The 8p11 myeloproliferative neoplasm (8p11 MPN) is a rare disorder that is molecularly characterized by fusions of diverse partners to the tyrosine kinase receptor gene FGFR1 . It can rapidly ...transform to acute myeloid leukemia. Here we report on a case with a t(8;13)(p11.2;q12.1) ZMYM2-FGFR1 fusion, with massive tumor lysis upon tyrosine kinase inhibition with imatinib. Upon reevaluation, we detected trisomy 21 in addition to the translocation. Sequencing revealed a nonsense c.958C →T RUNX1 mutation both at diagnosis and disease progression, resulting in a p.Arg320X carboxyl-terminal truncated RUNX1 protein. This is the first report on an 8p11 MPN with a trisomy 21 RUNX1 mutation.
Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We ...evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma.
In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383.
Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21–2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10−5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33–0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23–0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%).
D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma.
The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
Infections and endothelial cells KELLER, Tymen T; MAIRUHU, Albert T. A; DE KRUIF, Martijn D ...
Cardiovascular research,
10/2003, Letnik:
60, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation ...of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.
To assess the effect of a uterine niche resection on fertility and pregnancy outcomes. We compared these outcomes in women with and without infertility, as we hypothesized that in the group with ...infertility, the presence of the niche may contribute to the failure to conceive. The focus on reproductive and pregnancy outcomes as well as the differentiation in study populations is novel and has not been a topic of research up until now.
The databases PubMed, Embase, and Web of Science were systematically searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines from inception until July 19, 2021. Randomized controlled trials (RCTs), cohort studies, case-control studies, and case series with at least 10 women were included if they reported fertility and/or pregnancy outcomes after any type of niche surgery among women with infertility or without the diagnosis of infertility. The risk of bias and quality of the included studies were assessed using the Cochrane risk-of-bias tool, the Newcastle-Ottawa Scale, and a set of niche-specific criteria. The primary outcome was live birth rate. The secondary outcomes included pregnancy and miscarriage rates, occurrence of an ectopic pregnancy, uterine dehiscence, and other obstetric complications. A meta-analysis was performed for the outcomes live birth, pregnancy, and miscarriage rates. The proportion with corresponding 95% confidence interval (CI) was calculated for each individual study, stratified for type of surgery and fertility status.
A total of 3,825 records were identified, of which 21 articles were included (1 RCT, 1 case series, and 5 prospective and 14 retrospective cohort studies). The RCT compared a surgical intervention with expectant management, whereas the other studies had an observational design. Sixteen studies reported on fertility outcomes in women with infertility (n = 648), and 5 studies reported on fertility outcomes in women without a diagnosis of infertility (n = 237). The reported surgical procedures were hysteroscopic niche resection (HNR) (n = 14), vaginal niche resection (n = 7), laparoscopic niche resection (n = 7), and laparotomic niche resection (n = 2). The overall methodological quality of included studies was moderate to poor with a high risk of bias. The statistical heterogeneity among the included studies ranged between 0 and 88%. Overall, the effect of a niche resection on the live birth rate was lower in women without infertility than in women with infertility: 36% (95% CI, 26 %–46%) vs. 54% (95% CI, 44%–64%).The live birth rates per different operative technique showed similar trends: HNR, 52% (95% CI, 40%–64%) vs. 55% (95% CI, 38%–71%); laparoscopic niche resection, 36% (95% CI, 25%–48%) vs. 42% (95% CI, 30%–55%); and vaginal niche resection, 25% (95% CI, 9%–46%) vs. 60% (95% CI, 52%–67%). The only RCT performed showed a significantly higher pregnancy rate after HNR than that after expectant management (N = 61 women; relative risk, 2.41; 95% CI, 1.32–4.39) in women diagnosed with infertility. There were no significant differences in the pregnancy and miscarriage rates between the different populations. A cesarean scar pregnancy was reported in 0.97% of pregnancies. After a hysteroscopic approach, in 4 (2.8%) of 145 deliveries, a uterine dehiscence or rupture was reported. There was no uterine dehiscence described after the other niche interventions.
On the basis of the current available data, it is not advised to perform a niche resection to improve fertility outcomes. Well-designed comparative studies are necessary to investigate whether there is a role for niche surgery in patients with regard to fertility outcomes.
•There is currently insufficient evidence to support the implementation of niche surgery in routine daily practice to improve reproductive outcomes in patients with a niche.•Additional studies are needed to investigate whether there is a role for niche surgery in regard to optimizing reproductive outcomes and identify the characteristics of the patients who may benefit most from these surgical interventions.•Future comparative studies should focus on the long-term efficacy and safety of niche resection during a subsequent pregnancy.
BACKGROUNDIdentification of child abuse is a daily challenge in medical work. The estimated number of unreported cases of child abuse and neglect is high. OBJECTIVESThe aim of this study was to ...investigate the effectiveness of the redesigned clinical child protection program of a major German pediatric hospital and to improve programs in other hospitals for children and physicians through presentation of the advantages of the new structure. METHODSAll cases of child protection at the Altona Children's Hospital were retrospectively analyzed before and after restructuring of the clinic's child protection program for a two-year period each, and a comparison was made. The child protection program was restructured and the new program subsequently managed by a fulltime coordinator. RESULTSThe prevalence of both suspected and substantiated cases of child abuse was significantly higher after restructuring of the child protection program. Before the change, 24 cases were investigated, of which 23 were substantiated; afterward, 124 cases were investigated and 89 were substantiated. Despite the high number of false-positive suspected cases, stigmatization of the families during the clarification progress was avoided by using a very sensitive approach, and the family was not confronted until the suspicion was affirmed. CONCLUSIONThe presented concept of child protection in medical clinics seems to facilitate a higher detection rate of child abuse cases. The reduction in the number of undetected cases and thereby prevention of possible escalation of abuse, as well as the decline in the immense social follow-up costs, justifies the increased personnel costs.
