Clinical and Economic Implications of Hydroxyurea Intolerance in Polycythemia Vera in Routine Clinical Practice.

Background/Objectives: Polycythemia vera (PV) is a chronic hematologic neoplasm commonly treated with hydroxyurea (HU). We utilized the advanced digitalized database of Maccabi Healthcare Services to retrospectively investigate the clinical and economic implications of HU intolerance in the routine clinical care of PV patients in Israel. Methods: We collected data on demographics, physician visits, hospitalizations, laboratory results, medication purchases, cardiovascular and thrombotic events, mental health, economic outcomes, and mortality. Outcomes included cardiovascular and other thrombotic events, disease progression, mental health events, economic outcomes, and overall mortality. Results: Of the 830 patients studied, 3 (0.4%) were resistant to HU treatment, 318 (38.3%) were intolerant to HU treatment, and 509 (61.3%) were stable on HU treatment. The venous thrombosis rate was significantly higher among HU-intolerant compared to HU-stable patients (1.58 vs. 0.47 per 100 person-years [PY], respectively; p < 0.001). The rate of progression to myelofibrosis was 6 vs. 0.9 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001), and the rate of progression to acute myeloid leukemia (AML) was 1.16 vs. 0.2 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001). The phlebotomy requirement, mortality rate, and total hospitalization days among HU-intolerant patients were significantly higher than in HU-stable patients (p = 0.049, p < 0.001, p < 0.001, respectively). More mental health-related events were noted in HU-intolerant patients vs. HU-stable patients (p = 0.007), and the total healthcare cost ratio was 2.65 for the HU-intolerant patients compared with HU-stable patients. Conclusions: This study suggests that HU-intolerant patients are more likely to have worse outcomes than HU-stable patients, highlighting the need for the close monitoring of these patients for disease-related complications or progression.

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

Challenges in Implementing Guideline on Integrative Oncology and Pain: The Israeli Perspective.

CONTEXT AND OBJECTIVES: To explore the feasibility of implementing the joint guideline on integrative medicine for pain management in oncology, published by the Society for Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO), for integrative oncology (IO) services in supportive and palliative care. METHODS: A qualitative research methodology was co-designed by the SIO-ASCO guideline committee, with the Society for Complementary Medicine, Israel Medical Association (IMA). A questionnaire with five open-ended questions exploring barriers and enablers to implementing the guideline was distributed to chairs and board members of nine IMA-affiliated medical societies; four deans of Israeli medical schools; and nurses from the Israeli Society for Oncology Nursing. Respondent narratives were qualitatively analyzed using ATLAS.Ti software for systematic coding. RESULTS: Questionnaires were completed by 52 physicians and nurses from medical oncology, hematology, gynecological oncology, pediatric oncology, palliative medicine, pain, family medicine, internal medicine, and integrative medicine. The SIO-ASCO guidelines were endorsed by nine IMA-affiliated societies. The domains identified included the importance of guideline implementation in clinical practice; barriers and facilitators to implementation; practical aspects required for this implementation (e.g., IO training); clinical indications for referral; budget-related issues; and clinical and administrative models enabling practical implementation of the guideline. CONCLUSION: We found across-the-board consensus among the nine IMA-affiliated societies supporting the current guideline. This, while identifying potential facilitators and barriers in order to address the implementation of the SIO-ASCO guideline recommendations.

Inpatient recognition and management of HLH.

Hemophagocytic lymphohistiocytosis (HLH) is one of the life-threatening emergencies that a hematologist may be called upon to diagnose and manage. It is a hyperinflammatory process that develops in patients with genetic abnormalities, hematologic malignancies, chronic inflammatory states, or infections. The main clinical challenges are recognizing HLH, determining whether the immune response is aberrant or appropriate, and deciding upon therapy. Patients may present with fever, central nervous system symptoms, cytopenias, or elevated liver enzymes. Recognizing HLH is challenging because its features overlap with numerous systemic disorders, thus requiring a high level of suspicion and timely investigations to confirm the diagnosis and detect the underlying trigger. Once HLH is diagnosed, careful consideration of immunosuppressive therapy's potential benefit versus harm is necessary. Such therapy can sometimes be tailored to the underlying trigger. In the acute setting, the competing pressures of completing a thorough diagnostic process (including evaluation for the presence of lymphoma and infection) and the need for expedited treatment must be balanced. During the management of an HLH patient, continuous vigilance for the presence of as-yet unrecognized disease triggers, monitoring response, and identifying emerging complications is critical. This review will discuss the recognition and management of HLH in the inpatient setting.

Thrombosis in multiple myeloma: mechanisms, risk assessment and management.

Multiple myeloma (MM) is associated with an increased risk of venous and arterial thrombosis. Pathophysiologic mechanisms include patient, disease and treatment related factors. Risk assessment models have been developed to determine whichpatients are at highest thrombotic risk and pursuant to this, risk adapted thrombosis prophylaxis has been suggested. Areas in which further basic and clinical research is imperative include the molecular and cellular mechanisms of thrombosis in myeloma, the inclusion of relevant biomarkers in risk assessment scores and controlled clinical trials of VTE prophylaxis and treatment using direct oral anticoagulants.

