an efficient long-term follow-up care for prevention, early detection, and treatment of late effects, health education of CCS represents a challenge of public health. Objectives  Massive open online courses (MOOCs) are a recent innovative addition to the online learning landscape. This entertaining and practical tool could easily allow a deployment at a national level and make reliable information available for all the CCS in the country, wherever they live. Methods  The MOOC team brings together a large range of specialists involved in the long-term follow-up care, but also associations of CCS, video producers, a communication consultant, a pedagogical designer, a cartoonist and a musician. We have designed three modules addressing transversal issues (lifestyle, importance of psychological support, risks of fertility problems) and eight modules covering organ-specific problems. Detailed data on childhood cancer treatments received were used to allocate the specific modules to each participant. Results  This paper presents the design of the MOOC entitled “Childhood Cancer, Living Well, After,” and how its feasibility and its impact on CCS knowledge will be measured. The MOOC about long-term follow-up after childhood cancer, divided into 11 modules, involved 130 participants in its process, and resulted in a 170-minute film. The feasibility study included 98 CCS (31 males vs. 67 females; p  < 0.0001). Conclusion  Such personalized, free, and online courses with an online forum and a possible psychologist consultation based on unique characteristics and needs of each survivor population could improve adherence to long-term follow-up without alarming them unnecessarily.