A comprehensive overview of recent literature from 2003 concerning advances in enantioselective copper catalysed 1,4-addition of organometallic reagents to alpha,beta-unsaturated compounds is given ...in this critical review. About 200 ligands and catalysts are presented, with a focus on stereoselectivities, catalyst loading, ligand structure and substrate scope. A major part is devoted to trapping and tandem reactions and a variety of recent synthetic applications are used to illustrate the practicality and current state of the art of 1,4-addition of organometallic reagents. Finally several mechanistic studies are discussed (162 references).
TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, ...data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2
transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.
Purpose The main objective of this study is to gain a deeper understanding of how patients suffering from chronic myeloid leukemia (CML) cope with their illness. The study aims to reconstruct the ...subjective meaning-making process related to CML in order to gain insights into the impact the disease has on patients' emotions and everyday lives, as well as to explore the psychological impact of their being presented with the chance to suspend their therapy and recover from the disease. Methods Data were gathered from a qualitative study conducted in Italy on 158 Italian CML patients. Basing the study on the narrative inquiry approach, the patients were required to describe their patient journey in a qualitative narrative diary. These contained prompts to elicit the free expression of their needs, expectations, and priorities. A lexicographic analysis was carried out with T-LAB software and in particular a thematic analysis of elementary contexts (TAECs) and a word association analysis (WAA). Results The TAEC detected four thematic clusters related to two factors (temporal frame and contextual setting) that explained the variance among the narratives. The WAA evidenced a wide variety of emotions, both positive and negative, as patients reacted to the possibility of interrupting their therapy. Conclusions A better understanding of patients' experiences can offer insights into promoting the development of more sustainable healthcare services and into therapeutic innovation aimed at improving patients' quality of life and at engaging them more in their treatment. The findings of this study can also help make medical professionals more aware of the patient's burden and help them identify potential interactions and emotional levers to improve clinical relationships.
Essentials
The differential diagnosis among thrombotic microangiopathies (TMAs) is challenging.
We studied a case of TMA with neurologic symptoms, no renal impairment and normal ADAMTS‐13 levels.
Two ...novel mutations in complement factor I and thrombomodulin genes were identified.
Complement‐regulator genes can be involved in TMAs with normal ADAMTS‐13 regardless of renal damage.
Summary
Background
Thrombotic microangiopathies (TMAs) often represent a challenge for clinicians, because clinical, laboratory, and even genetic features are not always sufficient to distinguish among different TMAs.
Objectives
The aim of this study was to investigate the pathogenetic mechanisms underlying an acute case of TMA with features of both thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS).
Patients/Methods
We report the case of a 49‐year‐old woman who developed an acute TMA with neurologic involvement and no renal impairment. ADAMTS‐13, von Willebrand factor, and complement‐system biochemical characterization was performed on acute phase samples. Exome sequencing and direct Sanger sequencing of previously aHUS‐associated genes were performed. The functional consequences of the thrombomodulin (THBD) mutation were investigated by in vitro expression studies.
Results
Despite a clinical diagnosis of TTP, the patient had normal ADAMTS‐13 levels and increased VWF antigen levels with ultra‐large von Willebrand factor multimers. C3, C4, and complement factors H and I (CFI) were normal. Molecular analysis confirmed two novel heterozygous mutations in CFI (c.805G>A, p.G269S) and THBD (c.1103C>T, p.P368L), and in vitro expression studies showed a reduction in the generation of activated thrombin‐activatable fibrinolysis inhibitor (TAFIa) caused by mutated THBD. This proinflammatory condition, associated with the p.G269S mutation in CFI, probably leads to a complement‐mediated endothelial activation, with a relevant prothrombotic potential in case of transient environmental triggers.
Conclusions
This study identified the first case of acute TMA without renal involvement but with neurological damage carrying two novel mutations in complement‐regulator genes, highlighting the possible role of the complement system as a common pathogenetic mechanism in TMAs.
Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell disease that presents with haemolytic anaemia, thrombosis and bone marrow failure. We report a case of a 51-year-old ...male with a history of PNH in treatment with Eculizumab admitted to our Hospital for acute chest pain and dyspnoea. The diagnosis was a triple vessel disease and patient was scheduled for coronary artery bypass grafting surgery. To balance the risk between thrombosis and bleeding in this particular clinical setting, we decided to use thromboelastography (TEG) as point of care solution and we used the R parameter as the target of our anticoagulant therapy. The R parameter between 11 and 14 sec can be used as a target value to balance the risk; in addition, there was no evidence of acute hemolysis during the surgery and supplemental dose of Eculizumab was administered in order to minimize any potential exacerbation of intravascular hemolysis.
The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two ...chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in CHOP and 75.7% in the MACOP-B/VACOP-B group (P<0.001). The addition of IF-RT as consolidation improved the outcome, irrespectively of the type of chemotherapy (P=0.04). At a multivariate analysis, achievement of CR (P<0.0001) and type of CT (MACOP-B/VACOP-B) retained the significance for OS (P=0.008) and EFS (P=0.03). In our experience, MACOP-B/VACOP-B appears to positively influence OS and EFS in patients affected by PMLBCL, as compared to CHOP. Consolidation IF-RT on mediastinum further improves the outcome of CR patients.
The enantioselective, copper/phosphoramidite‐catalyzed 1,4‐addition of dialkylzinc reagents to acyclic dienones is described. The products of this reaction, obtained with enantioselectivities of up ...to 95 %, can be further functionalized by a second conjugate addition, or employed in an enolate trapping, ring‐closing metathesis protocol.