Introduction
Data from clinical trials indicate that elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies. However, overall survival ...is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index, caused by a high discontinuation rate due to toxicity. Therefore, there is a need for less toxic treatment for unfit and frail patients. In view of the favorable safety profile of ixazomib and daratumumab, we investigated the efficacy and feasibility of treatment with ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail patients. This trial was registered at www.trialregister.nl as NTR6297.
Methods
In this prospective multicenter phase II trial treatment consisted of 9 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15), daratumumab (D) 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dexamethasone (in combination with daratumumab (d); cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with I (days 1, 8, 15, 29, 36, 43) and D (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary objective is to determine the overall response rate (ORR) on induction therapy. Aiming for an ORR of at least 65% and considering 50% as a too low ORR, with an optimal Simon 2-Stage design, α = 0.10 and β = 0.20, 60 unfit and 60 frail patients should be included, increased to 66 for both populations to account for ineligibility. A pre-specified safety analysis was planned when for the first 10 unfit and 10 frail patients separately the data of the first 4 cycles of induction therapy are available.
Inclusion criteria were NDMM, either being unfit or frail according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 <50% of expected and a creatinine clearance of <20 ml/minute.
We here report the results of the planned safety interim analysis of the first 10/32 included frail patients who completed the first 4 induction cycles. The safety interim analysis of the first 10 unfit patients is planned in September, of which the results will be available at the ASH meeting. In addition, we here report the severe adverse events (SAE) for 58 eligible patients (26 unfit, 32 frail) who were included in the study until July 16, 2018.
Results
The demographic data of the first 10 frail patients are described in Table 1. Median FU of the first 10 frail patients is 5.2 months (range 0.6-9) and of the 58 included patients 1.6 months (range 0-9).
Toxicity is described in Table 2. Hematological toxicity was limited, being mainly thrombocytopenia; 3/10 grade 3, 1/10 grade 4, the latter being disease-related. Non-hematological toxicity was manageable, with only 2 grade 3 gastro-intestinal events and 1 pulmonary embolism. No infusion related reactions and neuropathy were reported. There were minor dose reductions only. The median and inter-quartile range of relative dose intensity (RDI) were 1.0 (0.9, 1.0) for ixazomib, 0.9 (0.9, 1.0) for daratumumab and 1.0 (0.9, 1.0) for dexamethasone. SAEs occurred in 9/26 unfit and 14/32 frail patients, mainly caused by prolongation of hospitalization (82% and 88% respectively).
Two patients died during cycle 1, both not related to therapy. One 81-year old patient unexpectedly died at home at day 35 of cycle 1 (delay due to low platelet count) after having recovered from thrombocytopenia and a decreased renal function, grade 3, probably caused by cotrimoxazole and valaciclovir. The second 81-year old patient had a thrombocytopenia of 18x109/l related to MM and died of gastrointestinal bleeding for which he declined therapy at day 15 of cycle 1. In the first included 58 patients a total of 4 patients died (6.9%, 4/32 frail (12.5%) and 0/26 unfit (0%)), of whom 2 not related to therapy (see above) and 2 possibly therapy-related; 1 due to Influenza B and 1 acute pre-renal failure due to vomiting and diarrhea.
Preliminary response during the first 4 cycles of therapy is promising is; ORR 70% of which 20% VGPR, 10% MR, 10% SD and 10% not evaluable.
Conclusion
This planned safety analysis of frail patients in the HOVON 143 showed that Ixazomib-Daratumumab-low dose dexamethasone is feasible with a low rate of therapy-related toxicity and mortality. Preliminary response rates are promising.
Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Summary
Background
The influenza season 2017–2018 of the northern hemisphere was the highest since 2001 and was caused predominantly by influenza B virus.
Methods
We performed a retrospective ...analysis of all patients in a university hospital in northern Germany with laboratory-confirmed influenza during the winter season 2017–2018 and analyzed underlying conditions, complications, and outcome.
Results
A total of 272 cases of influenza were diagnosed: 70 influenza A (25.7%), 201 influenza B (73.9%), and 1 co-infection. Of 182 adults, 145 were hospitalized, 73 developed pneumonia, 11 developed myocardial infarction, two a transient ischemic attack, one a stroke, and one perimyocarditis. Eleven of the 145 hospitalized adult patients (7.6%) died, ten of them because of pneumonia. All of them had preexisting diseases. Pneumonia was associated with a mortality of 13.7%. Underlying cardiac insufficiency was correlated with higher mortality (7/51 with versus 4/126 patients without cardiac insufficiency;
p
< 0.05). Ninety cases of influenza were diagnosed in 89 children (30 A, 60 B), one child had first influenza B, then influenza A. Twenty-eight children (31%) were hospitalized, 15 children developed one or more complications (lower respiratory tract infections, meningeal irritations, febrile seizures, otitis media, myositis). No child died. Influenza vaccination status was known in 149 adult patients, pneumonia occurred more frequently in non-vaccinated individuals (43/90; 47.8%) than in vaccinated patients (18/59; 30.5%,
p
< 0.05).
Conclusion
Patients with influenza should be monitored for secondary pneumonia and myocardial infarction, and vaccination should be enforced especially in patients with coronary heart disease and cardiac insufficiency.
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