KEY FINDINGS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash.
BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study.
DETAILS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash.
Copyright © John Wiley & Sons, Inc. All rights reserved.
Source: Gordon, M. J., Feng, L., Strati, P., et al. (2024). Safety and Efficacy of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Follicular and Marginal Zone Lymphoma: An Open Label, Phase 2 Study. Cancer, . 2024; 130(6): 876-885; Published: March 15, 2024. DOI: 10.1002/cncr.35114.
KEY FINDINGS: Authors report a prospective study involving children that showed overestimation of saturation by pulse oximetry that was attributable to skin tone. This overestimation could lead to undertreatment of hypoxemia and contribute to racial inequities in outcomes. Additional studies are needed in populations with a greater proportion of persons with darker skin tone. The findings emphasize that current FDA guidance for pulse-oximeter validation (https://www.fda.gov/media/72470/download?attachment), which recommends only limited involvement of persons with darkly pigmented skin without a formal definition, is inadequate in ensuring equity in pulse-oximetry accuracy. New guidance is currently under consideration. On the basis of these results, there is potential for improvement in both bias and precision.
BACKGROUND: Findings from the Pulse Oximetry and Skin Tone in Children (POSTer-Child) study were published February 12, 2025 in a letter to the editor of The New England Journal of Medicine. First author Joseph Starnes, MD, MPH, is a fellow in Pediatric Cardiology.
DETAILS: Retrospective studies have shown overestimation of oxygen saturation by pulse oximetry in adult and pediatric patients from races that may be associated with darker skin. These retrospective studies share key limitations, including race as a poor surrogate for skin tone and paired measurements of oxygen saturation as assessed by pulse oximetry (SpO2) and of arterial oxygen saturation (SaO2) in the medical record. Limited prospective laboratory-based and clinical studies that used measured skin tone in adults have shown worse pulse-oximeter performance among patients with darker skin than among those with lighter skin. Very few prospective studies have involved children.
In the Pulse Oximetry and Skin Tone in Children (POSTer-Child) study, authors enrolled 320 patients younger than 21 years of age undergoing cardiac catheterization in 2024. Skin tone was measured with the use of a spectrophotometer. SpO2 was recorded with the use of two pulse oximeters (Nellcor and Masimo) at the exact time of blood sampling for measurement of fractional saturation by co-oximetry. Pulse-oximetry bias (SpO2-SaO2), precision (standard deviation of bias), and accuracy root mean square error (ARMS) were calculated (for all three measures, higher values indicate worse pulse-oximeter performance), as was the percentage of patients with occult hypoxemia (SaO2 of <88% when SpO2 is >=92%). Additional methodologic details are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. The population was similar to the U.S. population but showed relative underrepresentation of Hispanic children. A total of 48 of 319 patients (15.0%) identified as Black, and 44 (13.8%) identified as Hispanic.
Average bias was 1.32 percentage points for the Nellcor device and 1.88 percentage points for the Masimo device. Bias was higher among children with darker skin (individual typology angle [ITA] category 5 or 6) than among those with lighter skin (ITA category 1 or 2) for both pulse oximeters (P<0.001). Precision and ARMS were also higher for children with darker skin. ARMS was substantially higher than the Food and Drug Administration (FDA) cutoff of three for children in ITA category 5 or 6. Occult hypoxemia was present in 4 of 56 children (7%) in ITA category 5 or 6 for the Nellcor device and in 5 of 60 children (8%) for the Masimo device, as compared with 0 of 81 children and 3 of 88 children (3%), respectively, in ITA category 1 or 2.
Copyright © Massachusetts Medical Society. All rights reserved.
Source: Starnes, J., Welch, W., Henderson, C. C., et al. (2024). Pulse Oximetry and Skin Tone in Children. NEJM. 2025; 392: 1033-1034; Published: February 17, 2025. DOI: 10.1056/NEJMc2414937.
KEY FINDINGS: IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.
BACKGROUND: The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear.
DETAILS: Goal of the study is to define the function of IQGAP3 in gastric cancer (GC) development and progression. Authors studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours. Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions.
