Identifying patients at risk for hereditary myeloid malignancy syndromes incorporating a novel, self-administered questionnaire to an initial screening platform.

INTRODUCTION: Four to 10% of cases of myeloid malignancies are inherited. We report our experience on hereditary myeloid malignancy syndromes (HMMS) incorporating a novel questionnaire in the screening platform for patients with myeloid malignancies and aplastic anemia. METHODS: The questionnaire was sent via electronic patient portal prior to clinic visits. Patients screened positive based on responses to questionnaire items, presence of suspicion disease characteristics (young age, family history, monosomy 7 etc.) and/or presence of signs of HMMS. Those deemed at-risk based on questionnaire responses, clinical features and/or somatic mutation profile were offered germline testing. RESULTS: A total of 408 patients were screened, 141 (35%) were deemed at-risk. Fifty-four (38%) of at-risk patients were seen in the genetics clinic. Forty-one (76%) of the patients seen agreed to germline testing and 13 declined due to cost or personal decision. Twenty pathogenic (P)/likely-pathogenic (LP) germline mutations were identified in 16 (39%) of the tested patients. Five patients also had a variant of uncertain significance (VUS) and an additional 13 had at least 1 VUS without P/LP mutations (total 29 VUS's were found in 18 (44%) of tested patients). The median age of diagnosis for patients with P/LP mutations was 56 years versus 66 years in the entire cohort. CONCLUSION: Incorporating an electronic questionnaire is an effective screening method for HMMS. Many patients declined testing due to cost. These results highlight the importance of germline testing in patients with myeloid malignancies, further research in HMMS, and coverage by healthcare plans.

Physician-scientist or basic scientist? Exploring the nature of clinicians' research engagement.

Theoretical understanding of what motivates clinician researchers has met with some success in launching research careers, but it does not account for professional identification as a factor determining sustained research engagement over the long-term. Deeper understanding of clinicians' research-related motivation may better foster their sustained research engagement post-training and, by extension, the advancement of medicine and health outcomes. This study used an integrated theoretical framework (Social Cognitive Career Theory and Professional Identity Formation) and appreciative inquiry to explore the interplay of professional identification and research context in shaping post-training research success narratives. To foreground professional identification, 19 research-active clinicians and 17 basic scientists served as interviewees. A multi-institutional, multi-national design was used to explore how contextual factors shape external valuation of research success. The findings suggest that research-active clinicians do not identify as the career scientists implied by the modern physician-scientist construct and the goal of many clinician research-training programs. Their primary identification as care providers shapes their definition of research success around extending their clinical impact; institutional expectations and prevailing healthcare concerns that value this aim facilitate their sustained research engagement. Integrated developmental and organizational interventions adaptive to research context and conducive to a wider range of medical inquiry may better leverage clinicians' direct involvement in patient care and advance progress toward human health and well-being.

Herpes Zoster During Immunosuppressive Therapy For Autoimmune Diseases.

BACKGROUND: Patients on immunosuppressive therapy are at a greater risk for herpes zoster reactivation and are more likely to have adverse outcomes. Propylactic antivrials and vaccinations may potentially prevent these complications. METHODS: Medical literature addressing the clinical course and therapy of herpes zoster in patients receiving immunosuppressive therapy for autoimmune disorders, and the roles of anti-viral prophylaxis and vaccination was reviewed. Research databases including PubMed, Ovid, Medline, Google Scholar and Cochrane were utilized. RESULTS: Acyclovir and its derivatives are most commonly used in this setting for treatment and reduction of post-zoster complications. Foscarnet may be used for acyclovir-resistant strains. At both conventional and ultralow doses, acyclovir has proven effective when used as prophylaxis, reducing the incidence of zoster and its complications in immunosuppressed patients. Additionally, ultra-low doses are associated with significantly reduced side effects. The zoster vaccine, Zostavax, a live-attenuated vaccine has shown promising results in several clinical trials. However, live-attenuated vaccines should be cautiously used in immunosuppressed patients. For patients who require immunosuppressive therapy, vaccination 2-3 months prior to therapy may be appropriate. CONCLUSIONS: Prophylactic antiviral therapy and vaccination help significantly reduce morbidity and mortality from zoster reactivation in patients receiving immunosuppressive therapy.

