The alternative lengthening of telomeres pathway may operate in non-neoplastic human cells.

The alternative lengthening of telomeres (ALT) mechanism represents an alternative to the enzyme telomerase in the maintenance of mammalian telomeres in 25-60% of sarcomas and a minority of carcinomas (about 5-15%). ALT-positive cells are distinguished by long and heterogeneous telomere length distributions by terminal restriction fragment (TRF) Southern blotting. Another diagnostic marker of ALT is discrete nuclear co-localized signals of telomeric DNA and the promyelocytic leukaemia protein (PML), referred to as ALT-associated PML bodies (APBs). Recently, we detected smaller sized co-localized PML and telomere DNA (APB-like) bodies in endothelial cells adjacent to astrocytoma tumour cells in situ. In this study, we examined a wide variety of non-neoplastic tissues, and report that co-localized signals of PML and telomere DNA are present in endothelial, stromal, and some epithelial cells. Co-localized signals of PML and telomere DNA showed an increased frequency in non-neoplastic cells with DNA damage. These results suggest that a mechanism similar to that in ALT-positive tumours also operates in non-neoplastic cells, which may be activated by DNA damage.

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.

Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction.

BACKGROUND: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. PATIENTS AND METHODS: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, -4.36 to 0.70 × 106/kg). RESULTS: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). CONCLUSION: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.

Prolonged argatroban clearance in a critically ill patient with heparin-induced thrombocytopaenia.

This is a case of argatroban use in a critically ill patient with heparin-induced thrombocytopaenia (HIT), presenting with unexpectedly prolonged drug clearance possibly secondary to hepatic congestion due to reduced cardiac contractility. A 63-year-old woman from Asia with end-stage renal failure was hospitalised in the critical care unit with non-ST elevation myocardial infarction with underlying triple vessel disease. She was subsequently started on intravenous unfractionated heparin infusion after an intra-aortic balloon pump was inserted. Six days after the initiation of heparin, she developed HIT and argatroban was started for treatment of HIT. Despite starting on the recommended dose of 2µg/kg/min, she developed significantly prolonged activated partial thromboplastin time (aPTT) with delayed clearance. Argatroban was stopped 14 hours after time of initiation in view of the markedly prolonged aPTT (in the range of 145 s), and levels only normalised at approximately 60 hours after argatroban was stopped.

Drug use evaluation of transdermal fentanyl in a tertiary hospital.

OBJECTIVES: The primary objective of the study was to assess the rationale of fentanyl patch initiation and continuation for pain. The secondary objectives were to analyse prescribing pattern between disciplines, monitoring criteria and adverse events profile of fentanyl patch in the inpatient wards for a tertiary hospital. METHODS: A retrospective case series review was undertaken of patients who received transdermal fentanyl for pain from April to June 2013 at the National University Hospital, Singapore. Relevant data were collected from electronic and physical medical records and audit criteria applied for indication, opioid tolerance, dosage regimen, adverse events and monitoring criteria. RESULTS: 40 patients were prescribed fentanyl patches for pain in the study period. 15 patients (62.5%) had one or more problems during initiation of fentanyl patch. Appropriate use during initiation was low with only 9 (38%) patients meeting all the required criteria. Most of the inappropriate use involved a lack of bridging opioids (58%), wrong opioid conversion dose (42%) and use in opioid-naïve patients (42%). In addition, three cases of inappropriate placement were observed. Monitoring for efficacy and adverse effects generally met audit criteria. There was a low incidence of discontinuation (21%) due to its well-tolerated side effect profile. CONCLUSIONS: This study highlighted high incidence of inappropriate initiation of fentanyl patch, and we proposed an in-house guideline to aid physicians in initiating fentanyl patches during admission and to educate nursing staff of the monitoring parameters for efficacy and toxicity.

Targeted therapy at the end of life in advanced cancer patients.

OBJECTIVE: We describe the use of systemic therapy in advanced cancer patients admitted to an acute care hospital, with a focus on targeted therapy. We aim to spotlight the utilization of targeted agents in the last months of life. METHODS: Adult patients (N=252) with advanced solid tumors who died as inpatients in the National University Hospital, Singapore, were included in this retrospective study. Patients' demographic and clinical data were extracted from hospital records. Information on systemic therapy was extracted from the time of diagnosis and all other data limited to the last three months before death. RESULTS: 187 adult patients received palliative systemic therapy from the time of diagnosis, of which 125 (66.8%) received it within three months of death. Of patients receiving only nontargeted systemic treatment (n=106), 60 (56.6%) and 26 (24.5%) received it within three months and one month of death respectively. Comparatively, 81 patients received palliative targeted systemic therapy, of which 65 (80.3%) and 40 (49.4%) had treatment within three months and one month of death respectively (p=0.001 and p<0.001). Targeted therapy was first initiated in the last three months of life in 38 patients. Oral agents targeting epidermal growth factor receptor (lung cancer patients) and vascular endothelial growth factor receptor (non-lung cancer patients) pathways were commonly employed. Lung cancer patients were more likely to have targeted therapy as their last line of systemic therapy: 26/54 lung cancer patients compared with 29/133 non-lung cancer patients (48.1% versus 21.8%, p<0.001). CONCLUSIONS: Targeted therapy is used in more than half of patients who received systemic therapy within three months of death. The degree to which these agents are being utilized near the end of life suggests the need to reexamine the risk/benefit profile of targeted therapy for this population, and the decision-making process around their use.