Citations

PURPOSE To investigate the clinical behavior of breast cancer in young BRCA carriers according to the specific BRCA gene ( BRCA1 v BRCA2 ) and the association of the timing of genetic testing (before v at diagnosis) with prognosis. METHODS This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in BRCA1 or BRCA2 , who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306 ). RESULTS Compared with BRCA2 carriers (n = 1,683), BRCA1 carriers (n = 3,069) had more frequently hormone receptor–negative (74.4% v 15.5%) and high-grade (77.5% v 49.1%) tumors. Similar outcomes were observed in BRCA1 and BRCA2 carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for BRCA at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% v 32.4%), less nodal involvement (N0: 65.9% v 50.8%), less frequently received chemotherapy (84.4% v 92.9%), and axillary dissection (37.5% v 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). CONCLUSION This global study provides evidence on the different clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers. Identifying a BRCA PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.

Abstract Objective Peri-implant enhancement can be seen on contrast-enhanced breast MRI, but its association with malignancy has not been described, leading to considerable variability in assessment and recommendations by radiologists. This study evaluated imaging features, management, and outcomes of implant-related enhancement. Methods This multisite IRB-approved retrospective review queried all breast MRI reports for keywords describing peri-implant enhancement, fluid, and/or masses (plus synonymous descriptions) and implant-associated malignancies, with subsequent imaging and chart review. Peri-implant enhancement and implant features were characterized. Assessments and outcomes were evaluated via clinical and imaging follow-up, aspiration/biopsy, and/or capsulectomy to evaluate for association of peri-implant enhancement with implant-related malignancy. Results A total of 100 patients had peri-implant enhancement. Uniform thin peripheral enhancement was most common (79/100, 79%). Capsulectomy was performed in 31/100 (31%), with benign capsular fibrosis/inflammation discovered in 26/31 (83.9%). Breast implant–associated anaplastic large cell lymphoma was present in 2/100 (2%), both with textured implants, while 98/100 (98%) had no implant-related malignancy. MRI recommendations varied: resume routine imaging (26/100, 26%), clinical management (18/100, 18%), follow-up MRI (17/100, 17%), MRI-directed US (17/100, 17%), aspiration/biopsy (11/100, 11%), and surgical consultation (10/100, 10%). Conclusion Peri-implant enhancement is a nonspecific imaging finding with a low malignant association, especially when seen in isolation (no associated effusion, mass, or adenopathy). Implant surface texture should be considered in management recommendations; diagnostic capsulectomy is not recommended in patients with smooth implants. Additional studies are encouraged to validate nonoperative management recommendations.

ABSTRACT This review provides an in-depth analysis of glucocorticoid therapy for lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus that affects up to 51.7% of patients. LN significantly increases the risk of mortality and progression to end-stage kidney disease. Glucocorticoids have been central to LN treatment for decades due to their anti-inflammatory properties, but optimal dosing strategies remain uncertain. The review discusses the historical evolution of glucocorticoid use, highlighting the shift from high-dose regimens to combined approaches with immunosuppressants and lower glucocorticoid doses to minimize adverse effects. Mechanistically, glucocorticoids exert effects through genomic and non-genomic pathways, modulating immune responses and metabolism. Long-term use is associated with risks such as infection, osteoporosis, hyperglycemia and cardiovascular disease. The review examines different dosing strategies, including intravenous pulse therapy and oral regimens, and presents evidence of their efficacy and safety. It also explores alternative approaches, such as low-dose and glucocorticoid-free regimens, which show promise but require further study. The review concludes by emphasizing the need for future research to optimize glucocorticoid regimens, refine tapering protocols and identify safer therapeutic combinations, as glucocorticoids remain a cornerstone in LN management despite their challenges.

ABSTRACTBackgroundCellulite is a localized skin condition that affects many women, particularly after puberty. It results from a complex interplay of several factors that lead to the characteristic dimpled appearance of the skin. Cellulite may cause psychological stress and negatively impact quality of life. Additionally, body skin laxity may further exacerbate cosmetic concerns in these patients. Consequently, multiple therapeutic options, including topical treatments, have been explored to address both cellulite and skin laxity.ObjectivesTo review the pathophysiology of cellulite and skin laxity, as well as topical skincare options for their management.MethodsA literature search from 2000 to 2024 was conducted using the databases PubMed, EBSCOhost, Scopus, and Google Scholar, with the key terms “cellulite,” “cellulite management,” “cellulite topical treatment,” “skin sagging,” “skin laxity,” and “loose skin.” The search included clinical trials, observational studies, book chapters, and review articles in English and Spanish.ResultsThe pathophysiologic mechanisms underlying cellulite involve a combination of histological, hormonal, genetic, and lifestyle factors. Several topical agents, including retinoids and methylxanthines, have shown potential in improving the cosmetic appearance of cellulite and may contribute to localized fat reduction. Emerging botanical extracts hold promise as topical treatments for cellulite and skin tightening.ConclusionsCellulite and skin laxity are prevalent cosmetic concerns with multifactorial and complex pathophysiologic origins. Topical treatments for cellulite and skin tightening require further investigation. Although some studies have demonstrated positive outcomes with skincare products and topicals, robust evidence and studies with extended follow‐up are still lacking. Additional research is necessary to evaluate the long‐term efficacy of topical treatments as standalone therapies for cellulite and skin tightening.

