Cost-effectiveness of bariatric surgery and non-surgical weight management programmes for adults with severe obesity: a decision analysis model.

OBJECTIVES: To determine the most cost-effective weight management programmes (WMPs) for adults, in England with severe obesity (BMI ≥ 35 kg/m2), who are more at risk of obesity related diseases. METHODS: An economic evaluation of five different WMPs: 1) low intensity (WMP1); 2) very low calorie diets (VLCD) added to WMP1; 3) moderate intensity (WMP2); 4) high intensity (Look AHEAD); and 5) Roux-en-Y gastric bypass (RYGB) surgery, all compared to a baseline scenario representing no WMP. We also compare a VLCD added to WMP1 vs. WMP1 alone. A microsimulation decision analysis model was used to extrapolate the impact of changes in BMI, obtained from a systematic review and meta-analysis of randomised controlled trials (RCTs) of WMPs and bariatric surgery, on long-term risks of obesity related disease, costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) measured as incremental cost per QALY gained over a 30-year time horizon from a UK National Health Service (NHS) perspective. Sensitivity analyses explored the impact of long-term weight regain assumptions on results. RESULTS: RYGB was the most costly intervention but also generated the lowest incidence of obesity related disease and hence the highest QALY gains. Base case ICERs for WMP1, a VLCD added to WMP1, WMP2, Look AHEAD, and RYGB compared to no WMP were £557, £6628, £1540, £23,725 and £10,126 per QALY gained respectively. Adding a VLCD to WMP1 generated an ICER of over £121,000 per QALY compared to WMP1 alone. Sensitivity analysis found that all ICERs were sensitive to the modelled base case, five year post intervention cessation, weight regain assumption. CONCLUSIONS: RYGB surgery was the most effective and cost-effective use of scarce NHS funding resources. However, where fixed healthcare budgets or patient preferences exclude surgery as an option, a standard 12 week behavioural WMP (WMP1) was the next most cost-effective intervention.

[POEMS syndrome: Diagnosis, stratification, treatments]. / Syndrome POEMS : diagnostic, prise en charge et traitements.

POEMS syndrome is a rare form of B-cell dyscrasia with multiple clinical signs including the acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. It is a paraneoplastic syndrome due to an underlying plasma cell disorder belonging to the monoclonal gammopathies of clinical significance (MGCS). The major criteria for this syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF), and the presence of Castleman's disease. Minor features include organomegaly, endocrinopathy, skin changes, papilledema, extravascular volume over-load, and thrombocytosis. The diagnosis of POEMS syndrome requires three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. VEGF plays a major role in the disease although anti-VEGF treatments have been disappointing. Risk stratification is based on clinical phenotype rather than specific molecular markers. Depending on bone marrow involvement and the number of sclerotic bone lesions, first line therapy should be irradiation or systemic therapy. For patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing irradiation therapy should receive antiplasma cell systemic therapy, the most effective being high dose chemotherapy with autologous stem cell transplantation. Lenalidomide seems to have a high efficacy with manageable toxicity. Thalidomide and proteasome inhibitors like bortezomib are also effective, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy.

[Aneurysm of the portal venous system: A rare and unknown pathology]. / Anévrisme du tronc porte : une pathologie rare et méconnue.

INTRODUCTION: Portal vein aneurysms are rare, representing 3% of venous aneurysms, with about 200 cases described in the literature, probably underestimated. CASE REPORT: A 66-year-old man, suspect of splenomegaly, underwent an abdominal ultrasound and a thoraco-abdomino-pelvic CT scan showing a 40mm portal vein aneurysm. Final diagnosis was T-cell hemopathy. Five and six months later, abdominal imaging was stable, suggesting congenital origin due to lack of obliteration of the vitelline vein. CONCLUSION: Portal vein aneurysms are often asymptomatic and an incidental finding. Monitoring is recommended because of their potential complications (thrombosis, rupture of aneurysm, portal hypertension, adjacent organs compression), annually if asymptomatic or more frequently with sometimes a surgical management in case of clinical manifestations.

