Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. METHODS: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. FINDINGS: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. INTERPRETATION: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. FUNDING: DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD.

BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Avoidable Blood Loss in Critical Care and Patient Blood Management: Scoping Review of Diagnostic Blood Loss.

BACKGROUND: Anemia remains one of the most common comorbidities in intensive care patients worldwide. The cause of anemia is often multifactorial and triggered by underlying disease, comorbidities, and iatrogenic factors, such as diagnostic phlebotomies. As anemia is associated with a worse outcome, especially in intensive care patients, unnecessary iatrogenic blood loss must be avoided. Therefore, this scoping review addresses the amount of blood loss during routine phlebotomies in adult (>17 years) intensive care patients and whether there are factors that need to be improved in terms of patient blood management (PBM). METHODS: A systematic search of the Medline Database via PubMed was conducted according to PRISMA guidelines. The reported daily blood volume for diagnostics and other relevant information from eligible studies were charted. RESULTS: A total of 2167 studies were identified in our search, of which 38 studies met the inclusion criteria (9 interventional studies and 29 observational studies). The majority of the studies were conducted in the US (37%) and Canada (13%). An increasing interest to reduce iatrogenic blood loss has been observed since 2015. Phlebotomized blood volume per patient per day was up to 377 mL. All interventional trials showed that the use of pediatric-sized blood collection tubes can significantly reduce the daily amount of blood drawn. CONCLUSION: Iatrogenic blood loss for diagnostic purposes contributes significantly to the development and exacerbation of hospital-acquired anemia. Therefore, a comprehensive PBM in intensive care is urgently needed to reduce avoidable blood loss, including blood-sparing techniques, regular advanced training, and small-volume blood collection tubes.

Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML.

BACKGROUND: Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. METHODS/DESIGN: This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL STATUS: Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. TRIAL REGISTRATION: ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.

Quality of life and outcome of patients with metastatic pancreatic cancer receiving first-line chemotherapy with nab-paclitaxel and gemcitabine: Real-life results from the prospective QOLIXANE trial of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer registry.

Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002). The QOLIXANE study is a prospective, noninterventional, multicenter substudy of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer (PARAGON) registry, which evaluated QoL in patients with mPC receiving first-line gemcitabine and nab-paclitaxel chemotherapy in real-life setting. QoL was prospectively measured via EORTC QLQ-C30 questionnaires at baseline and every month thereafter. Therapy and efficacy parameters were prospectively collected. Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months. Six hundred patients were enrolled in 95 German study sites. Median progression-free survival was 5.9 months (95% confidence interval [CI], 5.2-6.3). Median overall survival (OS) was 8.9 months (95% CI, 7.9-10.2), while median time to deterioration of GHS/QoL was 4.7 months (95% CI, 4.0-5.6). With a baseline GHS/QoL score of 46 (SD, 22.8), baseline QoL of the patients was severely impaired, in most cases due to loss in role functioning and fatigue. In the Kaplan-Meier analysis, 61% and 41% of patients had maintained GHS/QoL after 3 and 6 months, respectively. However, in the QoL response analysis, 35% and 19% of patients had maintained (improved or stable) GHS/QoL after 3 and 6 months, respectively, while 14% and 9% had deteriorated GHS/QoL with the remaining patients being nonevaluable. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a hazard ratio of 0.86 (P < .0001). Patients with mPC have poor QoL at baseline that deteriorates within a median of 4.7 months. Treatment with gemcitabine and nab-paclitaxel is associated with maintained QoL in relevant proportions of patients. However, overall, results remain poor, reflecting the aggressive nature of the disease.

[Palliative Surgery in Colorectal Cancer - Which Factors Should Influence the Choice of the Surgical Procedure?] / Palliativchirurgie beim kolorektalen Karzinom ­ welche Faktoren können bei der Wahl des operativen Vorgehens helfen?