Abstract Worldwide, valvular heart disease (VHD) is a common cause of hospitalization for acute heart failure. In acute heart failure caused by VHD, symptoms result from rapid haemodynamic changes and subsequent decline in cardiac function, and if left untreated, leads to acute decompensation and cardiogenic shock. Current evidence remains scarce and recommendations regarding the management of acute heart failure caused by VHD are lacking in most recent international guidelines. Herein, we review the management of acute heart failure caused by VHD with a focus on transcatheter therapies and describe currently available evidence based on a systematic literature search on the following valve pathologies: (i) aortic stenosis, (ii) aortic regurgitation, (iii) mitral regurgitation, and (iv) mitral stenosis. Articles reporting outcomes following urgent or emergent valve intervention in the setting of cardiogenic shock or acute heart failure were considered. After screening a total of 2234 articles, 76 published between 1994 and 2023 were included in subsequent analysis. Based on available evidence, proposed treatment algorithms to guide optimal management of acute heart failure caused by VHD were created. As the number of patients presenting with acute heart failure caused by VHD continues to rise and outcomes following transcatheter valve interventions continue to improve, it is inevitable that minimally invasive options will play an increasingly important role in the acute setting, especially given these patients are at an increased operative risk. This review aims to present an organized approach to the complex management and interventional treatment of patients with acute heart failure caused by VHD.

In this case series, we present several examples from participants (2 patients and 1 healthy control) of a 12-week pilot feasibility study to create a digital phenotype of depression (unipolar or bipolar) through active and passive data collection from a smartphone and a wearable device combined with routine clinical care for mood disorders. The selected cases represent real clinical examples that highlight the intrinsic challenges that should be expected when conducting similar studies, including appropriate health data privacy protection, clinical standardization, and interindividual differences in levels of engagement and acceptability of active and passive data collection (ie, self-reported, behavioral, cognitive, and physiological data), particularly with patient-generated data in mobile apps, digital proficiency habituation, and consistent use of wearable devices. In the context of the rapidly growing use of digital technologies in psychiatry, anticipating challenges for the integration of personal mobile devices and smartphone mental health apps as aides to track specific aspects of depressive disorders is critical for a clinically meaningful digital transformation of mood disorders care.

Objective To characterise the changing trends in the pharmacological management of SLE in the USA between 2007 and 2023 as new treatment options emerged. Methods In a retrospective cohort study using data from OptumLabs Data Warehouse, we characterised the annual prevalent (ie, all) and incident (ie, new) use of antimalarials, glucocorticoids and immunosuppressive medications among patients with SLE from 2007 to 2023 and assessed for changing trends over time. Results We identified 19 122 adults with SLE; they were 51.2 (SD 16.1) years of age, 89% were female, 61.3% were White, 18.5% were Black and 13.1% were Hispanic. The proportion of prevalent users of antimalarials has decreased from 79.4% in 2007 to 77.2% in 2023 (p=0.0055), while the proportion of incident users fluctuated between a lowest 5.8% in 2021 and a highest 8.1% in 2008 (p=0.008). The proportion of prevalent users of glucocorticoids increased from 64.6% in 2007 to 66.7% in 2023 (p=0.0132), as did the proportion of incident users (12.4% in 2007 to 21.7% in 2023; p<0.0001). The use of cyclophosphamide (2.0% in 2007 to 0.4% in 2023, p<0.0001) has decreased; the use of mycophenolate mofetil (7.7% in 2007 to 10.3% in 2023, p<0.0001), rituximab (1.4% in 2007 to 2.1% in 2023, p<0.0001) and belimumab (0.8% in 2011 to 6.1% in 2023, p=0.0001) has increased. Conclusions Despite increasing availability of alternative treatment options, patients with SLE in the USA increasingly rely on glucocorticoid-based therapy. Efforts to improve the use of antimalarials and steroid-sparing immunosuppressants are needed.

