The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are ...extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR
) and 17% (MR
) of patients at 2 years; 58% of the enrolled patients achieved a MR
at least once, with a sustained MR
in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).
The electronic surveillance system Hema e-Chart allowed us to prospectively collect data and to perform an analysis of invasive fungal infections (IFI) diagnosed in febrile patients as well as the ...procedures allowing their diagnosis and outcome according to the treatment given. Every patient admitted to 26 Italian Haematology Units with a new diagnosis of haematological malignancy and who was a candidate for chemotherapy was consecutively registered between March 2007 and March 2009. In all, 147 haematological patients with mycoses were identified. Yeasts were found in 23 infections; moulds were diagnosed in 17 proven, 35 probable and 72 possible mycoses. Galactomannan (GM) antigen was the most important test to diagnose probable mould infection; it was positive (cut-off >0.5) in 27 (77%) probable and in nine (53%) proven mould infections. Among patients with probable/proven mould infection who received no prophylaxis or non-mould-active prophylaxis with fluconazole, more patients (n = 26, 78.8%) had GM antigen positivity compared with patients (n = 10, 52.6%) given prophylaxis with mould-active drugs (p <0.05). First-line antifungal therapy was effective in 11/23 (48%) yeast infections and in 37/52 (71.2%) proven/probable mould infections. Twenty patients (14%) died within 12 weeks. The fungal attributable mortality was 30.4% and 17.3% in yeast and proven/probable mould infections, respectively. Among risk factors only age was independently associated (p 0.013) with mortality; sex, underlying haematological malignancy, previous prophylaxis and presence of neutropenia at diagnosis were not significant. A diagnosis of mould infection seemed to have a trend for a better outcome than the diagnosis of yeast infection (p 0.064).
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.
Background:
Immunoglobulin D (IgD) Multiple Myeloma (MM) is uncommon variant of myeloma affecting less than 2% of all myeloma patients. This subtype is characterized by a reversed light chain ratio ...and a very low M‐spike on SPEP. The clinical features are similar to those of the other isotypes, but there appears to be an increased incidence of extra osseous disease, renal failure and amyloidosis. The prevalence of extra osseous disease in IgD MM is around 19‐63% with usual sites being the chest wall, respiratory tract, gastrointestinal tract, skin, lymph nodes and paraspinal areas.
Aims:
We report clinical presentation, response to therapy with novel agents (bortezomib and thalidomide) and survival of six patients with IgD MM.
Methods
From December 2012 to December 2018 six patients with IgD MM were treated in our institution. Patient characteristics and laboratory findings are listed in Table 1. Diagnosis of MM was performed in according with International Myeloma Working Group (IMWG) and evaluation of response was based on the International Uniform Response Criteria. All pts had bone lesions documented by MRI and CT scan and four pts (67%) at onset presented extra osseous disease in paraspinal areas (3 pts) or in soft tissue of chest wall (1 pts). One patient showed extraosseous disease in paraspinal area at time of relapse.
Results:
All patients were treated with bortezomib based therapy; two pts received VTD combination (bortezomib‐thalidomide and dexamethasone), two VD (bortezomib and dexametasone), one patient PAD (bortezomib, doxorubicin and dexametasone and one VCD (bortezomib, cyclophosphamide and dexamethasone). The median number of cicles was 3 (range 2‐4)and the median time to response was 3 months; at evalutation after three‐four courses 2 pts (33%) achieved Complete Response (CR), one patient (17%) very good partial response (VGPR), and 3 pts (50%) had progressive disease (PD) and these last had a median overall survival of 6 months (range 4‐8 months). Four of six patients were transplant eligible, of them three showed at least VGPR after induction and underwent ASCT, while one patients was defined refractory and received second line treatment with lenalidomide plus dexamethasone. In transplant group the median progression free survival was 12 months (range 6‐42) and the median overall survival was 24 months (range 15‐46)
Summary/Conclusion:
In our case series IgD MM is characterized by aggressive clinical features and poor survival. The bortezomib–based regimen seems to be effective to achieving a response, but the duration of the response is very short. The approval of promising novel agents as new proteosome inhibitors (e.g. carlfizomib) and monoclonal antibodies (e.g. daratumumab), if used quikly at time of diagnosis, could be able to prevent the fast progression and appearance of extra‐osseous disease at the relapse in this subtype. More studies are needed to understand the biology of the IgD MM and to improve outcomes for our patients.