Neurotensin receptor type 2 protects B-cell chronic lymphocytic leukemia cells from apoptosis.

B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB. Functional and biochemical characterization revealed that the NTSR2-TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course. The NTSR2-TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. When NTSR2 was downregulated, TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death, reflected by DNA fragmentation and Annexin V presentation. Together, our findings demonstrate that the NTSR2-TrkB interaction plays a crucial role in B-CLL cell survival, suggesting that inhibition of NTSR2 represents a promising targeted strategy for treating B-CLL malignancy.

Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.

[Classification and therapeutic management of monoclonal gammopathies of renal significance]. / Classification et prise en charge thérapeutique des gammapathies monoclonales de signification rénale.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients.

We retrospectively reviewed 49 patients with light chain (LC) Fanconi syndrome (FS). Patients presented with chronic kidney disease (median estimated glomerular filtration rate (eGFR) of 33 ml/min/1.73 m2) and tubular proteinuria. All patients tested had elevated fractional excretion of phosphate, uric acid, generalized aminoaciduria and/or normoglycemic glycosuria. Thirty-eight patients had monoclonal gammopathy of renal significance and eleven patients had an overt hematological malignancy. The monoclonal LC isotype was kappa in 46/49 cases. Kidney biopsy in 39 patients showed various proximal tubular lesions and characteristic LC intracytoplasmic crystalline inclusions in 24 patients. Forty-two patients received chemotherapy. Patients with plasma cell proliferation (n=38) received bortezomib-based regimens (n=11), immunomodulatory agents (n=7) or alkylating agents (n=6). High-dose melphalan (HDM) followed by autologous stem cell transplantation was performed in 14 patients. Hematological response was obtained in 90% of evaluable patients, assessed on serum free light chains (FLC). GFR remained stable as long as hematological response was maintained and declined when serum FLC level rebounded. Improvement in proximal tubule function occurred in 13 patients. In patients with LC-associated FS, chemotherapy using HDM and/or new generation anti-myeloma agents can stabilize renal function and improve proximal tubule function. Serum FLC should be used to assess the hematological response, related to renal outcome.

International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

[AL amyloidosis]. / Amylose AL.

AL amyloidosis belongs to the group of conformational diseases. It is the most common type of amyloidosis with an estimated 500 new cases per year in France. It is due to a small and usually indolent plasma cell clone which synthesizes an unstable, misfolded monoclonal immunoglobulin light chain that is prone to aggregate and form amyloid fibrils. Non-invasive biopsy such as abdominal fat aspiration or minor salivary gland biopsy should be performed to confirm the diagnosis and if negative, involved tissues have to be examined. Clinical presentation is very diverse, as AL amyloidosis can affect almost any organ or tissue in the body, other than the brain. The kidney is the most frequent organ involved, whereas heart disease characterized by restrictive cardiomyopathy is the most severe. Early diagnosis, before advanced cardiomyopathy, is essential for improving outcome. The association of alkylating agent and high-dose dexamethasone is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylating agents achieve high response rates. Close monitoring of clonal and organ response is mandatory to guide therapy changes and duration. New treatments designed to eliminate amyloid deposits are under development.

Postural bipedance in paraplegics under neuromuscular electrical stimulation: is it possible to improve it based on sagittal spinal alignment?