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
Source: Shimura, M., Matsuo, J., Pang, S.,et al. (2024). IQGAP3 Signalling Mediates Intratumoral Functional Heterogeneity to Enhance Malignant Growth. Gut. 2025; 74(3): 364-386. Published: March, 2025. DOI: 10.1136/gutjnl-2023-330390.
KEY FINDINGS: Isatuximab, weekly bortezomib, and lenalidomide with limited dexamethasone was active and safe as initial therapy for older patients with multiple myeloma ineligible for autologous HSCT. A modified quadruplet regimen in which dexamethasone is omitted after two cycles can be used in this patient population.
BACKGROUND: Adding anti-CD38 monoclonal antibodies to standard therapies can improve outcomes in patients with multiple myeloma. Long-term treatment with corticosteroids increases the risk of infection. We aimed to evaluate the safety and activity of isatuximab, weekly bortezomib, lenalidomide, and limited dexamethasone in patients with newly diagnosed multiple myeloma ineligible for autologous haematopoietic stem-cell transplantation (HSCT).
DETAILS: REST is an academic, multicentre, single-arm, phase 2 trial of adults with newly diagnosed multiple myeloma and measurable disease as defined by International Myeloma Working Group criteria, ineligible for high-dose melphalan and autologous HSCT, Eastern Cooperative Oncology Group performance status of 0-3 (with 3 only allowed if related to myeloma). In 28-day cycles, patients received isatuximab (10 mg/kg intravenously on days 1, 8, 15, and 22 of cycle 1, and days 1 and 15 of cycles 2-18), bortezomib (1.3 mg/m2 subcutaneously on days 1, 8, and 15 of cycles 1-8), and lenalidomide (25 mg orally on days 1-21, until progressive disease). Dexamethasone was given 20 mg orally on days 1, 8, 15 and 22, limited to the two first cycles only. The primary endpoint was measurable residual disease (MRD)-negative complete response, assessed by next-generation flow cytometry (sensitivity 1.0 x 10-5), during or after 18 cycles of study treatment. MRD was tested in all patients who had at least complete response before cycle 19 and in all patients who had at least very good partial response at cycle 19. All patients enrolled initiated treatment and were included in the analyses. Between June 30, 2021 and Jan 19, 2023, we assessed for eligibility and recruited 51 patients (27 [53%] females and 24 [47%] males), with a median age of 77 years (IQR 73.5-80). 39 participants completed 18 cycles of treatment on protocol, of whom two had discontinued treatment but not protocol. At a median follow-up of 27.0 months (IQR 23.0-33.7), MRD-negative complete response was observed in 19 (37% [95% CI 25.3-51.0]) patients, with a median treatment duration of 22 months (IQR 15.2-28.8; range 1.4-35.1). Disease progression or death had occurred in 18 (35%) of 51 patients, and eight (16%) patients had died. During the first 18 cycles of study treatment, the most common adverse events of grade 3 or 4 were neutropenia (28 [55%] patients), infections (21 [41%] patients), and thrombocytopenia (11 [22%] patients). 48 serious adverse events of grade 3 or higher were reported in 27 (53%) patients. A total of 14 (27%) patients discontinued treatment before cycle 19, most commonly because of progressive disease (eight [16%]) and adverse events (four [8%]). Two deaths (one due to pneumonia and one due to sepsis) were assessed as possibly related to study treatment.
Copyright © Elsevier Ltd. All rights reserved.
Source: Askeland, F. B., Haukas, E., Slordahl, T. S., et al. (2024). Isatuximab, Bortezomib, Lenalidomide, and Limited Dexamethasone in Patients With Transplant-Ineligible Multiple Myeloma (REST): A Multicentre, Single-Arm, Phase 2 Trial. The Lancet Haematology. 2025; 12(2): e120-e127. Published: February, 2025. DOI: 10.101/FS2352-3026.
KEY FINDINGS:
BACKGROUND: Over several days in late September 2024, Hurricane Helene caused extensive damage to the southeastern United States. The storm affected the Baxter International's North Cove facility in North Carolina, the largest manufacturer of peritoneal dialysis and intravenous solutions in the United States, halting production.