BACKGROUND A successful oocyte cryopreservation programme is of utmost importance where a limited number of oocytes can be inseminated per cycle, to overcome legal and ethical issues related to ...embryo storage, for oocyte donation programmes and for fertility preservation (especially for cancer patients). Vitrification has been recently proposed as an effective procedure for this purpose. METHODS In order to validate the effectiveness of oocyte vitrification a non-inferiority trial was started on sibling metaphase II (MII) oocytes. To demonstrate the non-inferiority based on an absolute difference of 17% in the fertilization rate per sibling oocyte, a minimum of 222 oocytes were required. After oocyte denudation, MII oocytes with normal morphology were randomly allocated to fresh ICSI insemination or to vitrification procedure. If pregnancy was not obtained a subsequent ICSI cycle was performed with warmed oocytes of the same cohort. In both groups, three oocytes were inseminated per cycle by ICSI procedure. Primary end-points were fertilization rates calculated per warmed and per injected oocytes. Secondary end-points were zygote and embryo morphology. RESULTS A total of 244 oocytes were involved in this study. Of the 120 fresh sibling oocytes inseminated, 100 were fertilized (83.3%). Survival rate of sibling vitrified oocytes was 96.8% (120/124 oocytes). Fertilization rate after ICSI was 76.6% (95/124) per warmed oocyte and 79.2% (95/120) per survived/inseminated oocyte. No statistical difference in fertilization rates was observed between the two groups when calculated per sibling oocytes (absolute difference −6.73%; OR: 0.65; 95% CI = 0.33–1.29; P = 0.20) and per inseminated oocyte (absolute difference −4.17%; OR: 0.76; 95% CI = 0.37–1.53; P = 0.50). Embryo development was also similar in both treatment groups up till Day 2. The percentage of excellent quality embryos was 52.0% (52/100) in the fresh group and 51.6% (49/95) in the vitrification group (absolute difference −0.43%; OR: 0.98; 95% CI = 0.53–1.79; P = 0.9). The mean age of the 40 patients included in this study was 35.5 ± 4.8 years (range 26–42). Fifteen clinical pregnancies were obtained in the vitrification cycles of 39 embryo transfers performed (37.5% per cycle, 38.5% per embryo transfer), with an implantation rate of 20.2% (19/94). Three spontaneous miscarriages occurred (20%). Twelve pregnancies are ongoing (30.0% per cycle, 30.8% per embryo transfer) beyond 12 weeks of gestation. CONCLUSIONS Our results indicate that oocyte vitrification procedure followed by ICSI is not inferior to fresh insemination procedure, with regard to fertilization and embryo developmental rates. Moreover, ongoing clinical pregnancy is compatible with this procedure, even with a restricted number of oocytes available for insemination. The promising clinical results obtained, in a population of infertile patients, need to be confirmed on a larger scale. Clinical Trials Registration number: iSRCTN60158641.
BACKGROUND
An efficient method for cryopreservation of human oocytes may offer solutions to legal and ethical problems in routine infertility programs and may also be used for fertility preservation ...for medical and social reasons.
METHODS
We conducted an observational longitudinal cohort multicentric study to investigate the efficacy and reproducibility of oocyte cryopreservation outcomes in IVF/ICSI cycles. Moreover, the effects of patient and cycle characteristics on the delivery rate (DR) were analyzed.
