Citations

Abstract Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

This article shows how mitochondria in murine cardiac changes, importantly elucidating age-related changes. It also is the first to show that the MICOS complex may play a role in outer membrane mitochondrial structure.

AbstractIntroductionLeft bundle branch area pacing (LBBP) is a novel conduction system pacing method to achieve effective physiological pacing and an alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BVP) for patients with heart failure with reduced ejection fraction (HFrEF). We conduted this meta‐analysis and systemic review to review current data comparing BVP and LBBP in patients with HFrEF and indications for CRT.MethodsWe searched PubMed/Medline, Web of Science, and Cochrane Library from the inception of the database to November 2022. All studies that compared LBBP with BVP in patients with HFrEF and indications for CRT were included. Two reviewers performed study selection, data abstraction, and risk of bias assessment. We calculated risk ratios (RRs) with the Mantel–Haenszel method and mean difference (MD) with inverse variance using random effect models. We assessed heterogeneity using the I2 index, with I2 > 50% indicating significant heterogeneity.ResultsTen studies (9 observational studies and 1 randomized controlled trial; 616 patients; 15 centers) published between 2020 and 2022 were included. We observed a shorter fluoroscopy time (MD: 9.68, 95% confidence interval [CI]: 4.49–14.87, I2 = 95%, p < .01, minutes) as well as a shorter procedural time (MD 33.68, 95% CI: 17.80–49.55, I2 = 73%, p < .01, minutes) during the implantation of LBBP CRT compared to conventional BVP CRT. LBBP was shown to have a greater reduction in QRS duration (MD 25.13, 95% CI: 20.06–30.20, I2 = 51%, p < .01, milliseconds), a greater left ventricular ejection fraction improvement (MD: 5.80, 95% CI: 4.81–6.78, I2 = 0%, p < .01, percentage), and a greater left ventricular end‐diastolic diameter reduction (MD: 2.11, 95% CI: 0.12–4.10, I2 = 18%, p = .04, millimeter). There was a greater improvement in New York Heart Association function class with LBBP (MD: 0.37, 95% CI: 0.05–0.68, I2 = 61%, p = .02). LBBP was also associated with a lower risk of a composite of heart failure hospitalizations (HFH) and all‐cause mortality (RR: 0.48, 95% CI: 0.25–0.90, I2 = 0%, p = .02) driven by reduced HFH (RR: 0.39, 95% CI: 0.19–0.82, I2 = 0%, p = .01). However, all‐cause mortality rates were low in both groups (1.52% vs. 1.13%) and similar (RR: 0.98, 95% CI: 0.21–4.68, I2 = 0%, p = .87).ConclusionThis meta‐analysis of primarily nonrandomized studies suggests that LBBP is associated with a greater improvement in left ventricular systolic function and a lower rate of HFH compared to BVP. There was uniformity of these findings in all of the included studies. However, it would be premature to conclude based solely on the current meta‐analysis alone, given the limitations stated. Dedicated, well‐designed, randomized controlled trials and observational studies are needed to elucidate better the comparative long‐term efficacy and safety of LBBP CRT versus BIV CRT.

Abstract Background Alzheimer’s disease (AD) is a progressive neurological disorder with no specific curative medications. Sophisticated clinical skills are crucial to optimize treatment regimens given the multiple coexisting comorbidities in the patient population. Objective Here, we propose a study to leverage reinforcement learning (RL) to learn the clinicians’ decisions for AD patients based on the longitude data from electronic health records. Methods In this study, we selected 1736 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We focused on the two most frequent concomitant diseases—depression, and hypertension, thus creating 5 data cohorts (ie, Whole Data, AD, AD-Hypertension, AD-Depression, and AD-Depression-Hypertension). We modeled the treatment learning into an RL problem by defining states, actions, and rewards. We built a regression model and decision tree to generate multiple states, used six combinations of medications (ie, cholinesterase inhibitors, memantine, memantine-cholinesterase inhibitors, hypertension drugs, supplements, or no drugs) as actions, and Mini-Mental State Exam (MMSE) scores as rewards. Results Given the proper dataset, the RL model can generate an optimal policy (regimen plan) that outperforms the clinician’s treatment regimen. Optimal policies (ie, policy iteration and Q-learning) had lower rewards than the clinician’s policy (mean −3.03 and −2.93 vs. −2.93, respectively) for smaller datasets but had higher rewards for larger datasets (mean −4.68 and −2.82 vs. −4.57, respectively). Conclusions Our results highlight the potential of using RL to generate the optimal treatment based on the patients’ longitude records. Our work can lead the path towards developing RL-based decision support systems that could help manage AD with comorbidities.

