Tolerability of Daratumumab Amongst Asian Patients with Plasma Cell Dyscrasias - A Single Centre Experience.

Daratumumab is increasingly incorporated into the standard treatment regimens for patients with plasma cell dyscrasias in Asia, especially with cost-containment measures implemented by various regional health authorities. This analysis aimed to study daratumumab's tolerability amongst Asian patients. This is a retrospective medical records review of patients who received daratumumab between November 2016 and August 2021 as part of routine clinical care. Sixty-two patients were included in the study: 62.9% had renal impairment, and 27.4% had creatinine clearance (CrCl) \<30ml/min. Forty-five patients (72.6%) received daratumumab combination therapy, with a median 1 line of prior therapy. The median duration of follow-up was 12.4 months, and the median duration patients were on treatment with daratumumab was 12.3 months. Twenty-one of 62 (33.9%) patients experienced infusion-related reactions (IRRs) after the first dose of intravenous daratumumab. Seven developed mostly grades 1 and 2 respiratory events, and 14 showed grades 1 and 2 non-respiratory IRRs. Only one patient experienced a grade 1 IRR with the second infusion, with none developing any IRRs in the third or subsequent infusions. Eight (12.9%) patients were affected by hematological adverse events (AEs), mostly grades 2 and 3, with one experiencing grade-4 neutropenia without sepsis. Six (9.7%) patients experienced non-hematological AEs, the commonest being pneumonia and other infections, with one developing Nocardia pneumonia (grade 4) 14 months after the initiation of daratumumab. In conclusion, daratumumab is tolerable amongst Asian patients, including the elderly, and patients with severe renal impairment and chronic lung diseases.

PARP Inhibitors in Breast and Ovarian Cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.

Tumor-Associated Macrophages and Related Myelomonocytic Cells in the Tumor Microenvironment of Multiple Myeloma.

Multiple myeloma (MM) is the second-most common hematologic malignancy and remains incurable despite potent plasma cell directed therapeutics. The tumor microenvironment (TME) is a key player in the pathogenesis and progression of MM and is an active focus of research with a view to targeting immune dysregulation. Tumor-associated macrophages (TAM), myeloid derived suppressor cells (MDSC), and dendritic cells (DC) are known to drive progression and treatment resistance in many cancers. They have also been shown to promote MM progression and immune suppression in vitro, and there is growing evidence of their impact on clinical outcomes. The heterogeneity and functional characteristics of myelomonocytic cells in MM are being unraveled through high-dimensional immune profiling techniques. We are also beginning to understand how they may affect and be modulated by current and future MM therapeutics. In this review, we provide an overview of the biology and clinical relevance of TAMs, MDSCs, and DCs in the MM TME. We also highlight key areas to be addressed in future research as well as our perspectives on how the myelomonocytic compartment of the TME may influence therapeutic strategies of the future.

Indeterminate mycobacterium tuberculosis QuantiFERON post Moderna mRNA Covid-19 vaccination.

We report an interesting case of an indeterminate MTB QuantiFERON for a 26-year-old healthy soldier planned for a routine field exercise to Brunei. Further medical history revealed that the patient had a Moderna mRNA Covid-19 vaccine the day before his MTB QuantiFERON test. The patient was subsequently asked to repeat a T-spot test which was non-reactive, there were no longer any issues with the positive control for the T-spot test. Current Covid-19 research suggests that infection causes a dysregulation of the immune system, perhaps this might also be extrapolated where a Covid-19 vaccine might provoke an immune response which might interfere with some immunological assays. In summary there should be more research invested into the immunological interactions that the newly developed Covid-19 vaccinations have with our existing immunological tests such as QuantiFERON tests which forms a key cornerstone in our fight against tuberculosis.

Relationship between leukaemic stem cells and hematopoietic stem cells and their clinical application.

The world is aging and with it an associated increase in malignancies. Haematological malignancies especially Acute Myeloid Leukemia (AML) are no exception to this trend. With scientific advances, development of new AML treatments has improved patient mortality. One future research interest would be Leukeamic Stem Cells (LSC). This review aims to briefly highlight main LSC characteristics and their relationship with hematopoietic stem cells. Key LSC characteristics include dysregulated apoptosis, capacity for self-renewal, genomic instability, dysregulated energetics, immune privilege and an altered tumor microenvironment. Similar characteristics are also found in HSCs though in a regulated form. Classifying these characteristics will aid in the development of clinical biomarkers for LSC which is a potential clinical application of LSC biology. LSC biomarkers might prove to be critical in future AML management through improving accuracy of AML diagnosis, providing targeted treatment to minimize side effects, refinement of prognosis and relapse risk for earlier intervention.

Equitable and Holistic Public Health Measures During the Singaporean COVID-19 Pandemic.