Introduction Venetoclax + rituximab resulted in a 2-year progression-free survival estimate of 85% in the mostly 2nd-line, post-chemotherapy setting of the MURANO clinical trial (Seymour NEJM 2018). Short remissions with venetoclax in patients (pts) with prior cBTKi treatment (tx) for CLL are reported. However, these cohorts have included heavily pre-treated pts. Here, we report outcomes with venetoclax-based regimens in a contemporary cohort with cBTKi-exposed CLL and no prior chemotherapy. Methods We conducted a retrospective study of pts who received venetoclax for relapsed CLL after prior cBTKi tx at Mayo Clinic and across 8 centers in France. Pts with any prior chemotherapy tx were excluded. Pts were grouped as cBTKi-resistant (CLL disease progression on cBTKi) and cBTKi-exposed (any prior cBTKi tx but without disease progression). Overall survival (OS) was analyzed as the time from initiation of venetoclax until date of death or last known to be alive. Time to next therapy or death (TTNTD) after venetoclax was defined as the time from venetoclax initiation until the earliest date of next tx or death. Cox proportional hazards regression models were used to estimate associations of factors with OS and TTNTD. Results A total of 85 pts received venetoclax, including: venetoclax monotherapy (n=13, 15%), venetoclax + rituximab (n=45, 53%), and venetoclax + obinutuzumab (n=27, 32%). Patient characteristics at the time of venetoclax start were as follows: median age 69 years (interquartile range [IQR] 62-77), 59 (69%) male, 45% (33/73 evaluated) with TP53 disruption (del(17p) or TP53 mutation), 82% (46/56 evaluated) with unmutated IGHV, and 41% (15/37 evaluated) with complex karyotype (CK; ≥3 clonal structural or numerical abnormalities on karyotype). The median prior lines of therapy was 1 (IQR 1, 2); 32 (38%) pts had received prior anti-CD20 monoclonal antibody and 8 (9%) pts had received 2 prior cBTKi. Prior cBTKi tx was stopped for a reason other than disease progression in 46 (54%) pts (cBTKi-exposed) and due to CLL progression in 39 (46%) pts (cBTKi-resistant). TP53 disruption, unmutated IGHV, and CK were more common in the cBTKi-resistant subgroup. Among pts with cBTKi-resistant CLL, 60% (12/20 evaluated) had a BTK and/or PLCG2 mutation. Median follow-up from start of venetoclax-based therapy was 20 months. The median TTNTD and OS for the entire cohort was 36 (95% CI 29-not evaluable [NE]) and 68 (95% CI 39-NE) months, respectively. Among the 46 pts with cBTKi-exposed CLL, the median duration of prior cBTKi tx was 6.7 months (IQR 1.8, 23.7). The median TTNTD and OS from venetoclax start were both 78 months in pts with cBTKi-exposed CLL. The 24-month TTNTD and OS estimates were 73% and 81%, respectively. Among the 39 pts with cBTKi-resistant CLL, the median duration of prior cBTKi tx was 42.3 months (IQR 23.4, 60.1). The median TTNTD from venetoclax start in pts with cBTKi-resistant CLL was 30 months. The 24-month TTNTD estimate was 65% in the cBTKi-resistant subgroup, 53% with venetoclax monotherapy (n=5), 62% with venetoclax + rituximab (n=30), and 100% venetoclax + obinutuzumab (n=4). The median OS from venetoclax initiation was 39 months overall in pts with cBTKi-resistant CLL. The 24-month OS estimate was 84% in the cBTKi-resistant subgroup overall, 53% with venetoclax monotherapy, 87% with venetoclax + rituximab, and 100% with venetoclax + obinutuzumab. On a univariate analysis in the whole cohort, only TP53 disruption was associated with shorter TTNTD (HR 2.23; 95% CI 1.02-4.87; P=0.04) and only older age was associated with shorter OS (HR 1.05; 95% CI 1.007-1.095, P=0.02). On a univariate analysis in the cBTKi-resistant subgroup, only TP53 disruption was associated with shorter TTNTD (HR 6.68; 95% CI 1.51-29.46; P=0.01) and OS (HR 7.95; 95% CI 1.02-61.97; P=0.04). Duration of prior cBTKi exposure (as a continuous variable) was not associated with survival outcomes in the cBTKi-resistant subgroup. Conclusions Pts with chemotherapy-naïve, cBTKi-treated CLL had worse than expected outcomes with venetoclax-based tx in a mostly 2nd-line tx cohort, particularly pts with cBTKi-resistant CLL. The frequency of high-risk disease features, shorter duration of disease control with their initial cBTKi tx, and small cohort size warrant caution in generalizing these results to all pts with cBTKi-resistant disease. Novel tx trial strategies in 1st- and 2nd-line settings remain a high priority for high-risk pts.