Abstract Defects in the homologous recombination (HR) pathway, particularly in BRCA2, are of particular therapeutic relevance in mCRPC as they confer sensitivity to PARP inhibitors (PARPi). Nevertheless, durable responses to PARPi remain elusive and primary resistance is an additional major challenge. As a result, dissecting therapeutic vulnerabilities in HR-aberrant patients is crucial and may reveal novel PARPi-based combinations for evaluation in future clinical trials.In this multi-institutional study, we used the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay that assesses 152 genes to profile plasma from 375 mCRPC patients from Australia and the USA. Reportable alterations included pathogenic single-nucleotide (somatic and germline) and copy number variants. Association between alterations and clinical outcomes were assessed using log rank, cox proportional, and chi-squared analyses.Overall, 65 patients (17%) had evidence of a pathogenic BRCA2 aberration, which were commonly hemizygous (78% vs 22% homozygous deletions), monoallelic (70% vs 30% bi-allelic), somatic (87% vs 13% germline), and clonal (83% vs 17% subclonal) in nature. There was no significant difference in plasma tumour fraction in patients with single vs two-copy loss of BRCA2, and BRCA2 zygosity did not have differing effects on outcomes, with both being similarly associated with shorter overall survival (HR 0.48, p&lt;0.002, and HR 0.45, p=0.003, respectively). Pathogenic BRCA1 aberrations were present in 10 patients (3%). PSA response rates to androgen-receptor pathway inhibitors (ARPI) were significantly lower in patients with a BRCA1 and/or a BRCA2 aberration (32% vs 60%, p=0.02), and we observed this BRCA-defective subgroup to be enriched for AR aberrations (71% had &gt;1 AR aberration vs 38% in BRCA-intact patients, p=0.001). BRCA-defective cancers were also significantly enriched for aberrations in key neuroendocrine markers TP53 (62% vs 28%), RB1 (60% vs 17%), and MYC (27% vs 9%), as well as for PI3K pathway aberrations (PTEN 63% vs 25% and PIK3CA 37% vs 14%). In summary, we show that BRCA alterations are associated with worse prognosis in mCRPC and reduced benefit from ARPI, and that the prognostic and predictive utility of cfDNA-detected BRCA2 may be independent of zygosity state, potentially due to constraints with copy number loss identification in samples with low tumour DNA. Additionally, on top of a high proportion of AR alterations, BRCA-defective cancers were also enriched in a number of potentially actionable targets and neuroendocrine markers. Clinical trials that leverage rational co-targeting strategies will provide an opportunity to enhance the efficacy of PARPi in mCRPC. Citation Format: Heidi Fettke, Chao Dai, Edmond M. Kwan, Tiantian Zheng, Winston Tan, P Du, Nicole Ng, Patricia Bukszynska, Maria Docanto, L K. Graham, Kate Mahon, Lisa G. Horvath, Shidong Jia, Manish Kohli, Arun A. Azad. Adverse clinical outcomes and distinct genomic phenotype of BRCA-deficient metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2303.

AbstractIt has been challenging to target mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity. In this regard, SOS1 inhibition has arisen as an attractive approach for mKRAS CRC given its essential role as a guanine nucleotide exchange factor for this GTPase. Here, we demonstrated the translational value of SOS1 blockade in mKRAS CRC. We used CRC patient‐derived organoids (PDOs) as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406. A combination of in silico analyses and wet lab techniques was utilized to define potential predictive markers for SOS1 sensitivity and potential mechanisms of resistance in CRC. RNA‐seq analysis of CRC PDOs revealed two groups of CRC PDOs with differential sensitivities to SOS1 inhibitor BI3406. The resistant group was enriched in gene sets involving cholesterol homeostasis, epithelial−mesenchymal transition, and TNF‐α/NFκB signaling. Expression analysis identified a significant correlation between SOS1 and SOS2 mRNA levels (Spearman's ρ 0.56, p < 0.001). SOS1/2 protein expression was universally present with heterogeneous patterns in CRC cells but only minimal to none in surrounding nonmalignant cells. Only SOS1 protein expression was associated with worse survival in patients with RAS/RAF mutant CRC (p = 0.04). We also found that SOS1/SOS2 protein expression ratio >1 by immunohistochemistry (p = 0.03) instead of KRAS mutation (p = 1) was a better predictive marker to BI3406 sensitivity of CRC PDOs, concordant with the significant positive correlation between SOS1/SOS2 protein expression ratio and SOS1 dependency. Finally, we showed that GTP‐bound RAS level underwent rebound even in BI3406‐sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1‐targeting agents in CRC.

PURPOSE Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy–proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

There is limited literature analyzing pediatric hurdle injuries based on sex and age. This study compares hurdle-related injury types, injured body parts, and injury mechanisms by age and sex in pediatrics. Hurdle-related injury data from the National Electronic Injury Surveillance System were used to retrospectively review the injuries of hurdlers 18 years and under. Differences in injured body parts, injury types, and mechanisms were analyzed by age (pre-high school vs. high school) and sex (male vs. female). A total of 749 cases were extracted. Fractures were more common in pre-high schoolers (34.1% vs. 21.5%, p = 0.001), while more sprains were identified in high schoolers (29.6%) than pre-high schoolers (22.8%, p = 0.036). Males suffered more fractures than females (35.1% vs. 24.3%, p = 0.001). Females sustained more joint sprains (29.1% vs. 21.0%, p = 0.012) and contusions/hematomas (12.7% vs. 7.5%, p = 0.020). Ankle injuries were more common in females (24.0%) than males (12.0%, p = 0.001), while wrist injuries were more prevalent in males (11.7% vs. 7.2%, p = 0.034). The most common injury mechanism was apparatus-related, with no differences based on age or sex. Injury types and injured body parts differed depending on age and sex in pediatric hurdle injuries seen in emergency departments. These findings may be helpful for injury prevention and medical care for pediatric hurdlers.