Background:Pneumocystis jirovecii pneumonia (PJP) is highly fatal once infection is established. In this study, we investigated the risk of PJP mortality in patients with inflammatory bowel disease (IBD). Methods: We conducted a retrospective observational study of case data from IBD patients who developed PJP, compiled from 17 collaborating institutions. Parameters such as age, sex, medications used, and blood test results were analyzed to identify risk factors for mortality. Results: The mortality rate among the 28 IBD patients who developed PJP was 17.9%. A low serum albumin level at the start of IBD treatment was identified as a risk factor for mortality and showed the following association with probability of death (P): P = 1/[1 + exp(–5.5 + 2.4 × Alb). The probability of death exceeded 0.5 when serum albumin was 2.2 g/dL or lower. Conclusion: Patients with IBD who develop PJP have a high mortality rate and often cannot continue treatment with medication alone. Therefore, it is necessary to pay attention to albumin levels at the start of immunosuppressive therapy when creating a treatment plan.
Multiple myeloma (MM) is an incurable plasma cell neoplasm with an incidence of 100 patients per year in Singapore.Major advances have been made in the diagnosis, risk stratifi cation and treatment of MM in the recent past.The reclassifi cation of a subset of patients with smouldering MM, based on high-risk biomarkers, and the development of the revised international staging system are among the key new developments in diagnosis and staging.The use of novel agent-based treatment has resulted in signifi cant improvements in the survival and quality of life of many patients with MM.Determining the optimal use of proteasome inhibitors, immunomodulators and, more recently, monoclonal antibodies is an area of ongoing investigation.In this guideline, we aim to provide an overview of the management of MM, incorporating the latest developments in diagnosis and treatment.
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.
p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM).We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3.The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells.This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy.
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