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Background: Hypomethylating agent (HMA) and venetoclax (VEN) therapy is a standard of care frontline treatment of acute myeloid leukemia (AML) amongst patients (pts) ineligible for intensive therapy. Despite its convenient flat dose, oral nature, and static excretion irrespective of body weight (wt), VEN has a large, variable volume of distribution and extensive protein binding (Yang, Molecules, 2022). Body mass index (BMI) is a more accurate, albeit imperfect, indicator of body fat that has not been evaluated as an independent predictor of differential VEN exposures and clinical outcomes. We sought to evaluate this possibility amongst pts treated with frontline HMA+VEN in a multi-center, real-world, retrospective study. Methods: We conducted a multi-center, retrospective study through four US academic centers in the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). 368 pts treated with frontline HMA+VEN from 6/2016-8/2023were evaluated based on BMI within 30 days of induction. Responses were defined by European LeukemiaNet (ELN) 2022 criteria. Pearson's chi-squared test and Wilcoxon rank-sum test were used for comparison between groups. The Kaplan-Meier method and multivariable Cox regression model were applied to overall survival (OS). Continuous variables were summarized as a median with interquartile range (IQR), and categorical variables were reported as a frequency (percentage). Results: The median age was 75 (IQR: 70-79) years, 58% were male, and 76% were white. 107 (29%) had a normal BMI of 18-25 kg/m2, 141 (38%) were overweight (BMI 25-30 kg/m2), and 120 (33%) were obese (BMI >30 kg/m2). There were no significant differences in baseline pt-, disease-, and treatment-specific factors when comparing pts with normal wt to BMI >25.The cohort was enriched for complex karyotype and TP53-mutated disease (27% and 32%, respectively), with 73% categorized as adverse risk by ELN 2022. There was no difference in 30-, 60-, and 90-day mortality rates (6-8%, 14-18%, 19-29%, respectively) by BMI group. Complete remission (CR/CRi) rate was 50% overall and was not impacted by BMI (41%, normal wt; 55%, overweight; 52%, obese) (p=0.10). Overall response rate (ORR) (CR/CRi/MLFS) was 59% overall and differed by BMI groups (50%, normal wt; 66%, overweight; 58%, obese) (p= 0.047). The median OS was 6.6 months for normal wt, 13.7 months for overweight, and 8.3 months for obese pts, and not significantly different when comparing normal to overweight (p=0.052) or obese pts (p=0.756). In multivariable analysis, the effect of BMI varied by the composite remission rate used. Overweight was borderline significantly associated with higher likelihood of achieving CR compared to normal wt (odds ratio [OR] 1.98, 95% confidence interval [CI] 0.99-4.03; p=.056), whereas obesity was not (OR 1.78, CI 0.86-3.74; p=.13). Other co-variates with a significant association with achieving CR included diagnosis of secondary AML (sAML) (OR 0.37, CI 0.18-0.74; p=.006) and presence of IDH (OR 2.81, CI 1.30-6.15; p=.009), ASXL (OR 0.39, CI 0.15-0.96; p=.046), TET2 (OR 2.43, CI 1.17-5.09; p=.02), and DNMT3A (OR 2.37, CI 1.19-4.78; p=.02) mutations. There was a trend towards higher likelihood of achieving CR/CRi for both overweight (OR 1.74, CI 0.92-3.32; p=.09) and obese pts (OR 1.88, CI 0.96-3.74; p=.07). Diagnosis of sAML and presence of TET2, ASXL, and DNMT3A mutations no longer had a significant association with achieving CR/CRi, while IDH mutations maintained an association (p=.01). None of these variables demonstrated a significant impact on ORR (inclusive of MLFS) except overweight (OR: 1.99, CI 1.06-3.80; p=.03) and sAML vs de novo (OR: 0.53, CI 0.29-0.99; p=.047). In multivariable logistic regression, higher ECOG score was associated with risk of early mortality within 60 (p=.01) and 90 (p=.01) days, but not 30 days. sAML vs de novo associated with higher 90-day mortality, presence of NPM and TP53 mutation associated with higher 30-day mortality, and cytogenetic risk associated with higher 60- and 90-day mortality. Conclusions: This multi-center, real-world study demonstrates that BMI may not have a linear effect on response to frontline HMA+VEN, with some indication of negative impact at both lower and higher BMI categories. However, additional dedicated studies are needed to determine if differences in BMI is associated with altered drug exposure as an explanation for these differences.