BACKGROUND: The surgical procedure for patients with colorectal cancer (CRC) in the palliative situation cannot be adequately standardised. The present study was initiated to identify criteria for the decision for resection of the malignancy with or without anastomosis. PATIENTS/MATERIAL AND METHODS: In a unicentric retrospective analysis, 103 patients after palliative resection with or without anastomosis due to CRC were examined. Using univariate and logistic regression analysis, the influence of a total of 40 factors on postoperative morbidity and mortality was assessed. RESULTS: In 46 cases, resection with primary anastomosis and in 57 cases a discontinuity resection was performed. Postoperative morbidity was 44.7% and mortality 17.5%. After one-stage resection with anastomosis, nicotine abuse (OR 4.2; p = 0.044), hypalbuminaemia (OR 4.0; p = 0.012), ASA score > 2 (OR 3.7; p = 0.030) and liver remodelling/cirrhosis (OR 3.6; p = 0.031) increased the risk for postoperative complications. Hypalbuminaemia (OR 1.8; p = 0.036), cachexia (OR 1.8; p = 0.043), anaemia (OR 1.5; p = 0.038) and known alcohol abuse (OR 1.9; p = 0.023) were identified as independent risk factors for early postoperative mortality. After discontinuity resection, renal failure (OR 2.1; p = 0.042) and cachexia (OR 1.5; p = 0.045) led to a significant increase in the risk of postoperative morbidity, alcohol abuse (OR 1.8; p = 0.041) in mortality. Hypalbuminaemia (OR 2.8; p = 0.019) and an ASA score > 2 (OR 2.6; p = 0.004) after resection and reconstruction increased the risk of major complications according to Clavien-Dindo, while pre-existing renal failure (OR 1.6; p = 0.023) increased the risk after discontinuity resection. In univariate analysis, an ASA score > 2 (p = 0.038) after simultaneous tumour resection and reconstruction, and urgent surgery in both groups with or without primary anastomosis were additionally identified as significant parameters with a negative influence on mortality (p = 0.010 and p = 0.017). CONCLUSION: Palliative resections of colorectal carcinomas have high morbidity and mortality. Especially in cases of pre-existing alcohol abuse and/or urgent indication for surgery, more intensive monitoring should be performed. In the case of anaemia, cachexia, hypalbuminemia and an ASA score > 2, discontinuity resection may be the more appropriate procedure.

Predictive factors of early outcome after palliative surgery for colorectal carcinoma.

OBJECTIVES: A significant number of patients with colorectal cancer are presented with various conditions requiring surgery in an oncologically palliative setting. We performed this study to identify risk factors for early outcome after surgery to facilitate the decision-making process for therapy in a palliative disease. METHODS: We performed a retrospective chart review of 142 patients who underwent palliative surgery due to locally advanced, complicated, or advanced metastatic colorectal carcinoma between January 2010 and April 2018 at the "Elbland" Medical Center Riesa. We performed a logistic regression analysis of 43 factors to identify independent predictors for complications and mortality. RESULTS: Surgery included resections with primary anastomosis (n=31; 21.8%) or discontinuous resections with colostomy (n=38; 26.8%), internal bypasses (n=27; 19.0%) and stoma formation only (n=46; 32.4%). The median length of hospitalization was 12 days (2-53 days), in-hospital morbidity was 50.0% and the mortality rate was 18.3%. Independent risk factors of in-hospital morbidity were age (HR: 1.5, p=0.046) and various comorbidities of the patients [obesity (HR: 1.8, p=0.036), renal failure (HR: 1.6, p=0.040), diabetes (HR: 1.6, p=0.032), alcohol abuse (HR: 1.3, p=0.023)] as well as lung metastases (HR: 1.6, p=0.041). Arteriosclerosis (HR: 1.4; p=0.045) and arterial hypertension (HR: 1.4, p=0.042) were independent risk factors for medical complications in multivariate analysis. None of the analyzed factors predicted the surgical morbidity after the palliative procedures. Emergency surgery (HR: 10.2, p=0.019), intestinal obstruction (HR: 9.2, p=0.006) and ascites (HR: 5.0, p=0.034) were multivariate significant parameters of in-hospital mortality. CONCLUSIONS: Palliatively treated patients with colorectal cancer undergoing surgery show high rates of morbidity and mortality after surgery. In this retrospective chart review, independent risk factors for morbidity and in-hospital mortality were identified that are similar to patients in curative care. An adequate selection of patients before palliative operation should lead to a better outcome after surgery. Especially in patients with intestinal obstruction and ascites scheduled for emergency surgery, every effort should be made to convey these patients to elective surgery by interventional therapy, such as a stent or minimally invasive stoma formation.