This Covid-19 pandemic has been a trying time for all countries, governments, societies, and individuals. The physical, social, and organizational infrastructure of healthcare systems across the world is being stressed. This pandemic has highlighted that the healthcare of the country is as strong as its weakest link and that no aspect of life, be it social or economic, is spared from this pandemic. The authors would like to highlight some of the lessons learned from Singapores management of the Covid-19 pandemic. During the Singaporean Covid-19 pandemic, public health policy planning was all encompassing in its coverage, involving various stakeholders in government and society. The important role of individuals, governments, industry, and primary healthcare practitioners when tackling COVID-19 are highlighted. Singapores management of the Covid-19 pandemic involved an approach that involved the whole of society, with a particular focus on supporting the vulnerable foreign worker population, which formed the majority of Covid-19 cases in the country. Hopefully amidst the trying times, valuable lessons are learnt that will be etched into medical history and collective memory. We hope to highlight these lessons for future generations, both for members of the public and fellow healthcare practitioners.

The Effectiveness of Strategies to Promote Walking in People With Musculoskeletal Disorders: A Systematic Review With Meta-analysis.

OBJECTIVE: To evaluate the effect of walking promotion strategies on physical activity, pain, and function in people with musculoskeletal disorders. DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: We performed the searches in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Physiotherapy Evidence Database (PEDro) from inception to August 2019. STUDY SELECTION CRITERIA: We included randomized controlled trials evaluating interventions that promote walking in people with musculoskeletal disorders. DATA SYNTHESIS: We used the PEDro scale for assessing risk of bias and the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the quality of evidence. We expressed pooled effects for between-group differences as mean differences or standardized mean differences and 95% confidence intervals, or as risk ratios and 95% confidence intervals, using random-effects meta-analyses. RESULTS: Twelve eligible trials (n = 1456 participants) were identified. There was moderate- to very low-quality evidence of no difference in physical activity levels for walking promotion interventions when compared to minimal interventions, and a significant effect favoring walking promotion when compared with usual care in the short term. There was moderate-quality evidence that walking promotion was modestly effective for reducing pain and improving function compared with minimal intervention and usual care. There was no difference in pain and function for walking promotion compared to supervised exercise. Walking promotion was not associated with different rates of adverse events compared to control conditions. CONCLUSION: Strategies to promote walking did not increase physical activity in people with musculoskeletal disorders. Walking promotion was associated with small improvements in pain and function compared to minimal intervention and usual care. J Orthop Sports Phys Ther 2020;50(11):597-606. doi:10.2519/jospt.2020.9666.

PRE-WORKOUT SUPPLEMENT INDUCED CARDIAC ISCHAEMIA IN A YOUNG FEMALE.

The popularity of pre-workout supplements is rising amongst professional athletes and fitness enthusiasts. Despite increased usage, the safety profile of pre-workout supplements is likely to be not well understood. Additionally, many different brands use various undisclosed proprietary blends of active ingredients creating safety regulation difficulties. This lack of oversight could prove unsafe for certain patients. This patient MK is a 33-year-old healthy housewife who presented with central chest tightness, pre-syncope and mild dyspnoea to the emergency department via ambulance. The presentation was in the context of recent strenuous exercise and ingestion of a pre-workout supplement (Alpha Lean-7). Most striking in her presentation was a troponin rise of 50 ng/L, while not very high it is unusual given her lack of cardiac risk factors. She had a 3-day uneventful admission with a downtrending troponin prior to discharge. This case highlights the possible dangers of pharmacologically active ingredients in pre-workout supplements.

Five cases of orbital extramedullary plasmacytoma: diagnosis and management of an aggressive malignancy.

Purpose: Multiple myeloma is an insidious haematological malignancy characterised by monoclonal proliferation of plasma cells in the bone marrow. Extramedullary plasmacytoma is a rare manifestation of multiple myeloma and usually occurs in the upper respiratory tract. Orbital involvement is particularly uncommon, but may be associated with devastating visual impairment and poor clinical outcomes. Therefore, this article aims to highlight the need for multidisciplinary management of orbital extramedullary plasmacytoma. Methods: This is a retrospective observational case series of five patients. All presented to the authors for management of orbital extramedullary plasmacytomas from 2004 to 2015 at Prince of Wales and Mater Hospitals in Sydney, Australia. Medical records were reviewed for pertinent information including demographics, disease features, management strategy, and clinical progress. The study met Medical Ethics Board standards and is in accordance with the Helsinki Agreements. Results: This case series of five patients underscores the poor prognosis of orbital extramedullary plasmacytoma. Despite aggressive multidisciplinary management, four of these five patients succumbed to their illness during the study period. However, multidisciplinary management did manage to minimise symptoms and preserve quality of life. Conclusions: On a case-by-case basis, patients may derive palliative benefit from orbital surgery in conjunction with radiotherapy and chemotherapy. Orbital surgeons are encouraged to work within a multidisciplinary framework of medical specialists, including haematologists and radiation oncologists, when determining the optimal management plan in cases of orbital extramedullary plasmacytoma.