Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry.

[Posted 6/Nov/2023]

AUDIENCE: Oncology, Pediatric

KEY FINDINGS: RT can be omitted in patients with IRS I eRMS. RT improves LCS and EFS in IRS II and III. RT improves OS in patients with HN-PM, with proton RT comparable with photon RT. Doses of 32 Gy (HART) or 36 and 41.4 Gy (CFRT) had comparable efficacy in patients with favorable risk profiles and 44.8 Gy (HART) or 50.4 and 55.8 Gy (CFRT) in the unfavorable groups.

BACKGROUND: Objective of this study is to analyze and compare the indications, doses, and application methods of radiotherapy (RT) and their influence on prognosis of patients with localized rhabdomyosarcoma (RMS). Radiotherapy (RT) is one of the local control modalities in patients with rhabdomyosarcoma (RMS) but is associated with severe acute and late toxicities. Authors have analyzed and compared the indications, doses, and application methods of RT and their influence on prognosis for patients with localized RMS.

DETAILS: One thousand four hundred seventy patients with localized RMS 21 years and younger entered on CWS-96, CWS-2002P, and SoTiSaR were eligible for the analysis. The median follow-up was 6.5 years (IQR, 3.3-9.5). The 5-year event-free survival (EFS) and local control survival (LCS) for 910 (62%) irradiated versus nonirradiated patients were 71% versus 69% and 78% versus 73% (P = .03), respectively. Ninety-five percent of patients in IRS I (90% embryonal RMS [eRMS]) were nonirradiated (EFS, 87%). Irradiated patients with IRS II had improved LCS (91% v 80%; P = .01) and EFS (not significant). In IRS III, EFS and LCS were significantly better for RT patients: 71% versus 56% (P = 3.1e-06) and 76% versus 61% (P = 4.1e-07). Patients with tumors in the head and neck region (orbita, parameningeal, and nonparameningeal) and in other sites had significantly better EFS and LCS and in parameningeal also overall survival (OS). The efficacy of low RT doses of 32 Gy (hyperfractionated, accelerated RT [HART]) and 36 and 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable groups and higher doses of 44.8 Gy (HART) and 50.4 and 55.4 Gy (CFRT) in the unfavorable groups was comparable. Proton RT was used predominantly in head/neck-parameningeal (HN-PM) tumors, with similar EFS and LCS to photon RT.

Copyright © American Society of Clinical Oncology. All rights reserved.

Source: Koscielniak, E., Timmermann, B., Munter, M., et al. (2023). Which Patients With Rhabdomyosarcoma Need Radiotherapy? Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry. J Clinical Oncology. 2023; 41(31): 4916-4926.Published: November 1, 2023. DOI: 10.1200/JCO.22.02673.

[Posted 25/Mar/2025]

AUDIENCE: Pediatric, Family Medicine

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.

[Posted 14/Mar/2025]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

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.

A Multicentre, Single-Arm, Phase 2 Trial

[Posted 4/Mar/2025]

AUDIENCE: Hematology, Oncology

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.

[Posted 17/Oct/2024]

AUDIENCE: Emergency Medicine

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

• Assess inventory, supply, and conserve available IV solutions.
• Determine the type of IV solutions your pharmacy or facility uses, including expiration dates, and whether this supply disruption will impact your facility.
• Monitor current and future supplies of IV solutions at your facility.
• Report any potential shortages or interruptions to the Food and Drug Administration (FDA) at DrugShortages@fda.hhs.gov.
• Implement a facility-specific action plan to optimize the use of IV solutions using evidence-based fluid management protocols.
• Evaluate all protocols, including the clinical need to continue IV fluid replacement at every shift change, bag change, and during the transition of care unless clinically necessary.
• Ensure that advisory committees with appropriate authorities are established to determine complex issues in supply disruptions and allocation of limited resources and patient triage as needed.
• Use oral formulations when IV options are not available and when appropriate and safe.
• Identify safe and effective alternative IV options (e.g., working with a nearby facility or licensed manufacturer who is not affected by the supply disruption).
• Review standing orders, including drug records and order sets.
• Ensure thorough documentation of the situation, including consumption of IV solutions.
• See FDA's Temporary Policies for Compounding Certain Parenteral Drug Products, for compounders to help fill the gaps from the impact of Hurricane Helene on Baxter International's North Cove facility.
• Ensure multidisciplinary team involvement to determine and develop conservation and stewardship strategies using IV solutions in specific patient populations.
• Include providers from various expertise (including key outpatient settings such as emergency departments, hematology/oncology, ambulatory surgery centers, wound care centers, infusion centers, home healthcare, etc.), pharmacists, nurses, infection control, informatics, patient safety, supply chain leadership, and emergency preparedness.
• Provide education and training to healthcare providers regarding any changes in protocols.
• Communicate changes in current practice, disruption, new shortages, and action plan adjustments to hospital leadership and frontline staff.
• Communicate with patients to assess supplies and provide a mechanism to notify their providers of insufficient supplies.

Providers and Administrators in Dialysis Facilities

• Assess and monitor inventory of available PD solutions.
• Review current practices to identify changes that extend the PD solution supply safely.
• Monitor current and future supplies of PD solutions.
• Report any interruptions to the FDA at DrugShortages@fda.hhs.gov.

• Implement an action plan for emergency PD treatment protocols
• Assess emergency PD protocols.
• Ensure optimal PD catheter function and flow of all patients to maximize ultrafiltration and solute exchange (malposition, etc.).
• Optimize prescriptions; overall approaches should prioritize bag-sparing rather than solution-sparing.
• For example, consider changing dwell times rather than adding a PD solution bag if a prescription change is needed for a patient.
• Monitor patients closely after prescription adjustments, including phone check-ins.
• Communicate with patients receiving peritoneal dialysis at home and their care providers.
• Assess supplies and provide a mechanism to notify their provider of insufficient supplies.
• Provide education and training to patients and their care providers regarding any changes in PD bags or associated products (e.g., adaptors, tubing, etc.) used for their treatments.
• Consider options for individual patients, keeping safety in mind.
• Continuous ambulatory PD (CAPD) may be a good option for some patients.
• Transitioning to hemodialysis (HD) should be avoided as much as possible. However, if adjustment of PD prescription has been explored and exhausted, a temporary transition to HD may be necessary if the available supply is insufficient to provide adequate PD.
• Reinforce patient safety principles when not using usual products and procedures to prevent patient injury and medical errors.

State, Tribal, Local, and Territorial Health Departments

• Maintain situational awareness of the severity of the supply disruption and implement strategies.
• Where possible, facilitate communication across health systems within the jurisdictions related to acute supply needs.

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.

[Posted 2/Sep/2024]

AUDIENCE: Internal Medicine, Nursing

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.

Copyright © ScienceDaily or by other parties, where indicated. All rights reserved.

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.