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis.

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5 % (4-7 %). Incidence in allogeneic-HSCT was 4 % (2-6 %) and in autologous-HSCT was 4 % (1-15 %). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35 % (20-54 %), whereas in acute GVHD it was 47 % (32-62 %). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population.

Central nervous system prophylaxis in diffuse large B-cell lymphoma.

Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.

Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor-specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells.

Comparison of the clinical presentations of Naegleria fowleri primary amoebic meningoencephalitis with pneumococcal meningitis: a case-control study.

BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rare but fatal infection caused by Naegleria fowleri. The infection is acquired by deep nasal irrigation with infected water. Patients present with signs and symptoms similar to pneumococcal meningitis, leading to delayed diagnosis and treatment and hence high mortality. METHODS: We conducted a case-control study comparing culture proven cases of PAM with pneumococcal meningitis presenting to our center between April 2008 and September 2014. Only patients with blood and/or cerebrospinal fluid cultures positive for Streptococcus pneumoniae during the same time period were included for comparison. RESULTS: There were 19 cases of PAM and pneumococcal meningitis, each. When comparing PAM with pneumococcal meningitis, patients with PAM were more likely to be male (89.5 vs. 36.8 %), younger (mean age: 30 vs. 59 years), present with seizures (42.1 vs. 5.3 %). Both groups of patients presented with similar vital signs and there were no remarkable differences on physical examinations, Glasgow Coma Scale scores, laboratory and radiological investigations and cerebrospinal fluid parameters. PAM was also more likely to present if the city's average maximum temperature was higher in the previous week (mean: 34.6 vs. 30 °C). There was history of fresh water contact in only one patient. On multivariate analysis, PAM was more likely if patients presented when the city's average maximum temperature was high, being young males. CONCLUSION: PAM and pneumococcal meningitis remain virtually indistinguishable; however, these predictive features should be validated in a prospective study and may lead to a viable algorithm for early management of these patients.

Health-Related Anxiety and Hypochondriacal Concerns in Medical Students: A Cross-Sectional Study From Pakistan.

UNLABELLED: Phenomenon: Transient health-related anxiety/hypochondriacal concerns in medical students are well documented. The literature suggests that after studying a particular disease, medical students are likely to consider any symptoms earlier regarded as normal to be signs of the disease they are studying. The aim of this study was to investigate the prevalence of these phenomena and their cognitive and distress aspects among medicals students in Karachi, Pakistan. APPROACH: This was an analytical, cross-sectional study. Self-administered questionnaires comprising demographic details, the Short Health Anxiety Inventory, Medical Students' Disease (MSD) Perception Scale, and MSD Distress Scale were distributed to 1st- through 5th-year medical students. FINDINGS: In total, 513 medical students (66% female) participated. Their mean age was 21 ± 1.6 years. Three hundred seventy-five students (73%) reported having visited a doctor at least once in the past 6 months. Fifty students (9.9%) admitted to having addictions. The overall prevalence of significant hypochondriacal concerns was 11.9% (61 students). The presence of addiction was associated with a greater likelihood of developing significant health-related anxiety (odds ratio = 3.82, p = .003), 95% confidence interval [1.51, 7.11]. Age, gender, medical school, year of medical school, and visits to the doctor in the previous 6 months were not associated with greater likelihood of developing significant health-related anxiety. Second-year medical students experienced a significantly greater degree of worry (MSD-Distress scale) than 5th-year students (M score = 12.6 ± 4.6 vs. 10.7 ± 4.4, p = .04). Insights: The prevalence of substantial hypochondriacal concerns in medical students in Pakistan was low in comparison to similar studies published in literature. Student health physicians should be aware of the true prevalence of hypochondriacal concerns and behavior and not dismiss legitimate complaints. Educational sessions to counteract this phenomenon can be incorporated into the curriculum of undergraduate medicine. By defining heightened awareness of symptoms as a normal process, different coping techniques can be discussed to help medical students reduce their level of stress.