[Thrombotic Microangiopathies]. / Thrombotische Mikroangiopathien.

Thrombotic microangiopathies are almost devastating diseases leading to death at high frequency if untreated. They consist of at least five distinct entities, TTP, HUS, aHUS, TMA due to drug interference, systemic disease or post therapy TMA. Around 10 years ago there was only one established therapeutic approach as plasmapheresis. Meanwhile, there are new drugs been licensed or within licensing process. Patients with atypical HUS can be treated successfully by the Complement inhibitor Eculizumab. In addition, there is a new inhibitor of von-Willebrand-Polymerisation available. Caplacizumab provides a significantly better remission and decrease in TMA-related death. For therapy associated TMA as VOD/SOS Defibrotide could be established within a phase III study to significantly improve outcomes. In order to select these new medical approaches individual diagnostic parameters need to be established in order to rapidly distinguish between the TMA entities and start targeted therapy.

Rapid reconstitution of CMV-specific T-cells after stem-cell transplantation.

OBJECTIVE: As reconstitution of virus-specific T-cells is critical to control cytomegalovirus (CMV)-viremia following stem-cell transplantation (SCT), we characterized the dynamics in CMV-specific T-cell reconstitution after SCT. METHODS: Cytomegalovirus-specific T-cells from 51 SCT-recipients were prospectively quantified and phenotypically characterised by intracellular cytokine-staining after specific stimulation and HLA class-I-specific pentamers using flow cytometry. RESULTS: Cytomegalovirus-specific CD4 T-cells reconstituted after a median of 2.3 (IQR, 2.0-3.0) weeks following autografting, and 4.0 (IQR, 3.0-5.6) weeks after allografting, with CMV-specific T-cells originating from donors and/or recipients. The time for reconstitution of CMV-specific CD4 and CD8 T-cells did not differ (P = .58). Factors delaying the time to initial reconstitution of CMV-specific CD4 T-cells included a negative recipient serostatus (P = .016) and CMV-viremia (P = .026). Percentages of CMV-specific CD4 T-cells significantly increased over time and reached a plateau after 90 days (P = .043). Relative CMV-specific CD4 T-cell levels remained higher in long-term transplant recipients compared with those in controls (P < .0001). However, due to persisting lymphopenia, absolute numbers of CMV-specific T-cells were similar as in controls. CONCLUSION: Cytomegalovirus-specific T-cells rapidly reconstitute after SCT and their percentages remain high in the long term. In the face of persistent lymphopenia, this results in similar absolute numbers of CMV-specific T-cells as in controls to ensure sufficient pathogen control.

Phylogenetic analysis of Wheat dwarf virus isolates from Iran.

Wheat dwarf virus (WDV) adversely affects cereal production in Asia, Europe, and North Africa. In this study, sequences of several WDV isolates from Iran which is located in the Fertile Crescent were analyzed. Analysis revealed a new geographic cluster for WDV-Wheat from Iran. Recombination analysis demonstrated the existence of several breakpoints in different regions of the viral genome. Data analysis demonstrated that WDV-Barley has an older history and lower diversity than WDV-Wheat. Sequence analysis identified a rare occasion of a co-infection of wheat with WDV-Wheat and WDV-Barley.