Introduction: TP53 mutations are found in 18% of adult patients (pts) with acute lymphoblastic leukemias (ALL), and portends poor prognosis (Saygin, Blood Cancer Discov 2024). TP53 mutations are often associated with low hypodiploidy and Li Fraumeni syndrome (germline) in children. However, we and others have shown that TP53-mutant (TP53-m) ALL arises from pre-existing TP53-m clonal hematopoiesis in adults as opposed to germline origin. The impact of co-occurring mutations, TP53 allelic frequency (AF) and different types of treatment on outcomes of TP53-m ALL are not fully characterized. We set out to investigate the clinical and molecular predictors of outcomes in adults with TP53-mutant ALL. Methods: We retrospectively studied 107 patients with TP53-m ALL treated at seven different academic centers in North America. Genetic profiling of pre-treatment bone marrow samples was performed with a comprehensive panel covering 147 myeloid and lymphoid genes. We also performed RNA-sequencing to identify fusions that define ALL subtypes. Single nucleotide polymorphism (SNP) array was used to define low hypodiploidy. Results: The median age at diagnosis was 59 years (range, 10-80), 42% were female, 70% White. 89% of pts had B-ALL while 11% had T-lineage ALL. 24% of pts were classified to have therapy-related ALL based on their history of exposure to genotoxic therapy for another cancer. 45% of pts had hypodiploid karyotype, 79% of whom were low-hypodiploid. 7% had hyperdiploid karyotype and 5% had BCR::ABL1. 11 pts had two different TP53 variants. 90% of TP53 variants involved the DNA binding domain. Most frequently observed co-occurring mutations involved CDKN2A (20%), NOTCH1 (12%) and RB1 (10%) genes. 71% of pts were treated with standard cytotoxic chemotherapy, while the remaining pts received newer antibody-based therapies (i.e., inotuzumab, blinatumomab) or venetoclax in first-line setting. 11% of pts received allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) while 3% received HCT after relapse (CR2 or CR3). When patients with vs without low hypodiploidy were compared, we did not observe a significant difference in overall survival (OS) as outcomes were poor in both groups (median, 17 vs 19 months, p= 0.89). However, pts who had TP53 AF >0.5 had significantly worse OS when compared to pts with TP53 VAF <0.5 (13 vs 25 months, p= 0.03). Conclusions: TP53-m ALL is a very high-risk disease subtype and its dismal outcome is independent from presence of co-existing low hypodiploidy. Loss of heterozygosity, characterized by TP53 AF >0.5 is associated with even worse survival. New therapies are urgently needed to improve outcomes in this subset.