MUMPS MYOCARDITIS: A FORGOTTEN DISEASE?

Mumps is an acute viral illness that follows a self-limiting course but up to 10% of cases have a complicated course with the involvement of other organ systems. Myocarditis is reported as a complication but the incidence has greatly fallen ever since the development of the mumps vaccine. A child presented to our department with parotid swelling and fever. Persistent tachycardia with irregular pulse led to further cardiac work up which showed decreased ejection fraction and raised serum cardiac enzymes, indicating myocardial damage. With ionotropic agents and supportive care, there was complete normalization of ejection fraction and serum cardiac enzyme levels. He was discharged within a week of admission. This case highlights the importance of suspecting myocarditis in the setting of mumps, a diagnosis that precludes early suspicion in mumps patients suffering from cardiac symptoms not explained by other potential aetiologies. Early suspicion and timely supportive care are essential to ensure favourable outcomes.

Sorafenib-induced tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma.

Tumor lysis syndrome is a potentially lethal complication of chemotherapy, usually associated with aggressive hematologic malignancies. We describe the case of a young patient with metastatic hepatocellular cancer who developed rapid and fatal tumor lysis syndrome following initiation of sorafenib therapy. Although rare with sorafenib therapy for hepatocellular carcinoma, tumor lysis syndrome is serious complication. Patients with a high burden of disease at therapy initiation should have their metabolic parameters measured prior to starting therapy and closely followed for the first 1-2 weeks while being treated.

Can we prevent or treat graft-versus-host disease with cellular-therapy?

Acute and chronic graft-versus-host disease (GvHD) are the most important causes of treatment-related morbidity and mortality after allogeneic hematopoietic cell transplants for various diseases. Corticosteroids are an effective therapy in only about one-half of affected individuals and new therapy options are needed. We discuss novel strategies to treat GvHD using cellular-therapy including adoptive transfer of regulatory T-cells (Tregs), mesenchymal stromal cells (MSCs), cells derived from placental tissues, invariant natural killer T-cells (iNKTs), and myeloid-derived suppressor cells (MDSCs).These strategies may be more selective than drugs in modulating GvHD pathophysiology, and may be safer and more effective than conventional pharmacologic therapies. Additionally, these therapies have not been observed to substantially compromise the graft-versus-tumor effect associated with allotransplants. Many of these strategies are effective in animal models but substantial data in humans are lacking.

Outcome of hairy cell leukemia patients treated with cladribine - a 10-year single-center experience in Pakistan.

INTRODUCTION AND OBJECTIVE: Hairy cell leukemia is an uncommon, indolent B-cell lymphoproliferative disorder. Therapy with cladribine (2-chlorodeoxyadenosine) is able to induce complete remission (CR) in the majority of patients after a single course of treatment. We report the outcomes of patients treated at Aga Khan University Hospital, Karachi, Pakistan. METHODS: This was a retrospective review. Medical records of patients were used to collect data. RESULTS: A total of 21 patients with hairy cell leukemia were treated with cladribine. All patients achieved an initial CR. Four patients (19%) required hospitalization and therapy for neutropenic fever. Six patients (29%) relapsed at a median of 48 months. All 6 patients were treated for relapse, out of which 4 achieved CR, 1 had partial response and 1 had refractory disease. The overall survival rate was 90.5%, with a median follow-up of 35 months. CONCLUSION: A single course of cladribine is able to induce CR in a vast majority of patients. Unfortunately, relapse is not uncommon. Patients who relapse can be successfully retreated with cladribine. Cladribine has impressive efficacy and a favorable acute and long-term toxicity profile when administered to patients with HCL.

Infections in patients with multiple myeloma treated with conventional chemotherapy: a single-center, 10-year experience in Pakistan.

