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PURPOSE The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582 ) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (MBC). METHODS Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor–positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

OBJECTIVE Glucagon-like peptide-1 (GLP-1) agonists are established therapeutics for weight loss that are increasingly used for BMI optimization prior to spine surgery. However, emerging evidence has suggested that GLP-1 agonists might reduce bone mineral density (BMD), increasing the risk of postoperative biomechanical complications. CT-based Hounsfield units (HUs) have gained popularity as a method for measuring spinal BMD. The aim of this study was to evaluate the effects of GLP-1 agonist–induced weight loss on spinal BMD as measured by opportunistic CT-based HUs. METHODS Patients who were treated with any GLP-1 agonist (2017–2022) for > 3 months were retrospectively identified. Patient body weight (BW), BMI, and HU measurements in the L1 vertebral body were measured before and after GLP-1 therapy. Patients were grouped according to the percentage of weight loss during GLP-1 therapy. One-way ANOVA was used to compare the mean changes in spinal HUs across the groups. RESULTS Among the 102 included patients, the mean ± standard error of the mean BW reduction was 14.5 ± 2.5 kg over 15.9 ± 1.2 months of GLP-1 agonist therapy. Of these, 7 patients (6.9%) lost > 20% BW (mean decrease of 31.9 ± 7.0 HU, p = 0.011), 14 (13.7%) lost 15%–20% BW (mean decrease of 19.1 ± 8.3 HU, p = 0.038), 14 (13.7%) lost 10%–15% BW (mean decrease of 12.2 ± 5.1 HU, p = 0.036), 24 (23.5%) lost 5%–10% BW (mean decrease of 15.7 ± 3.3 HU, p < 0.0001), 26 (25.5%) lost < 5% BW (mean decrease of 14.7 ± 6.0 HU, p = 0.022), and 17 (16.7%) gained BW during GLP-1 therapy (mean decrease of 6.3 ± 5.0 HU, p = 0.229). One-way ANOVA testing did not show a significant difference in HU reduction across the weight loss groups (F = 1.12, p = 0.355). In addition, there was a significant correlation between the decrease in L1 HUs and the duration of GLP-1 therapy (r = −0.38, p = 0.0001) but not the amount of weight loss (r = −0.18, p = 0.070). In the multivariate analysis, the duration of GLP-1 therapy (p = 0.032) was a significant independent predictor of vertebral HU reduction, but the amount of weight loss (p = 0.664) was not. CONCLUSIONS Despite similar pretreatment BW and HU measurements, all weight loss groups had significant decreases in vertebral HUs following GLP-1 agonist therapy, with a significant correlation observed between HU reduction and treatment duration. This suggests that long-term GLP-1 agonist therapy can significantly diminish spinal BMD regardless of the amount of weight loss achieved.

OBJECTIVE The aim of this study was to compare 3 electrode designs—a novel 22-contact circular grid, standard 6-contact strip, and high-density (HD) grid between 32 and 64 contacts—for the detection of epileptiform activity during awake craniotomy. METHODS This study included patients who underwent functional brain mapping with and without direct electrical stimulation during awake craniotomy. Demographic, clinical, and electrocorticography (ECoG) data were collected. RESULTS A total of 194 patients were included, with 264 instances of electrode use: 113 circular grid, 96 strip electrode, and 55 HD grid. The HD grid (15%) was used less to record ECoG during direct electrical stimulation than the circular grid (80%, p < 0.001) and strip electrodes (69%, p < 0.001). Sporadic interictal epileptiform activity was better detected with circular (45%, p < 0.001) and HD (40%, p = 0.006) grids compared with strip electrodes (16%). Spontaneous seizures were recorded more frequently with the circular grid (16%, p = 0.018) compared with the strip electrode (9.4%) and HD grid (1.8%). Afterdischarges were more frequently detected by the circular grid (69%, p = 0.031) and with circular and HD grids (combined) compared with strip electrodes (67% vs 48%, p = 0.024), at lower median intensity (3 mA vs 5 mA, p < 0.001). Multivariable analyses demonstrated circular grids (p < 0.001) to be more sensitive in detecting spontaneous epileptiform activity than strip and HD grid electrodes, and grids (circular and HD) to be better in recording stimulus-induced epileptiform activity (p = 0.01). CONCLUSIONS This study demonstrates a higher rate of detection of epileptiform activity with circular and standard grids when compared with strip electrodes. The standard HD grid was used less during electrical stimulation, demonstrating the importance of both the number of contacts and design array when considering optimal conditions for ECoG and functional brain mapping.