Introduction: Acute myeloid leukemia (AML) has been considered by many to be an oncologic emergency often leading to hospital admission for expeditious evaluation and treatment. Previous studies reported that time from diagnosis to treatment (TDT) does not impact outcomes (Sekeres, Blood, 2009), (Bertoli, Blood, 2013), (Rollig, Blood, 2020), however these analyses were restricted to intensively treated and/or non-United States (US) patients (pts). We report on a multi-center, retrospective analysis of TDT in adults with newly diagnosed AML receiving Hypomethylating agent (HMA) + venetoclax (Ven) using real-world data from the COMMAND. Methods: Eight US academic medical centers with AML expertise performed a review of adult pts within their center treated with HMA+Ven for newly diagnosed AML. TDT was defined as days from diagnosis of AML to initiation of treatment with HMA+Ven. Cytoreduction with hydroxyurea or leukapheresis was included to control for the effects of severity of presentation on TDT. The primary outcome was impact of TDT on overall survival (OS) (defined as date of diagnosis to date of death). TDT was treated continuously for time-to-event analyses. Secondary outcomes included measurable residual disease (MRD) by flow cytometric analysis (sensitivity <0.1%), complete response (CR), complete response with incomplete count recovery (CRi), defined by European LeukemiaNet (ELN) 2022 Guidelines (Dohner, Blood,2022), and early mortality (death within 30 and 60 days of initiation of HMA+Ven). Pre-planned subgroup analyses included those based on disease biology (FLT3 ITD, IDH1/2, TP53 mutation, ELN 2022 risk), HMA used (azacitidine vs decitabine) and age (<75 vs ≥75 years). For those analyses where TDT was significant in univariable analysis (P=0.1), multivariable analysis was conducted controlling for the following: ECOG performance status (PS), age, receipt of cytoreduction, ELN 2022 risk, and presence of individual pathogenic variants detected on broad myeloid gene next generation sequencing panels used at each institution. All analyses were conducted by a central statistician using RStudio statistical package. Results: 488 pts were included in the analysis. Median age was 76 (interquartile range: 70-80) and the majority of pts had an ECOG PS of 0 or 1 (56%). Most pts (67.6%) had adverse risk with 9.4% and 18.6% of pts having favorable and intermediate risk disease by ELN 2022, respectfully. The most common mutations identified were TP53 (27.5%), IDH1/2 (19.3%), NPM1 (16.4%), DNMT3A (16.8%), ASXL1 (15.4%), and FLT3-ITD (13.7%). Twenty-eight percent of pts received cytoreduction prior to initiation of HMA+Ven. Azacitidine+Ven was the most common regimen utilized (53.9%). Median number of cycles of HMA+Ven was 3 (IQR: 1-6). MRD (-) CR, MRD (+) CR, and CRi was achieved in 21.5%, 10.5%, and 16.4% of pts after one cycle of HMA+Ven. Median OS for the cohort was 10.4 months (95% CI: 9.4-12.6). Median TDT for the cohort was 9 days (IQR: 5-17). In univariate Cox model, longer TDT was associated with improved OS (HR: 0.989, 95% CI: 0.981 to 0.998; p = 0.013). In multivariable analysis, longer TDT was still associated with improved OS (HR: 0.987; 95% CI: 0.973-0.999; p=0.049). TDT and presence of bZIP in-frame CEBPA mutations were the only factors associated with improved OS, while ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.035 and 0.0002, respectively) and therapy-related AML (p=0.002), were associated with worse OS. Notably, ELN 2022 risk and IDH1/2 or NPM1 mutation status did not impact OS. Discussion: In this real-world, multi-center, US-based analysis of pts with newly diagnosed AML treated with HMA+Ven we show that longer TDT is associated with improved OS even when controlling for severity of presentation, ELN 2022 risk score, ECOG PS, and age. This finding is consistent with data in pts treated with 7+3. Similar to results published in an electronic medical record-based analysis out of Germany (Baden, Haemotologica, 2024) in pts treated with lower-intensity Ven regimens, our results show that pts with newly diagnosed AML eventually treated with HMA+Ven are best served with a complete appraisal of disease biology and treatment planning before initiation of induction therapy. Given the consistent negative impact of ECOG PS and the findings of our study, future consideration for potential patient optimization strategies to improve ECOG PS prior to therapy initiation are warranted.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

