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The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) is a commonly used intensification regimen for patients with Hodgkin lymphoma. As etoposide and cytarabine dosing are not defined, we conducted a retrospective, multicenter study, to compare efficacy and toxicity in 130 patients with Hodgkin lymphoma receiving etoposide and cytarabine at either 200 mg/m2/d (n = 50), 400 mg/m2/d (n = 35), or etoposide 200 mg/m2/d and cytarabine 400 mg/m2/d (n = 45). Progression-free survival and overall survival were not associated with the intensity of conditioning. Increased conditioning intensity was associated with longer duration of thrombocytopenia, a higher number of transfused RBC and platelet units and a higher frequency of mucositis, but serious adverse events or infectious complications were not increased. The intensity of BEAM regimen was not associated with survival but with the rate of cytopenia and mucositis advocating for the use of lower dosing in frail patients. [ABSTRACT FROM AUTHOR]

The solid and growing demand for fuels evidences the necessity of diversifying the countries' energy matrices. The present work proposed to carry out pretreatment tests, enzymatic hydrolysis, and batch fermentation of elephant grass biomass — a competitive lignocellulosic culture for obtaining ethanol due to low production costs and high levels of agricultural productivity. As a process and product economy strategy, the production of xylitol integrated with ethanol production was carried out. Therefore, two alkaline pretreatment methodologies were followed by enzymatic hydrolysis to obtain fermentable sugars. The pretreatments proved efficient in making cellulose available and removing the lignin content. The hydrolysates obtained showed 19.9 and 25.6 g/L of total sugars. Then, three fermentation conditions were carried out in each hydrolysate: (i) by the wild yeast strain Meyerozyma caribbica CHAP-096, (ii) by the industrial strain Saccharomyces cerevisiae PE-02, and (iii) by a combination of both yeasts in a 1:1 (v/v) ratio. A high ethanol yield of 0.42 gethanol/gglucose was reached through the combination of S. cerevisiae and M. caribbica strains, representing 83% of the maximum theoretical yield (0.511 gethanol/gglucose). The industrial strain S. cerevisiae PE-2 was also able to reduce xylose into another important component in biorefinery, xylitol, with a yield of up to 0.61 gxylitol/gxylose. [ABSTRACT FROM AUTHOR]

White oat (Avena sativa L.) is a cold season grass, with a very important role, both in animal and human food, due to the chemical composition of its grains, which have, among other beneficial components, fiber soluble food products, beta‐glucans. Therefore, the demand for grains of the crop is maximized, and it is important to increase grain production. This can be achieved through the adequate positioning of the genotypes in the growing environments to maximize the agronomic performance of the crop. Thus, the objective of this work was to decompose meteorological and geographic variables in the positioning of white oat genotypes. The study took place considering 39 genotypes of white oats in 21 environments (in 13 years), in six municipalities of Rio Grande do Sul, two locations in the state of Santa Catarina, 10 in Paraná, and three municipalities in the state of São Paulo. The average grain yield (GY) (kg ha−1) of the genotypes in each environment was used to determine the adaptability and stability of the genotypes through the application of the genotype and genotype by environment interaction (GGE biplot) biometric method and the reaction norm. The reaction norm pointed out that the genotypes UPFPS Farroupilha, UPFA Gaudéria, and URS Guará demonstrated general adaptability to all environments, whereas FAEM 006 and URS Charrua expressed stability, high GY, and higher than average genetic value. The GGE biplot graphically demonstrated that the genotypes URS Monarca and IPR Artemis demonstrated the highest GY and high stability in the environments Eldorado do Sul—RS (E7) and Pelotas—RS. Identifying genotypes with superior agronomic performance in specific environments minimizes the effects of genotype × environment interaction. These white oat genotypes can be used as sources of alleles for the development of new genotypes. Core Ideas: Higher maximum and minimum air temperatures enhance the grain yield of white oats.White oat genotypes with high grain yield were found for cultivation in Brazil.Genotypes with superior phenotypic responses were identified for each meteorological covariate. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400 mg/m2, n = 69) or lower (200 mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile. [ABSTRACT FROM AUTHOR]

Due to the low number of bacteraemias identified after the first day of fever, repeating blood cultures adds little additional information while potentially increasing iatrogenesis, costs, and the number of false positive blood cultures. Repeat blood cultures in children with persistent fever and neutropenia: diagnostic and clinical implications: repeat blood cultures for fever and neutropenia. The new blood culture sample strategy - four adequately filled blood culture bottles on day 1 - efficiently improved the diagnosis of bacteriemia over the three periods. [Extracted from the article]

