Consensus recommendations for optimising the diagnosis and treatment of paroxysmal nocturnal haemoglobinuria in Singapore.

Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.

Unmet Needs in the First-Line Treatment of Diffuse Large B-cell Lymphoma: Expert Recommendations From the Asia-Pacific Region With a Focus on the Challenging Subtypes.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease. This review article draws from the expertise of practicing hematologists/oncologists in the region, with the aim of integrating data from current scientific evidence to address the unmet needs and unique socioeconomic challenges faced by challenging high risk patient groups in the Asia-Pacific region.

Counterproductive effects of anti-CD38 and checkpoint inhibitor for the treatment of NK/T cell lymphoma.

Introduction: Natural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy. Methods: We conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses. Results and Discussion: Our analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies.

Investigating Factors Associated with the Development of Postnatal Depression After Cesarean Delivery: A Validation Cohort Study.

Purpose: This study aimed to validate a proposed association model previously published to determine the clinical relevance of pre-operative determinants in the development of PND after Cesarean delivery (CD). Patients and Methods: Parturients undergoing elective CD under neuraxial anesthesia were recruited for a prospective cohort study between Oct 2021 and Oct 2022 at KK Women's and Children's Hospital, Singapore. Predelivery pain, psychological and mechanical temporal summation, and demographic data were recorded. A follow-up survey was conducted at 6 to 10 weeks after CD. The primary outcome was the incidence of PND, defined as an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10. Results: A total of 180 patients were recruited for validation. PND 6 to 10 weeks post-delivery occurred in 18.9% of recruited parturients. Multivariate regression analyses showed that higher pre-operative CSI scores (p=0.0156), higher anxiety levels about upcoming surgery (p=0.0429), increased pre-operative pain scores on movement (p=0.0110), and higher pre-operative HADS subscale scores on anxiety (p=0.0041) were independently associated with the development of PND weeks post-CD. Lower anticipation of pain medication needs (p=0.0038) was independently associated with the development of PND post-CD. The area under curve (AUC) of this multivariable model (training cohort), internal cross validation (training cohort) and external cross validation (validation cohort) were 0.818 (95% CI, 0.746 to 0.889), 0.785 (95% CI, 0.707 to 0.864) and 0.604 (95% CI, 0.497 to 0.710) respectively. Conclusion: The proposed model performed well in a local population. Further refinement is necessary to test the proposed model in populations with social and cultural differences.

Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations.

Diffuse large B-cell lymphoma (DLBCL) represents the commonest subtype of non-Hodgkin lymphoma and encompasses a group of diverse disease entities, each harboring unique molecular and clinico-pathological features. The understanding of the molecular landscape of DLBCL has improved significantly over the past decade, highlighting unique genomic subtypes with implications on targeted therapy. At the same time, several new treatment modalities have been recently approved both in the frontline and relapsed settings, ending a dearth of negative clinical trials that plagued the past decade. Despite that, in the real-world setting, issues like drug accessibility, reimbursement policies, physician and patient preference, as well as questions regarding optimal sequencing of treatment options present difficulties and challenges in day-to-day oncology practice. Here, we review the recent advances in the therapeutic armamentarium of DLBCL and discuss implications on the practice landscape, with a particular emphasis on the context of the healthcare system in Singapore.

Delta-radiomics-based models for toxicity prediction in radiotherapy: A systematic review and meta-analysis.

INTRODUCTION: Delta-radiomics models are potentially able to improve the treatment assessment than single-time point features. The purpose of this study is to systematically synthesize the performance of delta-radiomics-based models for radiotherapy (RT)-induced toxicity. METHODS: A literature search was performed following the PRISMA guidelines. Systematic searches were performed in PubMed, Scopus, Cochrane and Embase databases in October 2022. Retrospective and prospective studies on the delta-radiomics model for RT-induced toxicity were included based on predefined PICOS criteria. A random-effect meta-analysis of AUC was performed on the performance of delta-radiomics models, and a comparison with non-delta radiomics models was included. RESULTS: Of the 563 articles retrieved, 13 selected studies of RT-treated patients on different types of cancer (HNC = 571, NPC = 186, NSCLC = 165, oesophagus = 106, prostate = 33, OPC = 21) were eligible for inclusion in the systematic review. Included studies show that morphological and dosimetric features may improve the predictive model performance for the selected toxicity. Four studies that reported both delta and non-delta radiomics features with AUC were included in the meta-analysis. The AUC random effects estimate for delta and non-delta radiomics models were 0.80 and 0.78 with heterogeneity, I2 of 73% and 27% respectively. CONCLUSION: Delta-radiomics-based models were found to be promising predictors of predefined end points. Future studies should consider using standardized methods and radiomics features and external validation to the reviewed delta-radiomics model.

