Citations

OBJECTIVE To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring. RESEARCH DESIGN AND METHODS At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks. RESULTS Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI −0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by >0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by >0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects. CONCLUSIONS In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia.

Background: CLL is one of the most common types of leukemia in the United States, with an estimated 20,700 new cases in 2024. Although cBTKis have become the standard of care for CLL/SLL in treatment-naïve and relapsed/refractory patients, cardiovascular (CV) toxicity is a known side effect. Further, clinical outcomes often worsen as patients progress beyond 1st-line therapy (1L), and the frequency of CV adverse events (CVAEs) may increase with age and as patients progress to 2nd-line or later therapies (2L+). This research evaluated the real-world incidence of CVAEs and clinical outcomes in patients who initiated cBTKi between 2020 and 2023. Methods: Adult patients diagnosed with CLL/SLL who initiated cBTKi treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Cohorts were assessed as those initiating 1L or 2L+, reflecting treatment-naïve and relapsed/refractory patients. Results were presented for patients with an incident CVAE (not present pre-index) and those without. Demographics, incident CVAEs, overall survival (OS) and proportion of patients who discontinued index cBTKi therapy, initiated next treatment or experienced death (NT+D) were assessed. Time to CV event (TTCE) for ibrutinib and acalabrutinib were determined using a Kaplan-Meier (KM) model and Log rank test. Results: Overall, 2,163 eligible patients were identified with a mean ± SD age of 73.8 ± 9.2 years, and 40.6% were female. Of these, 1,958 (90.5%) were included in the 1L cohort and 205 (9.5%) in the 2L+ cohort; 619 (31.6%) and 63 (30.7%) patients had CVAEs, respectively. The mean ± SD [median] observation period was 1.6 ± 0.9 [2.0] years in 1L and 1.5 ± 1.0 [1.0] years in 2L+. The most common cBTKi (in 1L and 2L+) at index were ibrutinib (55.5% and 55.6%), followed by acalabrutinib (40.3% and 38.5%), and zanubrutinib (4.1% and 5.9%). At 12-months post-index, the proportion of 1L patients with and without CVAEs who discontinued treatment was 44.9% and 41.6%, rising to 65.6% and 59.0% by 36-months post-index, respectively. For those in 2L+, 50.8% and 40.8% of those with and without CVAEs discontinued treatment by 12-months; 68.3% and 55.6% discontinued by 36-months. Among those with and without CVAEs, NT+D in 1L patients was 35.9% and 22.5% within 12-months post-index and 56.9% and 32.8% by 36-months. In the 2L+ cohort, 46.0% and 31.7% experienced NT+D by 12-months, rising to 63.5% and 41.5% by 36-months. OS in 1L patients was 84.7% and 93.1% in those with and without CVAEs at 12-months and 69.1% and 88.0% at 36-months. For 2L+ patients, OS was 71.4% and 88.0% at 12-months and decreased to 54.0% and 80.3% at 36-months, among those with and without CVAEs, respectively. The most common incident CVAEs following cBTKi initiation in the 1L and 2L+ cohorts were hypertension (31.2% and 21.7%), heart failure (14.6% and 17.7%), atrial fibrillation (13.9% and 18.4%), atrial flutter (13.3% and 16.9%), and ventricular arrythmias (13.0% and 14.5%). The occurrence of incident CVAEs between 1L patients who received acalabrutinib and ibrutinib was 3.4% and 13.2% for atrial fibrillation, 2.7% and 12.7% for atrial flutter, 9.3% and 31.0% for hypertension, and 6.8% and 11.7% for ventricular arrythmias. For 2L+, the proportion experiencing CVAEs with index acalabrutinib or ibrutinib were 8.6% and 14.8% for atrial fibrillation, 7.6% and 14.8% for atrial flutter, 10.5% and 25.0% for hypertension, and 10.1% and 8.8% for ventricular arrythmias. Among acalabrutinib and ibrutinib patients, KM estimates (medians not reached) in 1L showed that 84% and 72% of patients would not experience a CVAE by 12 months, with 57% and 52% not experiencing a CVAE at 36-months (p<0.001); 2L+ KM estimate rates were 77% and 73% at 12-months and 64% and 60% at 36-months (p=0.28). Mean TTCE for acalabrutinib and ibrutinib in 1L was 2.2 and 1.9 years with 1.6 and 1.2 years in 2L+. Summary/Conclusion: Utilizing real-world evidence from patients with CLL/SLL receiving cBTKIs, this study highlights the CV disease burden among patients who incur new CV events in 1L or later lines of therapy. This research underscores the need for innovative therapies with improved efficacy and CV safety profiles that delay progression to later lines of therapy, as well as careful CV monitoring to allow for early management and improved outcomes.