Heart valve disease in primary antiphospholipid syndrome.

OBJECTIVES: Antiphospholipid syndrome (APS)-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS associated HVD. METHODS: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). RESULTS: pAPS-HVD patients had more cerebrovascular events 56.3% vs 25% (p= 0.005) and livedo reticularis 24.2% vs 7.8% (p= 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, p= 0.034), recurrent thrombosis (33.3% vs 4.7%, p< 0.001), and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-B2GPI-IgG. [84.8% vs 63.2% (p= 0.034)], anti-cardiolipin IgG [90.9% vs. 64.8% (p= 0.005)] and triple positive aPL [75.8% vs 56.5% (p= 0.047)] were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. CONCLUSION: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as with specific serology namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients.

Low molecular weight heparin for venous thromboembolism prophylaxis in general Intensive Care Unit patients: an anti-factor Xa level-based approach.

BACKGROUND: Venous thromboembolism (VTE) in the Intensive Care Unit (ICU) is associated with significant morbidity and mortality therefore prevention is imperative to reduce its burden. VTE prophylaxis in ICU patients is primarily pharmacological using low molecular weight heparin (LMWH). Plasma anti-factor Xa (anti-FXa) levels may be used to measure LMWH activity. This study aims to determine the proportion of acutely ill patients in a general ICU receiving standard VTE prophylaxis that achieve adequate peak or trough anti-FXa prophylactic levels and to determine the effect of LMWH dose adjustment in patients not achieving adequate anti-FXa prophylactic levels. METHODS: Peak and trough anti-FXa levels were measured at four and 23 hours respectively after receiving the second consecutive daily enoxaparin 40 mg sc injection. Patients in whom peak anti-FXa levels were found to be sub-prophylactic (<0.2 IU/mL), were dose escalated to enoxaparin 60 mg once daily. Peak and trough levels were repeated as above. RESULTS: Sixty-one percent of study patients (N.=46) were found to have sub-prophylactic peak anti-FXa levels. Twenty-seven patients received an increased enoxaparin dose of 60 mg/d. Of these, nine patients (33.3%) still failed to achieve the target prophylactic peak anti-FXa level (0.2-0.4 IU/mL). Male gender and high body mass index (BMI) were significantly and strongly correlated with sub-prophylactic anti-FXa levels. CONCLUSIONS: Most ICU patients in this study did not achieve recommended prophylactic anti-FXa levels while receiving a standard dose of enoxaparin and these levels failed to increase after enoxaparin dose escalation in a significant proportion of patients. High BMI and male gender are associated with sub-prophylactic levels of anti-FXa in critically ill patients.

Direct Oral Anticoagulants in Special Patient Populations.

Anticoagulants are a cornerstone of treatment in atrial fibrillation. Nowadays, direct oral anticoagulants (DOACs) are extensively used for this condition in developed countries. However, DOAC treatment may be inappropriate in certain patient populations, such as: patients with chronic kidney disease in whom DOAC concentrations may be dangerously elevated; frail elderly patients with an increased risk of falls; patients with significant drug-drug interactions (DDI) affecting either DOAC concentration or effect; patients at the extremes of body mass in whom an "abnormal" volume of distribution may result in inappropriate drug concentrations; patients with recurrent stroke reflecting an unusually high thromboembolic tendency; and, lastly, patients who experience major hemorrhage on an anticoagulant and in whom continued anticoagulation is deemed necessary. Herein we provide a fictional case-based approach to review the recommendations for the use of DOACs in these special patient populations.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvß3 Integrin: In-Silico Based Study.

Background: Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvß3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvß3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking. Methods: In-silico docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvß3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol. Results: All TH molecules demonstrated negative free energy, suggesting affinity to the αvß3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3' T2 (3,3' T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket via divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5'. Summary: Three-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvß3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer.

Long Term Follow up of Patients With Primary Obstetric Antiphospholipid Syndrome.

Introduction: Primary obstetric antiphospholipid syndrome (OAPS) is defined by specific morbidities and/or losses of pregnancy in the presence of persistent antiphospholipid antibodies (aPL). This variant of APS is usually treated during pregnancy and the post-partum period. Data on occurrence of thrombotic event during long term follow-up of OAPS patients is limited. Methods: A multi-centre retrospectively cohort of female patients with primary APS (pAPS) was assembled during 2004-2019. Patients were grouped according to disease presentation as pure OAPS or thrombotic APS (tAPS) for those presenting with thrombosis. Clinical and serological data were compared between groups. Results: Of 219 pAPS female patients 67 (30.6%) were diagnosed with OAPS and 152 (69.4%) with tAPS. During >10 years of follow-up 24/67 (35.8%) OAPS and 71/152 (50%) tAPS suffered a new thrombotic event (p = 0.06), while obstetric morbidity was more likely in the OAPS group (31.3 vs. 10.5%, p < 0.001) respectively. Among patients with OAPS at presentation heart valve disease and the presence of ANA were related to thrombosis following diagnosis (25 vs. 4.7%, p = 0.02; and 45.8 vs. 20.8%, p = 0.04 respectively). Conclusion: Thrombotic event following diagnosis were common among female patients with pAPS regardless of disease presentation. Heart valve disease and ANA positivity may be risk factors for thrombosis during follow-up of patients presenting with pure OAPS.