Expert consensus on the management of chronic lymphocytic leukaemia in Asia.

In recent years, considerable progress has been made in the standard treatment for chronic lymphocytic leukaemia (CLL) due to the availability of new potent drugs. However, the majority of data on CLL were derived from Western populations, with limited studies and guidelines on the management of CLL from an Asian population perspective. This consensus guideline aims to understand treatment challenges and suggest appropriate management approaches for CLL in the Asian population and other countries with a similar socio-economic profile. The following recommendations are based on a consensus by experts and an extensive literature review and contribute towards uniform patient care in Asia.

AL amyloidosis: Singapore Myeloma Study Group consensus guidelines on diagnosis, treatment and management.

AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical suspicion to detect unexplained manifestations in the appropriate clinical setting. Early detection and treatment are crucial as the degree of cardiac involvement emerges as a primary prognostic predictor of survival in a patient with AL amyloidosis. Following the diagnosis of AL amyloidosis with appropriate tissue biopsies, prompt treatment with a bortezomib, cyclophosphamide and dexamethasone-based first-line induction with or without daratumumab should be initiated. The goal of treatment is to achieve the best haematologic response possible, ideally with involved free light chain <20 mg/L, as it offers the best chance of organ function improvement. Treatment should be changed if patients do not achieve a partial response within 2 cycles of treatment or very good partial response after 4 cycles or after autologous stem cell transplant, as achievement of profound and prolonged clonal responses translates to better organ response and long-term outcomes. Early involvement of multidisciplinary subspecialists such as renal physicians, cardiologists, neurologists, and gastroenterologists for optimal maintenance and support of involved organs is recommended for optimal management of patients with AL amyloidosis.

Clostridium septicum brain abscess.

We present a previously well woman in her 70s who was admitted for 2 weeks of progressively worsening abdominal pain, high fever and drowsiness. She was eventually diagnosed with Clostridium septicum brain abscess, meningoencephalitis and ventriculitis. The diagnosis was challenging as cerebrospinal fluid cultures were negative and a microbiological diagnosis was only obtained on brain biopsy. Despite early initiation of antibiotics that would have been effective against C. septicum, her central nervous system (CNS) infection progressed, and she eventually succumbed to the infection. Infections with C. septicum are typically fulminant and associated with high mortality. In a patient with a CNS infection and concomitant abdominal manifestations, infection with C. septicum should be considered.

An ex vivo platform to guide drug combination treatment in relapsed/refractory lymphoma.

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin's lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo-guided combination therapy in RR-NHL.

Two-year outcome of ventricular assist device via a modified left atrium to aorta approach in cardiac amyloidosis.

Cardiac amyloidosis is a debilitating disease associated with poor long-term survival. Medical or palliative treatment is the usual course of therapy, but patients are often intolerant of conventional heart failure treatment. The current standard of care of sequential heart and bone marrow transplant is usually not feasible for ill or frail patients or in countries with limited organ donors or without transplant programmes. Left ventricular assist devices (LVAD) are not usually offered to these patients due to high peri-operative risks and risks of suction events with the LVAD in a small left ventricle. We report the 2 year outcome and discuss the challenges faced in the management of our patient with end-stage heart failure due to cardiac amyloidosis, who was successfully supported with an LVAD using a modified left atrium to aorta implantation technique.

Case report: anaesthetic and surgical management of a diaphragmatic rupture with tension pneumothorax and iatrogenic bowel perforation in an undiagnosed Bochdalek hernia patient.