Background: Although Covalent BTKis have revolutionized treatment of CLL/SLL, cardiotoxicity is a known side effect, which can increase the total costs to the healthcare system. This study evaluated the real-world healthcare resource utilization (HCRU) and costs in patients who did and did not experience incident cardiovascular adverse events (CVAEs) during cBTKi treatment. Methods: Adult patients diagnosed with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Patients were stratified into two cohorts based on the presence of an incident CVAE during treatment with index cBTKi, defined as the occurrence of a CVAE not present in a patient's medical history. HCRU and costs were evaluated on a per 1,000 patient-months basis. Z tests and univariate gamma general linear models were used to compare HCRU and cost rates. HCRU between those who received ibrutinib or acalabrutinib were also assessed. Results: Overall, 2,069 eligible patients were identified with a mean ± SD age of 73.7 ± 9.1 years, and 40.4% were female. The mean ± SD [median] treatment-specific observation period was 11.4 ± 9.5 [8.5] months. Of the total cohort, 442 (21.4%) experienced at least one incident CVAE, while 1,627 patients (78.6%) experienced no CVAEs. Among those without a pre-index history of the specific CV AE of interest, the proportion of patients with incident events were 21.4% for hypertension, 9.8% for atrial fibrillation, 9.2% for atrial flutter, and 9.6% for ventricular arrhythmias. Patients who experienced an incident CVAE had 4,334 total days with medical service compared to 3,138 days in those who did not (p<0.001). The drivers of differences in total medical service days between those with and without CVAEs were inpatient days (690 vs 230), followed by outpatient days (2,798 vs 2,425), other visits (e.g., hospice; 662 vs 375), and emergency room (ER) visits (184 vs 109). Total days with medical service were 3,458 in those who received ibrutinib and 3,410 with acalabrutinib. Total healthcare cost rates in those who experienced an incident CVAE were $20,250,560 compared to $17,413,460 in those without CVAEs (p<0.001). Inpatient costs drove differences in total costs between those with CVAEs and those without ($3,417,948 vs $915,839, p<0.001), followed by outpatient ($2,415,060 vs $1,769,628, p<0.01) and ER costs ($186,820 vs $87,585, p<0.001). Pharmacy costs were the largest contributor to total cost rates for both cohorts ($14,016,900 for those with a CVAE vs $14,473,270 without any CVAEs, p<0.001). Regarding specific incident CVAEs, the cost difference in total costs between those with and without the event were $3,789,820 for atrial fibrillation (higher in those with the event), $3,867,160 for atrial flutter, $3,674,860 for ventricular arrhythmias, and $721,840 for hypertension. Inpatient costs were the largest driver in total cost differences between those with and without the specific CVAE of interest; inpatient cost differences were $3,255,699 higher in those with atrial fibrillation, $3,436,913 with atrial flutter, and $3,299,371 with ventricular arrhythmia. For hypertension, pharmacy costs drove differences in total costs and were $346,570 higher in those with the CVAE. Summary/Conclusion: Overall, the economic burden remains high in patients treated for CLL/SLL, especially in cBTKi patients experiencing an incident CVAE. These findings highlight the importance of careful treatment selection, safety monitoring, and early management of CVAEs in order to improve patient outcomes and reduce the downstream impacts on healthcare resources and costs.

OBJECTIVE To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference −12 mg/dL, 95% CI −22 to −2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.

AbstractBackgroundThe management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus.MethodsDuring the 14th Breast‐Gynecological and Immuno‐Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer.Results and ConclusionsThe consensus recommendations addressed different escalation and de‐escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

The proportion of the different types of fibers in a given skeletal muscle contributes to its overall metabolic and functional characteristics. Greater proportion of type I muscle fibers is associated with favorable oxidative metabolism and function of the muscle. Humans with obesity have a lower proportion of type I muscle fibers. We discuss how lower proportion of type I fibers in skeletal muscle of humans with obesity may explain metabolic and functional abnormalities reported in these individuals. These include lower muscle glucose disposal rate, mitochondrial content, protein synthesis, and quality/contractile function, as well as increased risk for heart disease, lower levels of physical activity, and propensity for weight gain/resistance to weight loss. We delineate future research directions and the need to examine hybrid muscle fiber populations, which are indicative of a transitory state of fiber phenotype within skeletal muscle. We also describe methodologies for precisely characterizing muscle fibers and gene expression at the single muscle fiber level to enhance our understanding of the regulation of muscle fiber phenotype in obesity. By contextualizing research in the field of muscle fiber type in obesity, we lay a foundation for future advancements and pave the way for translation of this knowledge to address impaired metabolism and function in obesity.

Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when ≥75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Summary: Most unstable metacarpal and phalangeal fractures for which operative treatment is indicated can be reduced and stabilized with either open or closed techniques using local anesthetic with epinephrine instead of intravenous sedation or general anesthesia. With the patient wide-awake during surgery, the hand can be taken through active range of motion to assess fracture stability. In this article, the authors review the rationale and technique for wide-awake, local anesthesia, no tourniquet surgery in the treatment of phalangeal and metacarpal fractures and impart pearls to optimize the patient experience and illustrate common fixation techniques using percutaneous Kirschner wires. The intraoperative assessment of fracture stability permits an accelerated, protected–range-of-motion protocol that minimizes postoperative stiffness and facilitates expedient recovery.

The model of the lung as an elastic continuum undergoing small distortions from a uniformly inflated state has been used to describe many lung deformation problems. Lung stress-strain material properties needed for this model are described by two elastic moduli: the bulk modulus, which describes a uniform inflation, and the shear modulus, which describes an isovolume deformation. In this study we measured the bulk modulus and shear modulus of human lungs obtained at autopsy at several fixed transpulmonary pressures (Ptp). The bulk modulus was obtained from small pressure-volume perturbations on different points of the deflation pressure-volume curve. The shear modulus was obtained from indentation tests on the lung surface. The results indicated that, at a constant Ptp, both bulk and shear moduli increased with age, and the increase was greater at higher Ptp values. The micromechanical basis for these changes remains to be elucidated.