INTRODUCTION: Multiple myeloma (MM) is a common hematologic malignancy with variable degrees of immunodeficiency. Disease- and treatment-related compromise of the immune system predisposes patients to infections, which are a major cause of morbidity and mortality. OBJECTIVE: We aimed to establish the incidence and main characteristics of infections in MM patients treated at our center over a 10-year period. METHOD AND RESULTS: Of the 412 patients retrospectively analyzed, 154 (37.4%) were documented to have at least one episode of infection and were included in this study. A total of 244 infectious episodes were documented. The most common site of infection was the lung, followed by the genitourinary system. The most common infections were bacterial, followed by viral. Escherichia coli were the most common organism. In 160 (65.5%) episodes, the organism was not isolated. Thalidomide with dexamethasone was the most common treatment regimen, followed by melphalan with dexamethasone. Infection was the main cause of death in 26 (6.3%) out of all 412 patients. CONCLUSION: Infections are a notable cause of morbidity and mortality in the clinical course of MM patients. By considering patient and disease characteristics, a risk-adapted selection of the MM treatment should be employed, with special attention toward patient age and disease-associated organ dysfunction. Patient education, access to healthcare and physician vigilance are also essential. Vaccination and antimicrobial prophylaxis may be considered prior to or during therapy.

Cytogenetic Abnormalities in Myelodysplastic Syndromes: An Overview.

Karyotype is one of the main constituents of the International Prognostic Scoring System (IPSS) and revised-IPSS that are the cornerstones for the prognostication of patients with myelodysplastic syndromes (MDS). Del(5q), -7/del(7q), +8 and -Y are among the most extensively studied cytogenetic abnormalities in MDS. The same applies for normal karyotype. There are hundreds of other rare cytogenetic abnormalities that have been reported in MDS, included but not limited to -X, 3q abnormalities, +13/del(13q), i(17q), +21/-21. However, due to a very low number of patients, their impact on the prognosis of MDS is limited. Knowledge of the molecular consequences of different cytogenetic abnormalities allows us to modify treatment regimens based on drugs most active against the specific karyotype present, allowing for the opportunity to individualize MDS treatment and improve patient care and prognosis.

Haploidentical Hematopoietic Stem Cell Transplantation: Expanding the Horizon for Hematologic Disorders.

Despite the advent of targeted therapies and novel agents, allogeneic hematopoietic stem cell transplantation remains the only curative modality in the management of hematologic disorders. The necessity to find an HLA-matched related donor is a major obstacle that compromises the widespread application and development of this field. Matched unrelated donors and umbilical cord blood have emerged as alternative sources of donor stem cells; however, the cost of maintaining donor registries and cord blood banks is very high and even impractical in developing countries. Almost every patient has an HLA haploidentical relative in the family, meaning that haploidentical donors are potential sources of stem cells, especially in situations where cord blood or matched unrelated donors are not easily available. Due to the high rates of graft failure and graft-versus-host disease, haploidentical transplant was not considered a feasible option up until the late 20th century, when strategies such as "megadose stem cell infusions" and posttransplantation immunosuppression with cyclophosphamide showed the ability to overcome the HLA disparity barrier and significantly improve the rates of engraftment and reduce the incidence and severity of graft-versus-host disease. Newer technologies of graft manipulation have also yielded the same effects in addition to preserving the antileukemic cells in the donor graft.

Genomic imbalances in peripheral blood confirm the diagnosis of myelodysplastic syndrome in a patient presenting with non-immune hemolytic anemia.

Myelodysplastic syndrome (MDS) is a clonal stem-cell disorder characterized by dyshematopoiesis. We report a patient who presented with cytopenias and microangiopathic hemolytic anemia. Chromosome microarray analysis (CMA), using single nucleotide polymorphism arrays, on peripheral blood revealed genomic imbalances indicative of MDS, which was confirmed by bone marrow examination. This report highlights the importance of suspecting MDS in patients with cytopenias and microangiopathic hemolytic anemia. CMA of peripheral blood may assist in the preliminary diagnosis of MDS, representing a comparatively less invasive diagnostic procedure and may aid bone marrow evaluation when an aspirate sample is insufficient for conventional cytogenetic analysis.