BACKGROUND: End colostomy reversal with colorectal anastomosis (Hartmann’s reversal) is a technically challenging procedure associated with significant morbidity due to adhesions and distorted anatomy after the index surgery. OBJECTIVE: To compare perioperative outcomes of open, laparoscopic, and robotic approaches for Hartmann’s reversal. DESIGN: Retrospective analysis of prospectively maintained data. SETTINGS: High-volume tertiary referral center with specialized colorectal surgery expertise. PATIENTS: A total of 218 patients who underwent Hartmann’s reversal between May 2018 and April 2023. MAIN OUTCOME MEASURES: Primary outcomes included hospital length of stay and rate of conversion. Secondary outcomes included overall complication rates and time to return of bowel function. RESULTS: Of 218 patients, 139 (63.8%) underwent open surgery, 48 (22.0%) underwent laparoscopic surgery, and 31 (14.2%) underwent robotic surgery. Robotic surgery had the lowest estimated blood loss (median 77.5 vs 100 mL laparoscopic and 150 mL open, p < 0.0001). Conversion to open surgery occurred in 16.1% of robotic cases compared with 35.4% of laparoscopic cases ( p = 0.0618). Minimally invasive approaches were associated with shorter hospital length of stay (median 3.0 vs 4.0 days, p < 0.0001) and faster return of bowel function (median 2.0 vs 3.0 days, p = 0.0095) compared to open surgery. Overall 30-day morbidity was 23.4%, with no significant difference among approaches ( p = 0.30). The temporal trend showed increasing adoption of robotic techniques, from 0% in 2018 to 53.8% in 2023, and a decrease in the proportion of cases approached by open surgery, from 76.9% in 2018 to 23.1% in 2023. LIMITATIONS: Retrospective design and single-institution experience with limited follow-up duration. CONCLUSIONS: Minimally invasive approaches to Hartmann’s reversal are associated with improved short-term outcomes compared to open surgery. The robotic approach shows promise in reducing conversion rates, potentially extending the benefits of minimally invasive surgery to more patients undergoing this challenging procedure. See Video Abstract . COMPARACIÓN DE LOS ENFOQUES ABIERTO, LAPAROSCÓPICO Y ROBÓTICO PARA LA REVERSIÓN DE HARTMANN: LA EXPERIENCIA DE LA CLÍNICA MAYO ANTECEDENTES: La reversión de la colostomía terminal con anastomosis colorrectal (reversión de Hartmann) es un procedimiento técnicamente complejo asociado a una morbilidad significativa debido a las adherencias y la distorsión anatómica tras la cirugía inicial. OBJETIVO: Comparar los resultados perioperatorios de los abordajes abiertos, laparoscópicos y robóticos para la reversión de Hartmann. DISEÑO: Análisis retrospectivo de datos mantenidos prospectivamente. ENTORNO: Centro terciario de referencia de gran volumen con experiencia especializada en cirugía colorrectal. PACIENTES: Un total de 218 se sometieron a la reversión de Hartmann entre mayo de 2018 y abril de 2023. PRINCIPALES MEDIDAS DE RESULTADOS: Los resultados primarios incluyeron la duración de la estancia hospitalaria y la tasa de conversión. Los resultados secundarios incluyeron las tasas generales de complicaciones y el tiempo de recuperación de la función intestinal. RESULTADOS: De los 218 pacientes, 139 (63,8 %) se sometieron a cirugía abierta, 48 (22,0 %) a cirugía laparoscópica y 31 (14,2 %) a cirugía robótica. La cirugía robótica tuvo la menor pérdida de sangre estimada (mediana, 77,5 ml frente a 100 ml en laparoscopia y 150 ml en cirugía abierta, p < 0,0001). La conversión a cirugía abierta se produjo en el 16,1 % de los casos robóticos frente al 35,4 % de los casos laparoscópicos ( p = 0,0618). Los abordajes mínimamente invasivos se asociaron con una estancia hospitalaria más corta (mediana de 3,0 días frente a 4,0 días, p < 0,0001) y un retorno más rápido de la función intestinal (mediana de 2,0 días frente a 3,0 días, p = 0,0095) en comparación con la cirugía abierta. La morbilidad global a los 30 días fue del 23,4 %, sin diferencias significativas entre los distintos enfoques ( p = 0,30). La tendencia temporal mostró un aumento en la adopción de técnicas robóticas, del 0 % en 2018 al 53,8 % en 2023, y una disminución en la proporción de casos abordados mediante cirugía abierta, del 76,9 % en 2018 al 23,1 % en 2023. LIMITACIONES: Diseño retrospectivo y experiencia de una sola institución con una duración de seguimiento limitada. CONCLUSIONES: Los enfoques mínimamente invasivos para la reversión de Hartmann se asocian con mejores resultados a corto plazo en comparación con la cirugía abierta. El enfoque robótico es prometedor para reducir las tasas de conversión, lo que podría ampliar los beneficios de la cirugía mínimamente invasiva a más pacientes que se someten a este procedimiento tan complejo. ( AI-generated translation ).

