Stage-related changes in functional capacity in Hodgkin’s disease: assessment by cardiopulmonary exercise testing before initiation of treatment

Our aim was to examine indices of cardiorespiratory capacity at rest and during exercise before initiation of therapy for Hodgkin’s disease. We prospectively studied 24 patients divided into two groups according to the disease stage. Group 1 included eight patients in stage IA and four in stage IIA; group 2 included four patients in stage IIB, six in stage III, and two in stage IV. All patients underwent detailed cardiopulmonary evaluations at rest using electrocardiogram, echocardiogram, spirometry, and measurement of pulmonary diffusing capacity (DLCO), and during exercise using a cardiopulmonary exercise test. Groups 1 and 2 were similar with respect to sex distribution (eight women and four men in each), mean age (35±36 vs37±4.6 years), body mass index, and hemoglobin concentration (12.7±0.2 vs 12.1±0.3 g l⁻¹). All patients had a normal cardiovascular status. All patients in group 1 had normal cardiorespiratory measurements at rest and during exercise. Forced vital capacity was significantly lower in group 2 (84.8±2.7% predicted) than in group 1 (105±3%, P<0.0001), without abnormalities in DLCO or in resting and exercise oxygen diffusion. Likewise, percentage predicted (65±4 vs 97±6, P<0.0002), oxygen pulse at peak exercise (0.12±0.01 vs 0.17±0.01, P<0.001), and slope (8.4±0.3 vs 10.2±0.4, P<0.003) were significantly lower in group 2 than in group 1. Functional capacity during exercise was markedly reduced in patients suffering from Hodgkin’s disease in advanced stages. This loss of exercise capacity appeared mainly related to a peripheral disorder.     

A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations

Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.     

Retrospective analysis of 24 recurrent glioblastoma after chemoradiation and treated with nitrosoureas or irinotecan and bevacizumab

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.     

Post-mortem MRI reveals CPT2 deficiency after sudden infant death

Inherited metabolic disorders are the cause of a small but significant number of sudden infant deaths in infants. We report on a boy who suddenly died at 10 months of age during an acute illness. Parents declined autopsy; nevertheless, they accepted a whole body MRI, which revealed hepatomegaly with steatosis. Acylcarnitine profile of a blood sample from neonatal Guthrie screening led to the diagnosis of type 2 carnitine palmitoyltransferase deficiency. To conclude, whole body MRI is useful in the investigation of some inherited metabolic causes of sudden infant death, which might prevent future deaths in the family. It is a good alternative when autopsy is refused.     

In vivo repopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients

Fanconi anemia (FA) is a rare inherited genomic instability syndrome representing one of the best examples of hematopoietic stem cell deficiency. Although FA might be an excellent candidate for bone marrow (BM) genetic correction ex vivo, knockout animal models are not sufficient to guide preclinical steps, and gene therapy attempts have proven disappointing so far. Contributing to these poor results is a characteristic and dramatic early BM-cells die-off when placed in culture. We show here that human primary FA BM cell survival can be ameliorated by using specific culture conditions that limit oxidative stress. When coupled with retrovirus-mediated transfer of the main complementation group FANCA-cDNA, we could achieve long-term reconstitution of the stem cell compartment both in vitro and in vivo. Gene-corrected BM cultures grew for >120 days, and after cultured cell transplantation into NOD/SCID mice, clonogenic human cells carrying the FANCA transgene could be detected 6 months after transduction. By comparison, untransduced cells died in culture by 15 days. Of necessity for ethical reasons, experiments were conducted on a very limited number of primary BM cells. By using low cytokine regimen and conditions matching regulatory requirements, a contingent of gene-corrected cells slowly emerges with an unmet potential for in vivo engraftment. Future therapeutic applications of stem cells might be expanding from these data. In addition, we provide a model of gene-corrected human primary cell growth that carries the potential to better delineate the combined role of both DNA damage and oxidative stress in the pathogenesis of FA.     

Fatty acid alterations in liver peroxisomes from n-3-deficient mice

A diet deficient in n-3 fatty acids dramatically reduces docosahexaenoic acid (4.8-fold) and 20:5n-3 content in murine total peroxisomal phospholipids, and conversely increases 22:5n-6 (17.1-fold) and also, to a lesser extent, 20:4n-6. This was also found in purified phosphatidylethanolamine and phosphatidylcholine. After changing the non-deficient diet (containing alpha-linolenic acid, ALA) to a deficient one (deficient in ALA), it took a very long time for docosahexaenoic acid concentration in peroxisomes to decline (>5 months). In contrast, after changing the deficient to a non-deficient diet, time to complete recovery was more rapid (3 weeks). Changes in 20:5n-3, 22:6n-3 and 20:4n-6 were generally stabilized within 2-4 weeks. Dietary n-3 fatty acids control the fatty acid composition of peroxisomal membranes, and thus possibly affect some of their functions.     

Pipestelides A-C: cyclodepsipeptides from the Pacific marine sponge Pipestela candelabra

Pipestelides A-C (2-4) are three new NRPS-PKS hybrid macrolides containing uncommon moieties, isolated from the Pacific marine sponge Pipestela candelabra. Their structures were elucidated on the basis of spectroscopic data. These cyclodepsipeptides appear to be biosynthetically related to jaspamide (aka jasplakinolide) (1) by chemical modification of the building blocks of the polyketide or peptide chains. Pipestelides A-C (2-4) contain a bromotyrosine [3-amino-3-(bromo-4-hydroxyphenyl)propanoic acid] unit, a polypropionate with a Z double bond, and a 2-hydroxyquinolinone, respectively. Revised chemical shift assignments are provided for the co-isolated known jasplakinolide C(a) (5). In addition, compounds 2 and 3 exhibited cytotoxic activities in the micromolar range.