Development of SSR markers for the genus Patellifolia (Chenopodiaceae).

PREMISE OF THE STUDY: Microsatellite primers were developed to promote studies on the patterns of genetic diversity within Patellifolia patellaris (Chenopodiaceae) and the relationship between the three species of the genus Patellifolia. METHODS AND RESULTS: The genomic sequence from P. procumbens was screened for simple sequence repeats (SSRs), and 3648 SSRs were identified. A subset of 53 SSR markers was validated, of which 25 proved to be polymorphic in the three species except for the P. webbiana-specific marker JKIPat16. The number of alleles ranged from 85 in P. patellaris, 187 in P. procumbens, and 202 in P. webbiana. CONCLUSIONS: The set of 25 new markers will facilitate studies of the relationships between the three Patellifolia species and of the spatial and temporal distribution of genetic diversity within the species.

First detection of wheat streak mosaic virus in Germany: molecular and biological characteristics.

Wheat streak mosaic virus is a serious threat in wheat-producing countries. In Germany, the virus was first recorded in 2013 near Hoym. The complete sequence of isolate Hoym was obtained and compared to all other known complete WSMV sequences, including newly collected and sequenced isolates from France and Austria. Phylogenetic analysis revealed that the European isolates group together with those from the Middle East to form a separate cluster characterized by a distinct putative P1 protease cleavage site. By means of quantitative reverse transcription polymerase chain reaction, it was shown that RNA of the USA type strain PV57 accumulated to higher levels in infected wheat cv. Alcedo than did RNA of isolate Hoym.

Update on paroxysmal nocturnal haemoglobinuria: on the long way to understand the principles of the disease.

The understanding of the clinical manifestations in paroxysmal nocturnal haemoglobinuria (PNH) has made great progress. The main symptoms of this disease such as abdominal pain, renal failure or pulmonary hypertension and even the basis of the dramatic thrombophilia can be related to intravascular haemolysis and liberation of free haemoglobin resulting in NO depletion. In addition, there has been a recent great progress in elucidating the pathophysiology of clonal expansion within PNH bone marrow. In the majority of patients with haemolytic PNH, there are additional mutations within genes beyond PIG-A and rather affecting growth and differentiation of clonal bone marrow cells. In contrast to the formerly proposed single mechanism hypotheses such as immune selection or intrinsic gain of clonal dominance, this appears to follow a pattern of a complex clonal hierarchy putatively integrating both earlier anticipated mechanisms. Treatment of PNH is mainly supportive. The only curative approach as allogeneic stem cell transplantation should only be applied to patients with complications such as secondary bone marrow aplasia or transformation into MDS or AML. Symptomatic haemolytic PNH will be treated with eculizumab, an inhibitor of the terminal complement cascade. Treatment with eculizumab can significantly prevent PNH-related symptoms including the abnormal thrombophilia. Recently, it was demonstrated that in contrast to untreated historic PNH patients, meanwhile a normal life expectancy is observed in eculizumab-treated patients. The recently approved vaccine against meningococci type B by the European Medical Agency (EMA) could probably further help to prevent meningococcal sepsis due to the induced complement deficiency by eculizumab.

Global-scale computational analysis of genomic sequences reveals the recombination pattern and coevolution dynamics of cereal-infecting geminiviruses.

Genetic diversity and recombination patterns were evaluated for 229 isolates of Wheat dwarf virus (WDV), which are important cereal-infecting geminiviruses. Recombination hot spots were concentrated at the boundary of the genes encoding for the replication protein (Rep), the coat protein (cp) and the movement protein (mp), as well as inside Rep and cp and in the short intergenic regions (SIR). Phylogenomic analyses confirmed that the global population of WDV clustered into two groups according to their specific host: wheat and barley, and the crucial regions for the division of two groups were mp and the large intergenic regions (LIR). The computationally inferred pattern of coevolution between amino acid residues and the predicted 3D structure for the viral proteins provided further differences among the strains or species at the genome and protein level. Pervasive interaction between Rep and Rep A proteins in WDV-wheat-specific group reflected their important and complex function in the replication and transcription of WDV. Furthermore, significant predicted interactions between CP and Rep and CP and Rep A proteins in the WDV-wheat-specific group are thought to be crucial for successful encapsidation and movement of the virus during infection.

Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib.

The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 × 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 × 10(9)/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier:00055874).

Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma.

PURPOSE: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard care for aggressive B-cell lymphoma. A prospective trial was conducted to investigate the role of additive radiotherapy (RT) to bulky and extralymphatic disease. PATIENTS AND METHODS: The best arm of the RICOVER-60 trial (6×R-CHOP-14+2R [R-CHOP administered once every 2 weeks plus two additional applications of rituximab] plus involved-field RT [36 Gy] to sites of initial bulky [≥ 7.5 cm] disease and extralymphatic involvement) was compared with a cohort receiving the same immunochemotherapy but without RT in an amendment to the RICOVER-60 trial (RICOVER-noRTh) in a prospective fashion. RESULTS: After a median observation time of 39 months, 164 of 166 RICOVER-noRTh patients were evaluable. In a multivariable analysis of the intention-to-treat population adjusting for International Prognostic Index risk factors and age (> 70 years), event-free survival (EFS) of patients with bulky disease was inferior without additive RT (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.5; P = .005), with trends for inferior progression-free (PFS; HR, 1.8; 95% CI, 1.0 to 3.3; P = .058) and overall survival (OS; HR, 1.6; 95% CI, 0.9 to 3.1; P = .127). In a per-protocol analysis with 11 patients in RICOVER-noRTh excluded for receiving unplanned RT, multivariable analysis revealed HRs of 2.7 (95% CI, 1.3 to 5.9; P = .011) for EFS, 4.4 (95% CI, 1.8 to 10.6; P = .001) for PFS, and 4.3 (95% CI, 1.7 to 11.1; P = .002) for OS for patients not receiving RT to bulky disease. CONCLUSION: Additive RT to bulky sites abrogates bulky disease as a risk factor and improves outcome of elderly patients with aggressive B-cell lymphoma. Whether RT can be spared in patients with (metabolic) complete remission after immunochemotherapy must be addressed in appropriately designed prospective trials.

Analysis of complete genomes of isolates of the Wheat dwarf virus from new geographical locations and descriptions of their defective forms.

Recently, the importance of the Geminiviruses infecting cereal crops has been appreciated, and they are now being studied in detail. Barley and wheat strains of Wheat dwarf virus are recorded in most European countries. Information on complete sequences of isolates from the United Kingdom, Spain, and Austria are reported here for the first time. Analysis revealed that their sequences are very stable. Recombination between strains was recorded only for the barley strain. We identified several defective forms of the barley strain from barley and wheat, which do not influence symptom expression. Sequences of barley isolates infecting wheat were obtained that did not differ from the isolates from barley. Based on specific features of the SIR of the barley strains, it is suggested that they are assigned to one of the two proposed new clusters, A1 or A2.

Severe conjunctivitis due to multidrug-resistant Neisseria gonorrhoeae and adenovirus 53 coinfection in a traveler returning from Thailand.

A male traveler returning from Thailand with severe bilateral conjunctivitis was tested for causative pathogens by culture and polymerase chain reaction in late 2010. The culturally grown Neisseria gonorrhoeae strain was resistant against penicillin, ciprofloxacin, and tetracycline. The patient was also found to have an eye infection with the unusual and likely recombinant adenovirus type 53. Besides multidrug-resistant gonococcal strains the unusual adenovirus strain is found circulating in Asia and both pathogens may be a risk for travelers.

Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.