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Annals of Hematology Jun 2024Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between... (Meta-Analysis)
Meta-Analysis
Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.
Topics: Polycythemia Vera; Janus Kinase 2; Humans; Alleles; Gene Frequency; Amino Acid Substitution; Mutation, Missense
PubMed: 38652240
DOI: 10.1007/s00277-024-05754-4 -
Current Oncology (Toronto, Ont.) Mar 2024Neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) that usually results in poor clinical outcomes and may be accompanied by paraneoplastic... (Review)
Review
Neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) that usually results in poor clinical outcomes and may be accompanied by paraneoplastic syndromes (PNS). NEPC is becoming more frequent. It can initially manifest as PNS, complicating diagnosis. Therefore, we reviewed the literature on the different PNS associated with NEPC. We systematically reviewed English-language articles from January 2017 to September 2023, identifying 17 studies meeting PRISMA guidelines for NEPC and associated PNS. A total of 17 articles were included in the review. Among these, Cushing's Syndrome (CS) due to ectopic Adrenocorticotropic hormone (ACTH) secretion was the most commonly reported PNS. Other PNS included syndrome of inappropriate Anti-Diuretic Hormone secretion (SIADH), Anti-Hu-mediated chronic intestinal pseudo-obstruction (CIPO), limbic encephalitis, Evans Syndrome, hypercalcemia, dermatomyositis, and polycythemia. Many patients had a history of prostate adenocarcinoma treated with androgen deprivation therapy (ADT) before neuroendocrine features developed. The mean age was 65.5 years, with a maximum survival of 9 months post-diagnosis. NEPC is becoming an increasingly more common subtype of PCa that can result in various PNS. This makes the diagnosis and treatment of NEPC challenging. Further research is crucial to understanding these syndromes and developing standardized, targeted treatments to improve patient survival.
Topics: Male; Humans; Aged; Prostatic Neoplasms; Androgen Antagonists; Paraneoplastic Syndromes
PubMed: 38534956
DOI: 10.3390/curroncol31030123 -
Frontiers in Oncology 2024Large cell neuroendocrine carcinoma (LCNEC) is a rare subtype of prostate cancer. The pathogenesis, clinical manifestation, treatment options, and prognosis are...
BACKGROUND
Large cell neuroendocrine carcinoma (LCNEC) is a rare subtype of prostate cancer. The pathogenesis, clinical manifestation, treatment options, and prognosis are uncertain and underreported.
MATERIALS AND METHODS
A systematic search was conducted in April 2022 through PubMed, Embase, and Cochrane. We reviewed cases of LCNEC developed either from or transformation from prostate adenocarcinoma and summarized the relevant pathophysiological course, treatment options, and outcomes.
RESULTS
A total of 25 patients with a mean age of 70.4 (range 43 87 years old) from 18 studies were included in this review. 13 patients were diagnosed with LCNEC of the prostate. 12 patients were from the transformation of adenocarcinoma post-hormonal therapy treatment. Upon initial diagnosis, patients diagnosed with prostatic LCNEC had a mean serum PSA value of 24.6 ng/ml (range: 0.09-170 ng/ml, median 5.5 ng/ml), while transformation cases were significantly lower at 3.3 ng/ml (range: 0-9.3 ng/ml, median 0.05 ng/ml). The pattern of metastasis closely resembles prostate adenocarcinoma. Six out of twenty-three cases displayed brain metastasis matching the correlation between neuroendocrine tumors and brain metastasis. Three notable paraneoplastic syndromes included Cushings syndrome, dermatomyositis, and polycythemia. Most patients with advanced metastatic disease received conventional platinum-based chemotherapy with a mean survival of 5 months. There was one exception in the transformation cohort with a somatic BRCA2 mutation who was treated with a combination of M6620 and platinum-based chemotherapy with an impressive PFS of 20 months. Patients with pure LCNEC phenotype have worse survival outcomes when compared to those with mixed LCNEC and adenocarcinoma phenotypes. It is unclear whether there is a survival benefit to administering ADT in pure pathologies.
CONCLUSION
LCNEC of the prostate is a rare disease that can occur or transformation from prostatic adenocarcinoma. Most patients present at an advanced stage with poor prognosis and are treated with conventional chemotherapy regimens. Patients who had better outcomes were those who were diagnosed at an early stage and received treatment with surgery or radiation and androgen deprivation therapy (ADT). There was one case with an exceptional outcome that included a treatment regimen of M6620 and chemotherapy.