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers.

Abstract Introduction Management of acute leukemia (AL) during pregnancy remains challenging. In the first trimester, chemotherapy is toxic to the fetus, while delaying treatment may endanger maternal health, often prompting recommendations for pregnancy termination. In later trimesters, although the risk of congenital malformations decreases, complications such as preterm labor remain prevalent. Delivery prior to chemotherapy may be considered in advanced gestation. This study aimed to describe maternal and fetal outcomes of patients diagnosed with AL during pregnancy. Methods Following institutional review board approval, we retrospectively identified pregnant patients diagnosed with AL between 1995 and 2025 across Mayo Clinic sites (Minnesota, Arizona, Florida). We recorded leukemia subtype, treatment course, maternal and fetal outcomes. Results We identified 18 patients diagnosed with AL during pregnancy, including 11 with acute myeloid leukemia (AML) and 7 with acute lymphoblastic leukemia (ALL). Ten were diagnosed in the first trimester, 3 in the second, and 5 in the third. In the AML group (n=11; median age 30 years, range 18-42), one patient had acute promyelocytic leukemia (APL). ELN 2022 risk stratification was favorable in 5 (45%), intermediate in 4 (36%), and adverse in 2 (18%). In the ALL group (n=7; median age 23 years, range 19-34), 5 had B-ALL (one Philadelphia chromosome-positive) and 2 had T-ALL. All ALL cases were diagnosed in the first trimester. Among first-trimester AMLs, 2 of 3 had core-binding factor (CBF) AML. All eight patients diagnosed in the second and third trimesters had AML (1 APL, 2 CBF AML, 1 KMT2A-rearranged, 1 with DEK::NUP214 fusion, 1 complex karyotype including t(8;21), 2 with normal karyotype). Overall, 15 (83%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) after initial induction. One patient had refractory disease and achieved partial remission after salvage, another had refractory disease and achieved CR after multiple lines of therapy, and a third achieved CR after FLAG-idarubicin and revumenib. Five patients received chemotherapy during pregnancy (3 in the first trimester, 1 in the second, 1 in the third); two of these resulted in live births. Among the 10 patients diagnosed in the first trimester, all underwent therapeutic or spontaneous abortion. Of the 3 second-trimester diagnoses, 2 underwent spontaneous or therapeutic abortion at 15 weeks. The third received 7+3 induction at 24 weeks for KMT2A-rearranged AML, followed by preterm delivery at 26 weeks and re-induction with FLAG-idarubicin plus revumenib, achieving CR. Among the 5 third trimester diagnoses, 4 delivered preterm infants (median gestational age 33 weeks) prior to chemotherapy. One patient received 7+3 at 29 weeks and delivered a viable preterm infant at 36 weeks. At a median follow-up of 6.5 years, 5 of 11 patients with AML (45%) and 3 of 7 patients with ALL (43%) died, mostly due to disease progression. Median overall survival was not reached in either group. Causes of death were as follows: 1 of AML, 1 of ALL, 3 of acute stem cell transplant (SCT) complications, 1 of chronic SCT complications, 1 of Hodgkin lymphoma, and 1 of pneumonia. Among patients diagnosed in the second and third trimesters (n=8, all with AML), 6 (75%) resulted in live births: 5 of 5 (100%) third-trimester diagnoses and 1 of 3 (33%) second-trimester diagnoses. All received intensive induction: 7+3 (n=5), 7+3 + ATRA (n=1), 7+3 + gilteritinib (n=1), and 7+3 + nilotinib (n=1). Of the second-trimester group, only one received induction prior to delivery; she later achieved CR with FLAG-ida and revumenib. Among the third-trimester group, one patient received chemotherapy prior to delivery and achieved CR followed by SCT. All but one of the 8 AML patients achieved CR after initial therapy. Conclusions Successful pregnancy outcomes were achieved in 75% of patients diagnosed with AML during the late second or third trimester. Notably, 5 (28%) of patients received chemotherapy during pregnancy. Larger, multi-institutional cohorts are warranted to further characterize the incidence and outcomes of AL in pregnancy.