Patterns of Recurrent Thrombosis in Primary Antiphospholipid Syndrome-Multicenter, Real-Life Long-Term Follow-Up.

Background: Antiphospholipid syndrome (APS) is an acquired hypercoagulable condition associated with antiphospholipid antibody (aPL) presence. Data on re-thrombosis following APS-diagnosis are limited. Methods: This is a retrospective analysis of new thrombotic events among primary APS (pAPS) patients followed for up to 15 years in three medical centers in Israel. Results: Among 312 primary-APS patients, 143 (46%) had new thrombotic event classified to three patterns: (1) Arterial-associated with heart valve disease (OR 7.24, 95% C.I. 2.26-24.6), hypertension (OR 3, 95% C.I. 1.44-6.25), elevated anti-B2-GPI IgM (OR 1.04, 95% C.I. 0.996-1.08), arterial thrombosis at presentation (OR 1.74 95% C.I. 0.992-3.26), and older age (41 vs. 34 years, p < 0.001). (2) Venous-linked with venous thrombosis at presentation (OR 12.9, 95% C.I. 5.27-31.6, p < 0.001), heart valve disease (OR 9.81 95% C.I. 1.82-52.9, p = 0.018), aGAPSS (OR 1.15 95% C.I. 1.02-1.29), and younger age (31 vs. 36.5 years, p = 0.001); and (3) Combined pattern-associated with heart valve disease (OR 40.5 95% C.I. 7.7-212) and pulmonary embolism (OR 7.47 95% C.I. 1.96-28.5). A 4th variant "the Breakthrough pattern" defined by re-thrombosis despite prophylactic therapy was observed in 100/143 (70%) patients and linked with heart valve disease (OR 8. 95% C.I. 2.43-26.3), venous thrombosis at presentation (OR 2.61 95% C.I. 1.47-4.66), leg ulcers (OR 12.2, 95% C.I. 1.4-107), hypertension (OR 1.99, 95% C.I. 0.92-4.34), and higher aGAPSS (OR 1.08, 95% C.I. 0.99-1.18). Conclusion: In this real-life observation, re-thrombosis was common among pAPS patients including in those recommended to receive prophylactic therapy. Different patterns of recurrence were identified and linked with presenting symptoms, specific serological markers, APS manifestations, and comorbidities. Studies that will address interventions to prevent recurrences of APS-related events are needed.

Recent advances in the treatment of polycythemia vera.

Polycythemia vera (PV) has long been recognized as a disease characterized by excess blood cell production leading to thromboembolic phenomena. While the focus of treatment is on prevention of thromboembolic complications, achieved by hematocrit control and administration of low dose aspirin, attention has begun to shift to other elements of this chronic neoplasm, namely symptom control and arrest of disease progression. Clearly, phlebotomy is not able to accomplish these goals, and the ability of cytoreductive agents such as hydroxyurea (HU), to influence these elements of the disease is limited. Novel and repurposed drugs have recently entered this space, based on promising initial studies demonstrating their effects on biologic outcomes such as JAK2 V617F variant allele frequency (VAF). In this review, we present updated results of randomized clinical trials of pegylated interferon (IFN) and ruxolitinib and summarize emerging data from early phase trials of novel agents in PV.

A Case of Chronic Lymphocytic Leukemia Complicated by Hemophagocytic Lymphohistiocytosis: Identifying the Aberrant Immune Response.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may complicate hematologic malignancies. HLH and malignancies have common clinical features, and HLH diagnostic criteria (HLH-2004/Hscore) were not validated in this specific population. We describe a case of a 72-year-old patient with a history of chronic lymphocytic leukemia stable for over 10 years who presented with fever and cytopenia. After excluding infectious etiologies and the progression of her disease, HLH was diagnosed. The patient was treated with etoposide, dexamethasone, intravenous immunoglobulin, and rituximab. Despite initial clinical improvement, the patient deteriorated and developed pulmonary aspergillosis and CNS involvement that reflected uncontrolled HLH. The patient died 45 days after her presentation. An unusual feature of this case was that HLH was not triggered by infection, disease transformation, or treatment. This case emphasizes the challenges of differentiating the development of overwhelming HLH from other complications associated with hematologic malignancy.

Childhood Disintegrative Disorder (CDD): Symptomatology of the Norwegian Patient Population and Parents' Experiences of Patient Regression.

Childhood Disintegrative Disorder (CDD) is a rare and little researched developmental disorder characterised by regression in language and social skills after a period of seemingly normal development until at least the age of 2 years. The study contacted all parents of CDD patients in Norway to assess patient symptomatology and parents' experiences of regression via questionnaire or interview. There were 12 participants. Symptomatology was in-line with previous studies, with universal regression in language and social skills and onset predominantly at 2-4 years. Regression was connected to feelings of 'loss' and uncertainty over the prognosis for CDD patients. The study supported CDD diagnostic criteria and showed that CDD patient regression has profound implications for parental well-being.