BACKGROUND: Congenital diaphragmatic defects are rare, with most cases presenting in childhood. Diagnosis in adulthood is usually incidental or when symptoms develop. We present a case of a strangulated Bochdalek hernia complicated by possible tension pneumothorax and iatrogenic bowel injury in a healthy young male. CASE PRESENTATION: A 23-year-old Chinese man initially presented with complaints of mild back pain and was discharged with symptomatic treatment. He presented again 3 days later, with dyspnea and left upper back pain and was haemodynamically unstable and hypoxic. A chest x-ray was reported as a moderately large left-sided pneumothorax with herniation of bowel into the left hemithorax. Needle decompression resulted in feculent fluid being aspirated with no resolution of symptoms. The patient required an immediate transfer to the operating theatre for surgical intervention of his left diaphragmatic rupture, complicated by visceral herniation and left tension pneumothorax, with accidental puncture of the herniated bowel. He underwent an emergent laparotomy with requirements for rapid lung isolation and continued aggressive resuscitation. CONCLUSIONS: Patients with congenital diaphragmatic hernias may present in adulthood, either incidentally or emergently. In the well adult patient with good reserves, these initial symptoms may be mild, and may be symptomatically treated with no further workup. However, patients may deteriorate rapidly once their compensatory mechanisms are exhausted. This is the first reported case of a patient with diaphragmatic rupture and bowel herniation, complicated by iatrogenic tension pneumothorax. This rare case illustrates the speed at which a diaphragmatic rupture may progress, possible pitfalls and offers insights on how a misdiagnosis may be avoided.

Treatment outcomes of T and natural-killer/T-cell lymphoma with ifosfamide, carboplatin and etoposide chemotherapy.

BACKGROUND: Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited. AIMS: We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore. METHODS AND RESULTS: Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively. CONCLUSION: In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

Laser-heated needle for biopsy tract ablation: In vivo study of rabbit liver biopsy.

PURPOSE: To investigate the efficacy of a newly-developed laser-heated core biopsy needle in the thermal ablation of biopsy tract to reduce hemorrhage after biopsy using in vivo rabbit's liver model. MATERIALS AND METHODS: Five male New Zealand White rabbits weighed between 1.5 and 4.0 kg were anesthetized and their livers were exposed. 18 liver biopsies were performed under control group (without tract ablation, n = 9) and study group (with tract ablation, n = 9) settings. The needle insertion depth (~3 cm) and rate of retraction (~3 mm/s) were fixed in all the experiments. For tract ablation, three different needle temperatures (100, 120 and 150 °C) were compared. The blood loss at each biopsy site was measured by weighing the gauze pads before and after blood absorption. The rabbits were euthanized immediately and the liver specimens were stained with hematoxylin-eosin (H&E) for further histopathological examination (HPE). RESULTS: The average blood loss in the study group was reduced significantly (p < 0.05) compared to the control group. The highest percentage of bleeding reduction was observed at the needle temperature of 150 °C (93.8%), followed by 120 °C (85.8%) and 100 °C (84.2%). The HPE results show that the laser-heated core biopsy needle was able to cause lateral coagulative necrosis up to 14 mm diameter along the ablation tract. CONCLUSION: The laser-heated core biopsy needle reduced hemorrhage up to 93.8% and induced homogenous coagulative necrosis along the ablation tract in the rabbits' livers. This could potentially reduce the risk of tumor seeding in clinical settings.

Acceptability and Feasibility of Perioperative Music Listening: A Rapid Qualitative Inquiry Approach.

Perioperative music decreases pain, anxiety, and analgesia requirements while increasing patient satisfaction. We investigated the acceptability of perioperative music at a women's and children's hospital in Singapore, seeking to uncover barriers and facilitators to implementation in routine practice over a 12-week period. We used an undergraduate-led Rapid Qualitative Inquiry approach that includes data collection from multiple sources, iterative analysis, and additional data collection when necessary. Participants consisted of anesthesiologists and nurses working in the preoperative area, operating room, and postoperative recovery areas. In Stage 1, nurses and anesthesiologists answered a survey assessing attitudes and knowledge about perioperative music and attended a presentation introducing the intervention. In Stage 2, the results of the Stage 1 survey were disclosed, and nurses and anesthesiologists completed a second survey (Stage 1 survey questions with an additional query about implementation). Twenty-nine nurses were interviewed with semi-structured questions on barriers and facilitators to implementation. In Stage 3, nurses retook the Stage 2 survey after one month of implementation. The implementation of perioperative music was both acceptable and feasible in Singapore. The nurses' and anesthesiologists' acceptability increased over time with mostly positive qualitative feedback. Implementation barriers, including patient interest, timing of patient turnover, and added staff workload, appeared minor and could potentially be overcome by utilizing the intervention in the preoperative instead of postoperative area, deploying music in operating rooms with slower turnover, and evenly distributing staff workload. Local implementation stakeholders may make additional recommendations for scaling-up perioperative music interventions to fit other workflows while improving the patient experience.

A preliminary assessment of vital-signs-integrated patient-assisted intravenous opioid analgesia (VPIA) for postsurgical pain.