PubMed: 38515575
DOI: 10.3389/fonc.2024.1341794 -
Blood Advances May 2024Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic... (Meta-Analysis)
Meta-Analysis
Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic benefits. However, no systematic data support this approach. To support objective risk/benefit assessment of cytoreductive drugs in patients with PV aged <60 years (PV<60), this systematic review and meta-analysis was conducted to evaluate toxicity and disease-related complications in PV<60 treated with interferon alfa (rIFN-α) or hydroxyurea (HU). A search of PubMed, Scopus, Web of Science and Embase identified 693 unique studies with relevant keywords, of which 14 met inclusion criteria and were selected for analysis. The weighted average age of patients treated with rIFN-α was 48 years (n = 744 patients; 12 studies) and for HU was 56 years (n = 1397; 8 studies). The weighted average duration of treatment for either drug was 4.5 years. Using a Bayesian hierarchical model, the pooled annual rate of discontinuation due to toxicity was 5.2% for patients receiving rIFN-α (n = 587; 95% confidence interval [CI], 2.2-8.2) and 3.6% for HU (n = 1097; CI, 1-6.2). The average complete hematologic response for rIFN-α and HU was 62% and 52%, respectively. Patients experienced thrombotic events at a pooled annual rate of 0.79% and 1.26%; secondary myelofibrosis at 1.06% and 1.62%; acute myeloid leukemia at 0.14% and 0.26%; and death at 0.87% and 2.65%, respectively. No treatment-related deaths were reported. With acceptable rates of nonfatal toxicity, cytoreductive treatment, particularly with disease-modifying rIFN-α, may benefit PV<60. Future randomized trials prioritizing inclusion of PV<60 are needed to establish a long-term benefit of early cytoreductive treatment in these patients.
Topics: Humans; Polycythemia Vera; Treatment Outcome; Interferon-alpha; Hydroxyurea; Adult; Middle Aged; Cytoreduction Surgical Procedures; Age Factors
PubMed: 38507746
DOI: 10.1182/bloodadvances.2023012459 -
The World Journal of Men's Health Jul 2024Hydroxyurea (HU) is a cytoreductive agent used as standard treatment option for sickle cell anaemia/disease (SCD), essential thrombocythemia (ET), and polycythaemia vera...
PURPOSE
Hydroxyurea (HU) is a cytoreductive agent used as standard treatment option for sickle cell anaemia/disease (SCD), essential thrombocythemia (ET), and polycythaemia vera (PV). Despite its overall good safety profile, its use also in relatively young patients raises an interest on its potential impact on spermatogenesis. To perform a systematic review of all published articles investigating fertility in male patients affected by SCD, ET, and PV and treated with HU. Two paradigmatic case reports of patients affected by PV and ET, respectively, have been also reported.
MATERIALS AND METHODS
PubMed, EMBASE, and Cochrane databases were queried for all the published studies indexed up to November 15th, 2022. A combination of the following keywords was used: "hydroxyurea," "fertility," "male," "sperm," "sickle cell anaemia," "sickle cell disease," "essential thrombocythemia," "polycythaemia vera."
RESULTS
Of 48 articles identified, 8 studies, involving 161 patients, were eligible for inclusion. Overall, the number of spermatogonia per round cross section of seminiferous tubule were decreased in patients with SCD compared to healthy males. HU treatment was always associated with a worsening of semen parameters, even up to azoospermia. Notably, treatment discontinuation was associated with an improvement of semen parameters and a trend toward normalization in the case of PV and ET, with a less clear amelioration in men with SCD. In both our patients with either PV or ET, HU discontinuation was associated with a significant improvement of spermatogenesis with successful spontaneous pregnancies.
CONCLUSIONS
Published evidence do not consistently report normalization of spermatogenesis after HU discontinuation in SCD cases. Conversely, the literature almost consistently reported an improvement of semen parameters at the discontinuation of HU therapy in PV and ET cases. Our real-life two cases confirmed those findings. The willing of fatherhood and the need for effective fertility treatment warrant further research to improve work-up management in men with hematological disorders.