Background : Rituximab is a monoclonal antibody that targets CD20 and can significantly improve the prognosis of patients with CD20-positive B-cell non-Hodgkin lymphoma (B-NHL). Nonetheless, a significant number of patients experience disease progression or relapse post-rituximab therapy. CD19-chimeric antigen receptor (CAR) T cells have demonstrated remarkable efficacy in B-NHL treatment. However, few studies have focused on the efficacy and safety of CD20 CAR-T cells in rituximab-refractory/relapsed (R/R) B-NHL patients, particularly those treated with rituximab for a short time. Here, we conducted a prospective study, aimed to assess the long-term remission and survival in patients with rituximab-R/R B-NHL after treatment with U16 (CD20 CAR-T cells). Methods : This first-in-human study is an open-label, single center investigator-initiated trial (IIT) to determine the safety and efficacy of CD20 CAR-T in R/R B-NHL after previous rituximab treatment failure (no. ChiCTR2000036350). CD20 CAR-T was administered at a target dose of 1.0×107 CAR-T cells/kg after a 3-day conditioning chemotherapy with fludarabine and cyclophosphamide. The primary objective was to assess the safety and tolerability of CD20 CAR-T. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate efficacy and pharmacokinetics (PK). Response was assessed per Lugano 2014 criteria. Results:A total of 16 patients with R/R B-NHL were enrolled.The median age was 49 years (range, 28-66). Median number of prior lines of therapy was 3 (range, 2-5). All patients had received rituximab therapy; of these, 9 had done so within the 3 months before CAR-T infusion. CRS occurred in all patients, with 11 patients (68.75%) experiencing grade 1 or 2 CRS and 5 patients (31.25%) experiencing grade 3 CRS. No patient developed grade 4 CRS , and only one patient had ICANS.The most common grade 3 or higher adverse events observed after infusion included leukopenia (93.3%), anemia (40%) and thrombocytopenia (60%). An overall response rate of 100% was observed among enrolled patients, with 11 patients (68.75%) achieving complete remission(CR) and 5 patients (32.25%) achieving partial remission(PR) within 3 months. The median follow-up time was 11.7 months(range 0.69-47.47). The median overall survival was not reached, and the median progression-free survival was 14.5 months. 9 patients remained CR or PR for 12 months, with 7 of them continuing in CR for up to 24 months. The pharmacokinetics of CD20 CAR-T cells were assessed using quantitative PCR to determine the expansion and persistence ability. Peak CAR amplification were detected 7-14 days after infusin. Patients 1, 2 and 4 achieved long-term remission, and persistent positive CAR-T cell copy numbers were detected for 15 months, 30 months and 26 months, respectively. However, patients 7, 8 and 12 relapsed within 3 months, and the CAR-T cell copies of all three patients were reduced to fewer than 1×103 copies/μg of DNA within 3 months. The qPCR results indicated that the maintenance of efficacy was closely related to the persistence of CAR-T cells. Notably, patients who received rituximab less than 3 months before CAR-T infusion had a poorer prognosis, with higher relapse rates (77.8% vs. 28.6%) and shorter progression-free survival, regardless of the degree of response. Conclusion : Long-term follow-up demonstrated that CD20 CAR-T therapy can produce a deep and durable response with a favorable safety profile in patients with rituximab-refractory/relapsed B-NHL. Notably, patients who had received rituximab within 3 months had a poorer prognosis.

ABSTRACT Background Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of anti-cancer Antibody Drug Conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-PD1 therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC Sacituzumab govitecan (SG), enhances the anti-PD1 response and improves T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate anti-tumor immunity and enhance immunotherapy response. What is already known on this topic Barrier-mediated immune exclusion is emerging as a mechanism of immune evasion in cancer such as triple-negative breast cancer (TNBC), but its molecular underpinnings remain poorly understood. TROP2 is a surface glycoprotein targeted by antibody-drug conjugates such as Sacituzumab govitecan, yet its functional role beyond drug delivery has been unclear. What this study adds This study identifies TROP2 as a key regulator of tight junction-mediated immune exclusion in TNBC, independent of its intracellular signaling function. TROP2 promotes an immune-cold tumor microenvironment by enforcing mechanical barriers that limit T cell infiltration. How this study might affect research, practice or policy These findings establish TROP2 as a functional driver of immune evasion and provide a mechanistic rationale for combining TROP2-targeting therapies with immune checkpoint inhibitors to overcome resistance in immune-excluded tumors.