BACKGROUND: We developed a Vital-signs-integrated Patient-assisted Intravenous opioid Analgesia (VPIA) analgesic infusion pump, a closed-loop vital signs monitoring and drug delivery system which embodied in a novel algorithm that took into account patients' vital signs (oxygen saturation, heart rate). The system aimed to allow responsive titration of personalized pain relief to optimize pain relief and reduce the risk of respiratory depression. Moreover, the system would be important to enable continuous monitoring of patients during delivery of opioid analgesia. METHODS: Nineteen patients who underwent elective gynecological surgery with postoperative patient controlled analgesia (PCA) with morphine were recruited. The subjects were followed up from their admission to the recovery room/ ward for at least 24 h until assessment of patient satisfaction on the VPIA analgesic infusion pump. RESULTS: The primary outcome measure of incidence of oxygen desaturation showed all patients had at least one episode of oxygen desaturation (< 95%) during the study period. Only 6 (31.6%) patients had oxygen desaturation that persisted for more than 5 min. The median percentage time spent during treatment that oxygen saturation fell below 95% was 1.9%. Fourteen (73.7%) out of 19 patients encountered safety pause, due to transient oxygen desaturation or bradycardia. The patients' median [IQR] pain scores at rest and at movement after post-op 24 h were 0.0 [2.0] and 3.0 [2.0], respectively. The average morphine consumption in the first 24 h was 12.5 ± 7.1 mg. All patients were satisfied with their experience with the VPIA analgesic infusion pump. CONCLUSIONS: The use of VPIA analgesic infusion pump, when integrated with continuous vital signs monitor and variable lockout algorithm, was able to provide pain relief with good patient satisfaction. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov registry (NCT02804022) on 28 Feb 2016.

Effectiveness of Paint Psoralen and Ultraviolet-A in Alopecia Areata - Our Experience in the National Skin Center.

BACKGROUND: Alopecia areata (AA) is usually a benign cause of patchy hair loss that often resolves within a few weeks to months. Most treatment modalities are ineffective in the treatment of severe AA. The use of paint psoralen and ultraviolet-A (PUVA) in the treatment of patients with severe forms of AA has been reported in the literature. AIMS AND OBJECTIVE: The aim of this study was to evaluate the effectiveness of paint PUVA therapy in the treatment of AA in Singapore. MATERIALS AND METHODS: We performed a 10-year retrospective analysis of patients who underwent paint PUVA for AA. We evaluated patient demographics and treatment outcomes in the form of percentage change in baseline severity of alopecia tool score and final amount of hair regrowth and relapse rate. RESULTS: Ten patients were included in this study. With paint PUVA therapy, significant hair regrowth was seen in six patients. Paint PUVA therapy in our study showed minimal side effects. CONCLUSION: PUVA gives fair response in AA in a reasonable time as per our center's experience in Singapore.

The Effect of Perioperative Music Listening on Patient Satisfaction, Anxiety, and Depression: A Quasiexperimental Study.

BACKGROUND: The effect of perioperative music listening has been proven to relieve preoperative anxiety and depression, while improving patient satisfaction. However, music listening has not been extensively studied in Singapore. Therefore, the primary aim of our study is to investigate the patient satisfaction towards perioperative music listening in the local setting. The secondary aim is to investigate the effect of perioperative music listening in reducing patient surgery-related anxiety and depression. METHODS: After obtaining ethics board approval, we conducted a quasiexperimental study on a cohort of female patients who were undergoing elective minor gynaecological surgeries. Apple iPod Touch™ devices containing playlists of selected music genres and noise-cancelling earphones were given to patients to listen during the preoperative and postoperative periods. Hospital Anxiety and Depression Scale (HADS), EQ-5D-3L questionnaire, music listening preferences, and patient satisfaction surveys were administered. Wilcoxon signed-rank and McNemar's tests for paired data were used for analysis. RESULTS: 83 patients were analysed with 97.6% of patients in the preoperative period and 98.8% of patients in the postoperative period were satisfied with music listening. The median (IQR [range]) score for preintervention HADS anxiety was 7.0 (6.0 [0-17]), significantly higher than that in postintervention at 2.0 (4.0 [0-12]) (P < 0.001). Similarly, there was a significant reduction in preintervention HADS depression as compared to postintervention (P < 0.001). Similarly, there was a significant reduction in preintervention HADS depression as compared to postintervention (. CONCLUSION: Perioperative music listening improved patient satisfaction and can reduce patient anxiety and depression. We hope to further investigate on how wider implementation of perioperative music listening could improve patient care.