Abstract Introduction: CSF3R mutations (CSF3RMUT), most commonly T618I, represent the defining genomic alteration in chronic neutrophilic leukemia (CNL), present in ~80% of cases. Despite emerging real-world data, information on treatment outcomes and prognostic factors remains limited due to rarity of the disease. In this two-center retrospective study, we examined clinical and molecular predictors of treatment response, overall survival (OS), and blast transformation (BT) and outcome following allogeneic stem cell transplant (ASCT). Methods: The study was approved by the institutional review boards of the Mayo Clinic (USA) and the University of Montreal (Canada). Electronic medical records were reviewed to identify patients with CSF3R mutated CNL at both institutions and extract relevant data. Statistical analyses were conducted using JMP Pro 17.0.0 software (SAS Institute, Cary, NC, USA). Results: Forty-four patients (68% male, median age 68 years [range: 26-93]) were included. At diagnosis, 20 (56%) were asymptomatic, 13 (36%) presented with constitutional/non-specific symptoms, and 20 (50%) had antecedent leukocytosis at a median of 13 months(mo) prior. Splenomegaly (palpable or radiological) was observed in 28 (67%) patients, hepatomegaly in 7 (17%) and lymphadenopathy in 4 (9.8%). Median white blood cell count (WBC) was 52×10⁹/L (range: 17-390). CSF3RMUT/variants included 39 (89%) with T618I (7 of the 39 had additional CSF3RMUT), 2 (5%) with M696T, and 1 (2%) each for I598I, Q739* and T640N. Frequent co-mutations included ASXL1 in 25 (63%) patients, SETBP1 in 14 (36%), and SRSF2 in 8 (31%), with overlapping occurrence; 10 (38%) patients had ≥2 of these 3 mutations. Ten patients (median WBC 29 x10⁹/L [range: 19–58]), were initially observed without treatment for a median of 8.6 mo; 2 remained on observation alone at 46 and 77 mo. Hydroxyurea (HU) alone or in combinations excluding ruxolitinib (Ruxo) was the most common first-line treatment (68%). Second-line therapies included Ruxo (39%), HU (25%), and hypomethylating agents (14%). WBC response (≥50% reduction from baseline) was 78% with HU vs. 60% with Ruxo (p=0.2). WBC response to HU was lower with abnormal karyotype (40% vs. 94%; p=0.02). WBC response to Ruxo was lower with SETBP1MUT (0% vs. 72%; p=0.05) and with male sex (40% vs. 100%; p=0.04). Seven patients underwent ASCT, including 2 after BT; four (57%) of the 7 remain alive, including 2 without evidence of disease (both 45 mo post-ASCT; one harbored ASXL1MUT) and the other 2 with active disease (both harbored ASXL1MUT). Three patients died from veno-occlusive disease (Day+34), CNS relapse with AML (at 105 mo post-ASCT), or unrelated causes (at 44 mo post-ASCT). Median OS was longer in transplanted patients (115 vs 23 mo; p=0.03). At a median follow-up of 44 mo for living patients, disease transformation occurred in 10 patients, including 7 with BT (6 with T618I, 1 T640N) and 3 with chronic myelomonocytic leukemia (2 M696T, 1 T618I). BT rate at 2, 3, and 5 years was 15%, 31%, and 43%, respectively. Univariate analysis (UVA) identified male gender (p&lt;0.01), &gt;5% immature WBCs (p=0.02), platelets &lt;160×10⁹/L (p=0.04), higher WBC (p=0.02), and ASXL1 or SETBP1 mutation (p&lt;0.01) as risk factors for BT. On multivariable analysis (MVA), only the latter remained significant. Median OS was 26 mo (95% CI: 21-43) for the entire cohort; 24 mo for patients with T618I CSF3RMUT vs 53 mo with other CSF3RMUT, p=0.1. In UVA, age &gt;60 years (HR 5.0, p=0.03), platelets &lt;160×10⁹/L (HR 3.4, p=0.006), WBC &gt;50×10⁹/L (HR 2.6, p=0.02), and ASXL1 or SETBP1 mutations (HR 4.2, p=0.01) were associated with shorter OS. In MVA, age &gt;60 (HR 6, p=0.03), WBC &gt;50×10⁹/L (HR 12, p&lt;0.01), and the presence of ASXL1MUT or SETBP1MUT (HR 9.5, p=0.01) remained significant. Based on the HRs on MVA, one adverse point was allocated for age &gt;60 years, and two adverse points each for WBC &gt;50×10⁹/L and presence of ASXL1 or SETBP1 mutations. Patients were accordingly stratified into low (0-2 points), intermediate (3) and high (4-5) risk groups with corresponding median OS of “not reached”, 29 mo, and 16 mo (p&lt;0.01). Causes of death included disease progression (82%), infection/bleeding (9%), and ASCT complications (9%). Conclusion: The current study highlights the prognostic relevance of “SETBP1 or ASXL1” mutation for both overall survival and risk of blast transformation. The study also signifies variable natural history and potential benefit from ASCT.