Abstract Objective Over the past years both donor and recipient profiles have changed in heart transplantation. Satisfactory clinical outcomes of marginal donors in candidates >60 years of age have ...led us to allocate suboptimal donors to younger recipients as well. Therefore, we retrospectively reviewed our experience. Methods Among 199 patients undergoing heart transplantation from January 2000 to February 2010, there were 83 (41%) aged 61–72 years. The other 116 (59%) ranged in age between 18 and 60 years. According to their clinical conditions as heart transplantation candidates, They were classified into 4 groups: younger recipients (n = 116) of either optimal donors (n = 72; group 1 G1) or marginal donors (n = 44; group 2 G2) and older recipients (n = 83) of either marginal grafts (n = 70, group 3 G3) or optimal grafts (n = 13; group 4 G4). The gender distribution, cause of end-stage heart failure, preoperative pulmonary hypertension incidence, pretransplantation clinical status, and mean follow-up were not significantly different among the 4 groups. Results Overall 30-day survival was 90 ± 1% and 10-year rate was 78 ± 9%. Among the groups, 30-day and 10-year actuarial survival rates were, respectively: 94 ± 4% and 87 ± 1% for G1; 86 ± 5% and 84 ± 7% for G2; 88 ± 4% and 71 ± 7% for G3 and were 100% and 82 ± 7% for G4 ( P = .7). In comparison among the 4 groups, there was no significant difference regarding freedom from graft failure ( P = .3), right ventricular failure ( P = .3), acute rejection episodes ( P = .2), chronic rejection ( P = .2), neoplasia ( P = .5), or chronic renal failure ( P = .1). Older recipients of marginal donors G3 had a 4% (n = 3) prevalence of permanent pacemaker implant, versus G2: 3% (n = 2) among ( P = .1). Conclusion Our results suggest that extended donor and recipient criteria do not compromise clinical outcomes after transplantation.
It is known the prevalence of varicoceles in adolescent men is 14–29% but there is debate surrounding implications on fertility. As obtaining a semen analysis (SA) may be challenging, there is need ...for objective tests as measures of fecundity. Our aim was to investigate the relationship between testicular volume differential (TVD), varicocele grade, and total testicular volume (TTV) on seminal parameters including total motile sperm count (TMSC).
We conducted a retrospective single-center chart review over 14 years of 486 Tanner V adolescent males. Three hundred and four met inclusion of palpable, non-operated left-sided varicocele who underwent at least one SA and ultrasound. Abnormal TMSC was defined by World Health Organization 2010 criteria for minimal reference ranges. Multivariate logistic regression, receiver operating characteristic analysis with Youden J-statistic and descriptive statistics were performed.
Three hundred and four Tanner V adolescents with median age of 18.0 years (18.0–19.0), median TTV of 34.5 cc (28.9, 40.2) and median TMSC of 62.5 million/ejaculate (25.4, 123.4) were evaluated. TTV cutoff of 29.5 cc was found to predict TMSC of <9 million/ejaculate with negative predictive value of 96.2% and odds ratio of 6.08 (2.13–17.42, p < 0.001). TVD greater than 20% did not reach statistical significance with an odds ratio of 1.66 (0.41–6.62, p = 0.50).
In clinical practice, each patient will need to have an individualized plan. Based on our data, for older adolescents (17 or 18 years) with varicocele and an abnormal TTV, clinicians may have a lower threshold for advising SA, and if unable to obtain, surgical intervention and/or closer surveillance should be stressed. Patients should be informed of their six-fold increase in abnormal SA. Patients with normal TTV should be advised they are at lower risk of having abnormal SA. Younger patients with varicocele and an initial TVD>20%, should be followed closely but intervention delayed until 17 or 18 to better assess TTV. The importance of trending patient data should be emphasized as a single measurement has low predictive value for developing adolescents. Limitations of our study include a retrospective design and the lack of uniform correlation between adolescent SA and paternity.
Total testicular volume less than 29.5 cc increased odds of abnormal semen analysis by over six times and had a negative predictive value of 96.2%. Ultrasound results may be useful for risk stratification and counselling on appropriateness of surgical intervention. Display omitted
PurposeReal-world data from patients with BRAFV600-mutated, resected, stage III melanoma treated with dabrafenib plus trametinib as adjuvant targeted therapy are limited, and it is important to gain ...an understanding of the characteristics of this patient population, as well as of the patient journey. Here we aimed to describe the characteristics, dosage reductions and discontinuations in patients with BRAFV600E/K-mutated melanoma receiving adjuvant dabrafenib plus trametinib after surgical resection through an Italian managed access program (MAP).Patients and MethodsEligible patients had completely resected cutaneous melanoma with confirmed BRAF V600E or V600K mutation, or initially resectable lymph node recurrence after a diagnosis of stage I or II melanoma. The starting dose of dabrafenib and trametinib was 150 mg twice daily and 2 mg once daily, respectively.ResultsA total of 557 patients received dabrafenib plus trametinib through the MAP (stage III resected disease at inclusion, 554). Median age was 54.0 years, and 40.2% of patients were female. The proportion of all treated patients who required a dose reduction was low (10.8%) as was the proportion of patients who discontinued treatment (13.5%). The main reason for treatment discontinuation was adverse events (36.0%).ConclusionNew treatments, including BRAF-targeted therapies and immunotherapy, have transformed the natural history of melanoma. This is the largest study to date describing patients treated with dabrafenib plus trametinib in routine clinical practice in Italy between 2018 and 2019. Results highlight the characteristics of the patients treated and their journey, as well as the tolerable safety profile of dabrafenib plus trametinib in a real-world patient population.