PubMed: 38164027
DOI: 10.5534/wjmh.230069 -
Journal of Clinical Medicine Nov 2023The distinct placental angioarchitecture in monochorionic (MC) pregnancies increases the risk of complications such as twin-twin transfusion syndrome (TTTS), twin anemia... (Review)
Review
The distinct placental angioarchitecture in monochorionic (MC) pregnancies increases the risk of complications such as twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), and selective fetal growth restriction (sFGR). The aim of this systematic review was to evaluate the incidence, type, and severity of cerebral injury and structural brain development on fetal and/or neonatal cerebral magnetic resonance imaging (MRI) in MC twins with or without complications. Twenty-three studies were included, covering a wide range of complications observed during MC pregnancies, with studies involving sIUFD ( = 12), TTTS ( = 7), mixed complications ( = 2), TAPS ( = 1), and uncomplicated MC pregnancy ( = 1). TAPS and sFGR were largely underrepresented in the current literature. The included studies reported that MC pregnancies with single intrauterine fetal demise (sIUFD) are most at risk for cerebral injury during the fetal period. The overall median incidence of cerebral injury after sIUFD was 28.3% (0-55%). Severe antenatal cerebral injury after sIUFD was detected antenatally in 6.5% (0-36%) of the cases. Three of the included studies described the incidence, type, and severity of cerebral injury on neonatal MRI in MC twins. Structural brain development based on cerebral biometry was only assessed in two studies, revealing significantly smaller biometric measurements of the cerebrum in cases of single sIUFD or smaller twins compared to singleton pregnancies. To enhance our understanding of the potential risks and pathophysiological mechanisms associated with cerebral injury and structural brain development in MC twins, there is a need for future studies and standardized protocols using serial fetal and neonatal MRI imaging in addition to routine ultrasound imaging.
PubMed: 38068261
DOI: 10.3390/jcm12237211 -
Clinical Pharmacokinetics Apr 2023Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to...
BACKGROUND AND OBJECTIVE
Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib.
METHODS
Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded.
RESULTS
Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations.
CONCLUSION
Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.
Topics: Animals; Humans; Female; Janus Kinases; Protein Kinase Inhibitors; Pyrazoles; Nitriles
PubMed: 37000342
DOI: 10.1007/s40262-023-01225-7 -
Biomedicines Jan 2023The impact of primary arterial hypertension (HTN) in myeloproliferative neoplasms (MPNs) remains unclear, with scant literature available, mostly focusing on... (Review)
Review
The impact of primary arterial hypertension (HTN) in myeloproliferative neoplasms (MPNs) remains unclear, with scant literature available, mostly focusing on cardiovascular risk factors as a singular entity or on organ-specific HTN. Furthermore, available studies reporting findings on drug-induced HTN in MPNs report varying and contradictory findings. In consideration of the above, this study set out to systematically review the available literature and shed light on the occurrence of HTN in MPNs, its association with thrombosis, as well as the drugs used in MPN management that could increase blood pressure. The literature search yielded 598 potentially relevant records of which 315 remained after the duplicates ( = 283) were removed. After we screened the titles and the abstracts of these publications, we removed irrelevant papers ( = 228) and evaluated the full texts of 87 papers. Furthermore, 13 records did not meet the inclusion criteria and were excluded from the systematic review. Finally, a total of 74 manuscripts were entered into the qualitative synthesis and included in the present systematic review. Our systematic review highlights that HTN is the most common comorbidity encountered in MPNs, with an impact on both the occurrence of thrombosis and survival. Moreover, drug-induced HTN remains a challenge in the management of MPNs. Further research should investigate the characteristics of patients with MPNs and HTN, as well as clarify the contribution of HTN to the development of thrombotic complications, survival and management in MPNs. In addition, the relationship between clonal hematopoiesis of indeterminate potential, HTN, cardiovascular disease and MPNs requires examination in upcoming assessments.
PubMed: 36830925
DOI: 10.3390/biomedicines11020388 -
Diagnostics (Basel, Switzerland) Jan 2023Philadelphia-negative myeloproliferative neoplasms (MPN) are most prevalent in the older population (median age at the diagnosis is above 60 years) and rarely diagnosed... (Review)
Review
BACKGROUND
Philadelphia-negative myeloproliferative neoplasms (MPN) are most prevalent in the older population (median age at the diagnosis is above 60 years) and rarely diagnosed in pediatrics. Thus, our knowledge about the clinical presentation, mutational status, and complications of MPNs in pediatrics is limited.
METHODS
The literature in English (PubMed, SCOPUS, and Google Scholar) was searched for studies, reviews, case series, and case reports of patients with Philadelphia-negative MPNs (including essential thrombocythemia, polycythemia vera, primary myelofibrosis, and profibrotic myelofibrosis) in the pediatrics age group (less than 18 years). Only studies that fulfilled WHO 2008 or 2016 criteria for MPNs were included. We aimed to describe the clinical characteristics, vascular and long-term complications, types of driver mutations, and treatment approaches in pediatric patients with MPNs.