Introduction: The combination of chemotherapy and immunotherapy, commonly referred to as chemo-immunotherapy (CIT), has long been a cornerstone in the treatment of lymphoma. Although this approach has resulted in successful treatments for many patients (pts), a significant number continue to experience unfavorable results, underscoring the urgency for improved treatments. There is still a significant gap in knowledge about the immune profile of lymphoma pts, specifically in terms of (1) how their immune phenotype compare to those of healthy individuals and (2) how treatment affects their immune system. This study aimed to compare the immune profiles of lymphoma pts (at baseline) to that of matched healthy controls, and track the changes in the immune system during and after lymphoma treatment. Methods: Pts with newly diagnosed, untreated lymphoma, without prior history of cancer or autoimmunity were enrolled in the Dyna-RISC study. Whole blood samples were collected at baseline (BL), on day 1 of cycle 2 (C2D1), on day 1 of last cycle (CLD1), and 6 months after completion of therapy (6mo). Age- and gender-matched healthy individuals provided blood for baseline comparison. Samples were stained fresh with a pre-mixed lyophilized cocktail containing 30 metal-tagged monoclonal antibodies (Maxpar Direct Immune Profile Assay), fixed and cryopreserved. Samples were barcoded and acquired in batches on the Helios CyTOF (cytometry by time-of-flight) system. Cytometry data was analyzed using OMIQ. Differential abundance analysis was performed using relative frequencies of cell subsets (% of parent) using a false-discovery rate of 0.05 to account for multiple comparisons. Results: Between 11/2020 and 06/2021, 15 lymphoma pts were enrolled. Median age was 62 years (range 43-86), 5 pts (33%) were female. Five pts had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL),1 had primary mediastinal B-cell lymphoma (PBML), 1 had classic Hodgking lymphoma (cHL), 1 had mantle cell lymphoma (MCL), 1 had plasmablastic lymphoma (PBL), 1 had splenic marginal zone lymphoma (SpMZL), 1 had ALK- anaplastic large cell lymphoma (ALCL), 1 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Four pts received bendamustine plus rituximab (BR) and 7 pts received R-CHOP. In total, more than 30 million cellular events were acquired, resulting in over 18 million analyzable live single-cell events after expert manual gating. A total of 27 cell subsets were identified within 9 major immune cell compartments. At baseline, lymphoma pts showed significant reduction (p&lt;0.05) of CD4+ naïve T cells (median 1.37%, range 0.33%-9.01%) compared to controls (median 9.28%, range 3.44-21.3%). Concurrently, lymphoma patients at baseline had significant elevation (p&lt;0.05) of intermediate monocytes (median 2.1%, range 0.64%-5.73%) compared to controls (median 0.8%, range 0.2%-2.73%). Naïve cytotoxic T cells were significantly increased (p&lt;0.05) in lymphoma pts at the 6mo timepoint (median 2.08%, range 0.7%-7.46%) compared to baseline (median 0.23%, range 0.03%-4.79%). A sub-group analysis restricted to patients who received either BR or R-CHOP with 6mo timepoint samples available (n=10), showed a significant reduction (p&lt;0.05) in the frequency of CD4+ central memory T cells in the BR group (median 0.76%, range 0.06%-1.02%) compared to the R-CHOP group (median 3.3%, range 2.19%-5.0%). Additional results describing the details of the immune profile dynamics at intermediate timepoints (C2D1, CLD1) will be presented at the conference. Conclusion: Our results suggest that lymphoma patients have an unfavorable immune profile (high intermediate monocytes combined with low naïve CD4+ T cells) at the time of diagnosis, compared to matched healthy individuals. Their immune profile is reshaped after treatment with increase in naïve cytotoxic T cells 6 months after therapy. Bendamustine-based treatment seems to particularly affect T cell recovery post-therapy, leading to a reduction in CD4+ central memory T cells, compared to patients treated with R-CHOP. These findings highlight the importance of studying baseline and treatment-mediated immune changes in lymphoma pts. This characterization is of special interest in the context of therapies that rely on the fitness of immune cells to mediate an effect, such as chimeric antigen receptor (CAR) T cell therapy and bispecific T cell engagers (BiTEs).