AbstractAimMinimally invasive transanal platforms are now the standard of care for select low‐risk rectal tumours. However, existing platforms come with persistent technical challenges. The da Vinci SP Surgical System™ offers a new alternative designed to work effectively in narrow spaces. This technology has the potential to enhance the feasibility and proximal extent of complex transanal resections. This study aimed to describe the morbidity and technical success in patients undergoing single‐port robotic transanal minimally invasive surgery (SPR‐TAMIS). Secondary outcomes include rates of local recurrence.MethodsA retrospective analysis was conducted on all patients who underwent SPR‐TAMIS at our institution between February 2019 and December 2023.ResultsThe study included 31 patients (19 men, 12 women) with a mean age of 61 ± 13.3 years. The average tumour distance from the anal verge was 10 cm. Thirty patients completed SPR‐TAMIS, with one patient requiring conversion to robotic sigmoidectomy due to location in the mid‐sigmoid colon. The mean operating time was 106 ± 42 min. Twenty‐eight out of 30 patients underwent full‐thickness excision and all but two were successfully closed. All specimens were resected intact, and margins were negative in 93.5% of cases. The average tumour size was 13 ± 34 cm2, with 13 lesions classified as adenomas and 16 as adenocarcinomas. All patients who did not undergo associated procedures were discharged on the day of surgery. Two patients experienced 30‐day morbidity. At a mean follow‐up of 18 months (± 13), no local or systemic recurrences were identified.ConclusionSPR‐TAMIS for excision of low‐risk rectal tumours is associated with high rates of technical success and low 30‐day morbidity. Further research is needed to compare SPR‐TAMIS with other techniques to determine potential advantages over current transanal platforms.

Noninvasive brain stimulation techniques have emerged as a promising therapeutic option for various central nervous system demyelinating diseases. Demyelinating diseases represent a group of pathological conditions that impact the central or peripheral nervous system. They are characterized by damage to or loss of the myelin sheath surrounding nerve fibers. This damage to myelin sheaths disrupts nerve signal transmission, leading to a wide range of signs and symptoms associated with neurological impairment. Treatment for demyelinating diseases usually aligns with the specific underlying cause. Noninvasive brain stimulation techniques can affect neuronal electrical activity and glial cell function, suggesting a potential option for intervention. In this narrative review, we explore the potential of noninvasive brain stimulation techniques for the treatment of central nervous system demyelinating disorders. Noninvasive brain stimulation techniques, including transcranial magnetic stimulation, transcranial electrical stimulation, transcranial focused ultrasound stimulation, optogenetic stimulation, low-intensity pulsed ultrasound, and transcranial photobiomodulation, have been shown to potentially intervene in the treatment of demyelinating diseases by affecting the electrical activity of nerve cells and glial cell function. In addition, this review summarizes the applications and mechanisms of noninvasive brain stimulation techniques in the treatment of central nervous system demyelinating diseases and how these techniques promote myelin regeneration and improve disease prognosis. This review also summarizes research advances in noninvasive brain stimulation techniques for the treatment of multiple sclerosis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, and neuromyelitis optical spectrum disorder. Noninvasive brain stimulation techniques can improve disease symptoms by promoting oligodendrocyte proliferation and differentiation, enhancing myelin regeneration, and modulating immune responses. Although noninvasive brain stimulation techniques have shown potential in the treatment of various neurological disorders, their use in treating demyelinating diseases remains challenging. For example, transcranial focused ultrasound stimulation is a relatively new noninvasive brain stimulation technique with the advantages of high spatial resolution and the ability to stimulate deep brain structures, but its safety and efficacy in clinical applications need to be further investigated. Optogenetic stimulation offers highly precise neuromodulation, but its feasibility in clinical practice is limited by technical and ethical constraints. Overall, noninvasive brain stimulation techniques have significant potential in the treatment of central nervous system demyelinating diseases, but further research is needed to optimize stimulation parameters, improve therapeutic efficacy, and gain insight into their mechanism of action. With the continuous development of technology and in-depth clinical trials, noninvasive brain stimulation techniques are expected to become an effective treatment for central nervous system demyelinating diseases and provide new therapeutic options for such patients.

SummaryBackgroundVarying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.ObjectivesWe conducted a two‐sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8 years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.MethodsSummary data were obtained from genome‐wide association study (GWAS) of BMI in 28 681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102 893 cases and 485 083 non‐cases).ResultsThere were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1‐standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1‐SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer‐site‐specific analyses.ConclusionsWe found little evidence of any associations between early life adiposity on later life CRC risk.