RESULTS
In 486 cycles performed in 450 couples, 2721 oocytes were warmed and 2304 of them survived cryopreservation (84.7%). Of the 2182 oocytes subjected to ICSI, the rates of fertilization and development to top-quality embryos were 75.2 and 48.1%, respectively. A total of 128 deliveries were obtained (26.3% per cycle and 29.4% per transfer) for 450 patients (28.4%) and 147 babies were live born from 929 embryos transferred (15.8%). The forward logistic regression analysis on a per patient basis showed that female age odds ratio (OR): 0.93, 95% confidence interval (CI): 0.88–0.98, number of vitrified oocytes (OR: 1.08, 95% CI: 1.01–1.17) and the day of transfer (OR: 1.97, 95% CI: 1.14–3.42) influenced DR. By recursive partitioning analysis, it can be estimated that more than eight oocytes vitrified are required to improve the outcome (22.6 versus 46.4% DR, respectively). When fewer oocytes are available in women aged >38 years, results are dramatically reduced (12.6 versus 27.5% DR, respectively). Conversely, when >8 oocytes are available, blastocyst culture represents the most efficient policy (62.1% DR; data from one center only).
CONCLUSIONS
Oocyte vitrification is an efficient and reliable approach, with consistent results between centers and predictable DRs. It should be applied routinely for various indications. A predictive model is proposed to help patient counselling and selection.
High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the ...search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results. However, the expression of PARP enzymes in human neuroblastoma and the biological consequences of their inhibition remained largely unexplored. Here, we show that high PARP1 and PARP2 expression is significantly associated with high-risk neuroblastoma cases and poor survival, highlighting its previously unrecognized prognostic value for human neuroblastoma. In vitro, PARP1 and 2 are abundant in MYCN amplified and MYCN-overexpressing cells. In this context, PARP inhibitors with high 'PARP trapping' potency, such as olaparib or talazoparib, yield DNA damage and cell death preceded by intense signs of replication stress. Notwithstanding the activation of a CHK1-CDC25A replication stress response, PARP-inhibited MYCN amplified and overexpressing cells fail to sustain a prolonged checkpoint and progress through mitosis in the presence of damaged DNA, eventually undergoing mitotic catastrophe. CHK1-targeted inhibition of the replication stress checkpoint exacerbated this phenotype. These data highlight a novel route for cell death induction by PARP inhibitors and support their introduction, together with CHK1 inhibitors, in therapeutic approaches for neuroblastomas with high MYC(N) activity.
► We analyze stellar occultations by Titan observed by the Cassini/UVIS instrument. ► We derive density and temperature profiles for the upper atmosphere of Titan. ► We derive extinction profiles for ...Titan aerosols near their production region. ► We find evidence for the presence of low frequency gravity waves in the atmosphere. ► The results are compared with previous Voyager and Cassini measurements.
Stellar occultations observed by the Cassini/UVIS instrument provide unique data that probe the mesosphere and lower thermosphere of Titan at altitudes between 400 and 1400km. This region is a site of complex photochemistry that forms hydrocarbon and nitrile species, and plays a crucial role in the formation of the organic hazes observed in the stratosphere, but has yet to be adequately characterized. We analyzed publicly available data obtained between flybys Tb in December 2004 and T58 in July 2009, with an emphasis on two stable occultations obtained during flybys T41 and T53. We derived detailed density profiles for CH4, C2H2, C2H4, C4H2, HCN, HC3N and C6H6 between ∼400 and 1200km and extinction coefficients for aerosols between 400 and 900km. Our analysis reveals the presence of extinction layers in the occultation data that are associated with large perturbations in the density profiles of the gaseous species and extinction profiles of the aerosols. These relatively stable features vary in appearance with location and change slowly over time. In particular, we identify a sharp extinction layer between 450 and 550km that coincides with the detached haze layer. In line with recent images obtained by Cassini/ISS, the altitude of this layer changes rapidly around the equinox in 2009. Our results point to unexpected complexity that may have significant consequences for the dynamics and physical processes taking place in the upper atmosphere of Titan.
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear
. Here we show that mtDNA mutations ...are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
Abstract
STUDY QUESTION
What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?
SUMMARY ANSWER
The high ...detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.
WHAT IS KNOWN ALREADY
About 2–4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple’s genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.
STUDY DESIGN, SIZE, DURATION
A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.
LIMITATIONS, REASONS FOR CAUTION
The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene–disease associations.
WIDER IMPLICATIONS OF THE FINDINGS
These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.
STUDY FUNDING/COMPETING INTEREST(S)
No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix.
TRIAL REGISTRATION NUMBER
N/A.
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