A circular economy is imperative for environmental sustainability. In this context, biorefineries stand out as a means of production able to reduce the carbon footprint and the impact of global warming. Biorefineries may employ lignocellulosic biomass from various plant sources to produce bioproducts with the potential to replace fossil derivatives through synthesis by microorganisms without competing with food crops. Brewer's spent grain (BSG), the residue of the brewery production process, is an option with potential for use, being a cheap raw material highly available throughout the year. The chemical composition of this biomass is quite variable, with significant amounts of hemicellulose, mainly consisting of xylose and arabinose monomers that can be technologically converted into value-added products such as xylooligosaccharides, xylitol, second-generation ethanol (2G ethanol), biofilms and furfural. To this end, catalysts are unusual in making biorefineries increasingly competitive in the market, selectively optimizing reactions and reducing the environmental impact of the production processes of these bioproducts. The present review addresses the primary methods for extracting and processing hemicelluloses from BSG using either biocatalysts (enzymes) or homogenous (acids, alkali, and salts) and heterogenous catalysts (solid acids and metal oxide) that can be used to pretreat the biomass and obtain the preferred byproducts. The state of the art of optimized catalysis mechanisms is also presented. [ABSTRACT FROM AUTHOR]

Therefore, in PV patients, both initial and validation cohorts, the worsening status was associated with a higher risk of death during the first 5 years post-assessment (i.e., 3-8 years after diagnosis), but not in a longer-term. They comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). C Kaplan-Meier curve represents overall survival according to the diagnosis (ET: essential thrombocythemia, PV: polycythemia vera) and the worsening status (W+: worsened at 3 years, W-: not worsened). [Extracted from the article]

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m2/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study. [ABSTRACT FROM AUTHOR]

Background: Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease‐free survival (DFS) survivals and non‐relapse mortality (NRM) in patients receiving HLA‐matched Allo‐HSCT, but their performance has scarcely been studied in the haploidentical Allo‐HSCT setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. Methods: To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo‐HSCT in four different centers. Results: With a median follow‐up of 35.6 months, 3‐year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (≥55 years old, p = 0.02) and of donors (≥40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM. Conclusion: The comorbidity scores do not predict survivals nor NRM in haploidentical Allo‐HSCT with PTCY, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo‐HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo‐HSCT. Methods: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically. Results: Average gamma globulin levels between D‐7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P =.65). Gamma globulin level <400 mg/dl was not associated with the occurrence of infection between the test studied and the next one (aOR 1.33 [0.84‐2.15], P =.24). The gamma globulin level was not predictive of bacterial or fungal infections (AUC 0.54 [95%CI: 0.47‐0.61]) nor of viral reactivations (AUC 0.51 [95%CI: 0.43‐0.60]). Conclusions: This confirmed that the humoral deficiency is a minor part of the immune deficiency in the 100 days post‐transplant. This questions the relevance of the indications of immunoglobulin substitution during this period. [ABSTRACT FROM AUTHOR]

IDH1 and IDH2 mutations (IDH1/2Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2Mut. Mutational patterns of IDH1/2Mut in T-ALL present some specific features compared to AML. Whereas IDH2R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients. Methods: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach. Results: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship. Conclusion: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: The R‐DHAP regimen (rituximab, cisplatin, dexamethasone, and high‐dose cytarabine) is standardly used to treat relapsed Non‐Hodgkin lymphoma (NHL). Despite scarce data, cisplatin is frequently substituted with oxaliplatin (R‐DHAOx) to avoid nephrotoxicity. We compared nephrotoxicity of cisplatin and oxaliplatin based on creatinine‐based trajectory modeling. Methods: All patients with NHL treated by R‐DHAP or R‐DHAOx in Angers hospital between January 01, 2007, and December 31, 2014, were included. Patients received cisplatin 100 mg/m2 or oxaliplatin 130 mg/m2 (d1) with cytarabine (2000 mg/m2, two doses, d2), dexamethasone (40 mg, d1‐4), and rituximab (375 mg/m2, d1). Creatinine levels were recorded before each cycle. Individual profiles of trajectories were clustered to detect homogeneous patterns of evolution. Results: Twenty‐two patients received R‐DHAP, 35 R‐DHAOx, 6 switched from R‐DHAP to R‐DHAOx due to nephrotoxicity. Characteristics of patients were similar between two groups. Patients receiving R‐DHAP experienced more severe renal injury than patients receiving R‐DHAOx (68% vs. 7.7%, P <.001). Two homogeneous clusters appeared: cluster A, with a majority of R‐DHAOx (32, 91.4%), was less nephrotoxic than B, with a majority of R‐DHAP (19, 86.4%), with a decreased average serum creatinine level (P <.0001). There were no other differences between clusters. Conclusions: Our study confirms that R‐DHAOx regimen causes less nephrotoxicity than R‐DHAP regimen. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials. [ABSTRACT FROM AUTHOR]