DETAILS: CDC is issuing this Health Alert Network (HAN) Health Advisory to inform healthcare providers, pharmacists, healthcare facility administrators, and state, tribal, local, and territorial health departments of a supply disruption of peritoneal dialysis (PD) and intravenous (IV) solutions from the Baxter International's North Cove facility in North Carolina, due to Hurricane Helene.
The supply disruption may impact patient care and require adjustments to the clinical management of patients. Healthcare providers, pharmacists, healthcare facility administrators, and state, tribal, local, and territorial health departments, regardless of supply chain disruptions, should immediately assess their supply and develop plans and mitigation strategies to reduce the impact on patient care.
This Health Advisory summarizes recommendations from the Food and Drug Administration (FDA); the Administration for Strategic Preparedness and Response Technical Resources, Assistance Center, and Information Exchange (ASPR TRACIE) ; the American Society of Health-System Pharmacists (ASHP); the American Society of Nephrology (ASN); and the American Society of Pediatric Nephrology (ASPN) among others, to address supply disruptions of PD and IV solutions.
Facilities can implement strategies early to conserve their fluid supplies and avoid waste to reduce the impact on services. Strategies must ensure patient safety, timely and effective safety notifications, and education of healthcare personnel and patients. Emergency medical and outpatient services must be included in these strategies.
Additional supply disruption may occur in the aftermath of Hurricane Milton.
Recommendations
Healthcare Providers, Pharmacists, and Healthcare Facility Administrators in Healthcare Facilities
Providers and Administrators in Dialysis Facilities
State, Tribal, Local, and Territorial Health Departments
Source: CDC Issues Health Alert In Light of Disruptions in Availability of PD and IV Solutions from Baxter International Facility in North Carolina. CDC. 2024; Published: October, 2024.
KEY FINDINGS: Scientists from the University of Copenhagen have detected lipid biomarkers in children and teenagers with obesity that indicate an increased risk of developing type 2 diabetes, liver and heart disease as adults. A one-year lifestyle intervention lowered the levels of these lipid biomarkers, which demonstrates the importance of early intervention for children with obesity.
BACKGROUND: The number of children and teens with obesity is increasing worldwide, with over 250 million expected to be affected by 2030. It is a major public health crisis, as children with obesity risk developing insulin resistance, fatty liver, and high blood pressure, which may lead to diseases such as cardiovascular disease, type 2 diabetes and liver disease, later in life.
DETAILS: Scientists think these diseases can be triggered by changes in the body's lipids -- a wide range of fats and oils in the body including triglycerides and cholesterol that serve many purposes including energy storage and cellular signalling. But it is still not well understood how lipid species change in children with obesity, and how they are linked to early cardiometabolic complications.
Now, scientists at the University of Copenhagen have discovered that lipid species linked to cardiometabolic disease in adults are strongly associated with cardiometabolic risk factors in children and teenagers with obesity. The findings could pave the way for tests that serve as an early warning system for cardiometabolic disease.
"Our study shows that the impact of cardiometabolic associated lipid species emerges early in life in children with obesity, particularly affecting liver function and glucose metabolism. These risk lipid species could potentially be explored further as biomarkers for diagnosing or predicting cardiometabolic risk in children at high risk, offering new insights for early detection and intervention," says Postdoc Yun Huang from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, and co-first author of the study in Nature Medicine.
Early intervention reverses cardiometabolic disease risk
The scientists made their discoveries by drawing on the HOLBAEK Study biobank of more than 4,000 children with and without obesity. at the Children's Obesity Clinic at Holbaek Hospital. Together with scientists at Steno Diabetes Center Copenhagen, they harnessed powerful mass spectrometry technology to map hundreds of individual lipid species, each with distinct structures and functions, providing a detailed picture of lipid metabolism. By analyzing the differences in the lipid profiles of 958 children with overweight or obesity and 373 who had normal weight, they gained deep insight into obesity altered lipid profiles and their link to cardiometabolic risk, and the ability to detect excessive fat in the liver.
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Source: University of Copenhagen - The Faculty of Health and Medical Sciences (2024). A Simple Blood Test Warns of Possible Cardiometabolic Complications for Children With Obesity. ScienceDaily. 2024; Published: September 20, 2024. DOI: 10.1038/s41591-024-03279-x.
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