RESULTS
We reviewed 33 articles of available published literature from 2008 to 2022 and collected data from a total of 196 patients of the pediatric population. Among the cohort of patients, 139 had essential thrombocythemia (ET), 20 had polycythemia vera (PV), and 37 had primary myelofibrosis (PMF). The median age at the time of diagnosis for each disease varied, with 8.8 years for ET, 10 years for PV, and 3.6 years for MF. There was a slight difference in gender prevalence between both gender groups and all three diseases. The presenting symptoms were not mentioned in more than 50% of studies. We found that JAK2 was the most prevalent among all mutations. Both bleeding and thrombosis were present equally in ET, with 9% of cases complicated by bleeding and 9% complicated by thrombosis. Hemorrhagic events did not occur in patients with PV; thrombosis in children with MF was also not found. The progression into AML occurred in two patients with PV and one with ET.
CONCLUSION
Given the rarity of MPNs in pediatrics and their different characteristics compared with adults, we believe there is a need for unique diagnostic criteria to match the different molecular statuses in pediatrics. Based on our review, the incidence of MPN complications in pediatrics, including thrombotic events, hemorrhage, and leukemic transformation, differs from that in adults.
PubMed: 36766480
DOI: 10.3390/diagnostics13030377 -
Ultrasound in Obstetrics & Gynecology :... Dec 2022To ascertain maternal and perinatal outcomes of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with the Solomon technique... (Meta-Analysis)
Meta-Analysis Review
Solomon technique vs selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome: systematic review and meta-analysis of maternal and perinatal outcomes.
OBJECTIVE
To ascertain maternal and perinatal outcomes of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with the Solomon technique compared with selective fetoscopic laser photocoagulation (SFLP) of placental anastomoses.
METHODS
MEDLINE, EMBASE and The Cochrane Library were searched to identify relevant studies. The outcomes observed were perinatal loss and survival, preterm prelabor rupture of membranes (PPROM), preterm birth (PTB), gestational age (GA) at delivery, interval between laser treatment and delivery, maternal bleeding, septostomy or chorioamniotic separation, placental abruption, twin anemia-polycythemia sequence (TAPS), recurrence of TTTS, neonatal morbidity and neurological morbidity. Random-effects head-to-head meta-analyses were used to analyze the data. Pooled odds ratios (OR) and mean differences (MD) and their 95% CIs were calculated.
RESULTS
Nine studies were included in the systematic review. There was generally no difference in the main maternal and pregnancy characteristics between pregnancies treated using the Solomon technique and those treated using SFLP of placental anastomoses. The risks of fetal loss (pooled OR, 0.69 (95% CI, 0.50-0.95); P = 0.023), neonatal death (pooled OR, 0.37 (95% CI, 0.16-0.84); P = 0.018) and perinatal loss (pooled OR, 0.56 (95% CI, 0.38-0.83); P = 0.004) were significantly lower in pregnancies treated using the Solomon technique than in those treated with SFLP. Likewise, pregnancies treated using the Solomon technique had a significantly higher chance of survival of at least one twin (pooled OR, 2.31 (95% CI, 1.03-5.19); P = 0.004) and double survival (pooled OR, 2.18 (95% CI, 1.29-3.70); P = 0.001). There was no difference in the risk of PPROM (P = 0.603), PPROM within 10 days from laser surgery (P = 0.982), PTB (P = 0.207), maternal bleeding (P = 0.219), septostomy or chorioamniotic separation (P = 0.224) or chorioamnionitis (P = 0.135) between the two groups, while the risk of placental abruption was higher in pregnancies treated using the Solomon technique (pooled OR, 2.90 (95% CI, 1.55-5.44); P = 0.001). In the Solomon technique group, pregnancies delivered at a significantly earlier GA than did those treated with SFLP (pooled MD, -0.625 weeks (95% CI, -0.90 to -0.35 weeks); P < 0.001), while there was no difference in the interval between laser treatment and delivery (P = 0.589). The rate of recurrence of TTTS was significantly lower in pregnancies undergoing the Solomon technique (pooled OR, 0.43 (95% CI, 0.22-0.81); P < 0.001), while there was no difference in the risk of TAPS between the two groups (P = 0.792). Finally, there was no difference in the overall risk of neonatal morbidity (P = 0.382) or neurological morbidity (P = 0.247) between the two groups.
CONCLUSIONS
Monochorionic twin pregnancies complicated by TTTS undergoing laser treatment using the Solomon technique had a significantly higher survival rate and lower recurrence rate of TTTS but were associated with an increased risk of placental abruption and earlier GA at delivery compared to those treated with SFLP. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Abruptio Placentae; Anemia; Fetofetal Transfusion; Fetoscopy; Gestational Age; Laser Coagulation; Laser Therapy; Lasers; Placenta; Polycythemia; Pregnancy, Twin; Premature Birth
PubMed: 36240516
DOI: 10.1002/uog.26095