STUDY DESIGN: Experimental trial based on the analytical study of radiographic standards of the sagittal spinal alignment in paraplegics in upright position under surface neuromuscular electrical stimulation (NMES). OBJECTIVES: To evaluate changes in radiographic standards of the sagittal spinal alignment of paraplegics under three different models of NMES used to optimize the global bipedal posture. SETTING: The University Hospital Ambulatory (UNICAMP), Campinas, SP, Brazil. METHODS: Ten paraplegic patients were selected. Each patient underwent three different models of NMES. The influence that each NMES model exerted over the sagittal balance of the spine was evaluated by lateral panoramic X-rays. Wilcoxon's test was used to compare the modifications observed in each NMES model in the group studied. RESULTS: Using the femoral quadriceps muscles' NMES as the starting point, the inclusion of the gluteus maximus' NMES generated an increase of the lumbar lordosis and a decrease of the spinal tilt angle. These alterations resulted in partial improvement of the anterior sagittal imbalance. NMES of the paralyzed paravertebral lumbar muscles resulted in a more expressive increase on the lumbar lordosis, with no significant change on the spinal tilt. On the latter model, however, an improvement of 20% was observed in the global sagittal imbalance due to a posterior translation of the spine as pointed out by the decrease in the C7-HA horizontal distance. CONCLUSIONS: The proposed NMES models were able to partially amend the anterior sagittal imbalance of the paraplegic patients in bipedal posture.

Sagittal spinal alignment in paraplegics: a new paradigm for the rehabilitation under neuromuscular electrical stimulation.

STUDY DESIGN: Radiographic analysis of sagittal spinal alignment of paraplegics in a standing position under surface neuromuscular electrical stimulation (NMES). OBJECTIVES: Describing the radiographic parameters of the sagittal spinal alignment of paraplegics going through a rehabilitation program with NMES. SETTING: The University Hospital's Ambulatory (UNICAMP), Campinas, São Paulo, Brazil. METHODS: Panoramic X-ray images in profile were taken for 10 paraplegics. All patients participated in the rehabilitation program and were able to perform gait through NMES of the femoral quadriceps muscles. The radiographic parameters used for the analysis were the same as those described in the literature for healthy people. The results were didactically organized into three groups: anatomical shape of the spine, morphology and kinetics of the pelvis and spinopelvic alignment. RESULTS: The physiological curvature of the spine in paraplegics showed average values similar to those described in the literature for healthy patients. The inversion of the pelvic tilt and the increase in the sacral slope were defined by the anterior backward rotation of the pelvis. The existing theoretical mathematical formulas that define lumbar lordosis, pelvic incidence and pelvic tilt showed normal values, despite the anterior intense sagittal imbalance. CONCLUSIONS: The adaptive posture of the spine in paraplegics standing through the stimulation of the femoral quadriceps does not allow for a neutral sagittal alignment. This novel radiographic detailed description of the various segments of the spine can be of assistance toward the understanding of the global postural control for such subjects.

L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature.

BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome. PATIENTS AND METHODS: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV. RESULTS: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed. CONCLUSION: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.

[Chronic inflammatory demyelinating polyneuropathy (CIDP) revealing an associated disease diagnostic and therapeutic pitfalls]. / Polyradiculonévrite inflammatoire démyélinisante chronique et maladie associée: problèmes diagnostiques et thérapeutiques.

The objective of this case report is to illustrate the problem's diagnosis of a CIDP revealing a associated disease. The patient had initially a sensory CIDP wich respond to prednisone. After 2 years, he worsened with motor deficit, pain and atypical skin's lesions. The diagnosis of POEMS syndrome was made only in the fourth research of monoclonal gammopathy. A specific treatment was realised but too late and a important motor deficit with axonal loss unfortunately persisted.

[Are PUFAs n-3 really important in diet?]. / Place des acides gras oméga 3 dans l'alimentation.

If cardiovascular secondary prevention as well as COPD benefit from PUFAs supplementation, mainly in our societies where n-3 lack is close to n-6:n-3 misbalance, the usefulness of these supplements in many diseases (inflammatory or psychiatric for instance), is not yet established despite numerous randomised controlled studies and meta-analysis. The only counter indication to their prescription now is the presence of an implantable defibrillator. Their effect on prostate cancer remains doubtful. PUFAs n-3 marine sources should be free of pollution.