Abstract: Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell‐derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long‐term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI. [ABSTRACT FROM AUTHOR]

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The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1-2.7, p = 0.04). Time between first organ injury and ICU admission was also associated with an increased in-hospital survival (OR 1.4, 95% CI 1.1-1.8, p = 0.02). A score combining these two covariates-the number of organ injuries/day (sum of days spent with each individual organ injury)-further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1-1.7, p = 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in-hospital mortality. [ABSTRACT FROM AUTHOR]

A large, multicentre, retrospective survey of patients with hairy cell leukaemia ( HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long-term effects of the established purine nucleoside analogues ( PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio ( SIR) of 1·86 (95% confidence interval ( CI): 1·34-2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90-8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective was to assess the efficacy and safety of splenectomy and cyclophosphamide as salvage therapies in severe thrombotic thrombocytopenic purpura (TTP). STUDY DESIGN AND METHODS: During a 10-year period, patients who did not improve with plasma exchanges, steroids, vincristine, and/or rituximab were considered for splenectomy or cyclophosphamide. Patients with a documented severe (<10% of normal value) acquired ADAMTS13 deficiency are reported here. RESULTS: Eighteen patients with a severe acquired ADAMTS13 deficiency required a salvage therapy. Thirteen patients had a splenectomy 19 (interquartile range [IQR], 10-51) days after TTP diagnosis. One patient died the day after splenectomy. The remaining patients improved platelets (PLTs) until Day 6, along with a rapid and major lactate dehydrogenase improvement. Six patients, however, subsequently experienced a transient worsening. Durable PLT count recovery in survivors was observed within 13 (IQR, 11.5-25.5) days. Postoperative complications included thromboembolic events (two cases) and infections (five cases). Five patients received pulses of cyclophosphamide 12 (IQR, 12-15) days after TTP diagnosis. All patients recovered PLTs 10 (IQR, 9-24) days after the first pulse and two experienced a transient worsening. Three patients experienced infections. Three relapses occurred 5 months, 2.5 years, and 4.5 years after splenectomy and one relapse occurred 3.5 years after cyclophosphamide. After a 2.5 (IQR, 0.75-6.2)-year follow-up, the overall survival was 94%. CONCLUSION: Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies. [ABSTRACT FROM AUTHOR]

Marrow cells from patients with higher-risk myelodysplastic syndrome ( MDS) exhibit constitutive nuclear factor ( NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m2, days 1, 4, 8 and 11) and low dose cytarabine arabinoside ( LDAC; 10 mg/m2, then 20 mg/m2 from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response ( CR, n = 1), marrow- CR ( n = 3), partial response ( PR, n = 5) and haematological improvement ( HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients ( P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow- CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes. [ABSTRACT FROM AUTHOR]

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder of the haematopoietic stem cell which can be associated with marrow fibrosis and/or osteosclerosis. Because bone progenitors and mature bone cells are influenced by the marrow microenvironment, cellular and tissular changes were assessed by histomorphometry in MMM. Thirteen patients, with a clinical proven MMM, had a bone biopsy of the iliac crest with double tetracycline labelling and osteoclast count. Histomorphometry was done at the 2D level (bone volume, osteoid parameters, bone histodynamic parameters and osteoclast count) and 3D level by microcomputed tomography. All patients had clusters of abnormal megakaryocytes in bone marrow. Newly apposed bone packets were observed in 12 patients and corresponded to an increased thickness of some bone units with new lamellae or focal areas of woven bone anchored on the pre-existing trabeculae. Osteoid parameters were unchanged, only bone formation rate appeared considerably increased in seven patients. There was a net tendency for decrease in osteoclast number and conversion of trabecular pillars into plates. An uncoupling of bone remodelling was evidenced with an increased life-span of osteoblasts associated with a normal/reduced osteoclast activity. A very complex network of factors is candidate to explain bone changes observed in MMM. [ABSTRACT FROM AUTHOR]

Focuses on the legal implications of assisted suicide under the law of Switzerland, under the article 115 of the Swiss penal code. Recollection of the historical context that led to the adoption of the article 115 under the Swiss Penal Code in 1943; Explanation of the scope of the criminal provision and stress of the legal questions it has raised in recent times; Discussion of the present proposals and future perspectives on regulating assisted suicide as well as euthanasia in the country.