Citations

BACKGROUND AND OBJECTIVES: Consensus guidelines do not exist to guide the role of stereotactic radiosurgery (SRS) in the management of patients with Spetzler-Martin Grade III-V arteriovenous malformations (AVMs). We sought to establish SRS practice guidelines for Grade III-V AVMs based on a critical systematic review of the published literature. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant search of Medline, Embase, and Scopus, 1986 to 2023, for publications reporting post-SRS outcomes in ≥10 Grade III-V AVMs with the median follow-up ≥24 months was performed. Primary end points were AVM obliteration and post-SRS hemorrhage. Secondary end points included dosimetric variables, Spetzler-Martin parameters, and neurological outcome. RESULTS : In total, 2463 abstracts were screened, 196 manuscripts were reviewed, and 9 met the strict inclusion criteria. The overall sample of 1634 AVMs consisted of 1431 Grade III (88%), 186 Grade IV (11%), and 11 Grade V lesions (1%). Total median post-SRS follow-up was 53 months for Grade III and 43 months for Grade IV-V AVMs (ranges, 2-290; 12-262). For Grade III AVMs, the crude obliteration rate was 72%, and among Grade IV-V lesions, the crude obliteration rate was 46%. Post-SRS hemorrhage was observed in 7% of Grade III compared with 17% of Grade IV-V lesions. Major permanent deficits or death from hemorrhage or radiation-induced complications occurred in 86 Grade III (6%) and 22 Grade IV-V AVMs (12%). CONCLUSION: Most patients with Spetzler-Martin Grade III AVMs have favorable SRS treatment outcomes; however, the obliteration rate for Grade IV-V AVMs is less than 50%. The available studies are heterogenous and lack nuanced, long-term, grade-specific outcomes.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Insulin is a key regulator of amino acid metabolism. Many plasma amino acids, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance (IR). In 18 overweight women with IR and polycystic ovary syndrome compared with 12 lean control women, high physiological insulin during a euglycemic clamp failed to normalize many elevated amino acid metabolites, including branched-chain and aromatic amino acids, α-aminobutyric acid, and lysine, but normalized α-AA. To understand the underpinnings of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared with control participants, we developed a kinetic model using [α-15N1]-lysine and [13C1]-α-AA as tracers and measured the two tracers simultaneously in α-AA by innovative mass spectrometry. High insulin increased lysine conversion to α-AA in the IR and control groups but failed to normalize plasma lysine concentrations in IR due to a decrease in lysine metabolic clearance rate (MCR). In contrast, despite higher conversion rates of lysine to α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal amino acids and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR. Article Highlights

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

ABSTRACT Background The unfolded protein response (UPR) is a proteostatic process that is activated in response to endoplasmic reticulum stress. It is currently unclear how aging influences the chronic and adaptive UPR in human skeletal muscle. Here we determined the effect of aging on UPR activation at rest, in response to exercise, and the associations with muscle function. Methods Thirty young (20–35 yr) and 50 older (65–85 yr) individuals were enrolled. Vastus lateralis biopsies were performed at rest and 3 and 48 h after a single bout of resistance exercise. The abundance of UPR-related transcripts and proteins was measured by RNA sequencing and Western blotting, respectively. Fractional synthetic rates of muscle protein were determined by mass spectrometry after intravenous infusion of 13 C 6 phenylalanine. Results Older adults demonstrated elevated transcriptional and proteomic markers of UPR activation in resting muscle. Resting UPR gene expression was negatively associated with muscle strength and power in older adults. The UPR is similarly activated by acute resistance exercise in young and older adults and positively associated with muscle function but not the anabolic response to exercise. Conclusions Skeletal muscle from older adults exhibits chronically activated UPR, which accompanies functional decline. The adaptive UPR is a proteostatic mechanism that is upregulated in response to exercise in young and older adults and positively associated with muscle function.

9000 Background: Despite IMGs accounting for up to one-third of all practicing oncologists in the United States, little is known about their contributions to presentations at international oncology meetings, such as the American Society of Clinical Oncology (ASCO). Therefore, we investigated the representation of IMGs in invited faculty roles at ASCO Annual Meetings. Methods: Speaker presentation details at ASCO 2022 and 2023 Annual Meetings were collected using publicly available program guides. We collected presentation-level variables of invited faculty roles (discussant, moderator, chairmanship, session topic presenter) and original research type (oral abstract, poster discussion, plenary session). Speaker-level variables comprised presumed gender, academic rank, and institution. Speakers were categorized into the following groups - American Medical Graduate (AMG): currently affiliated with a US institution, completed medical school in the US; IMG: affiliated with a US institution, completed medical school outside the US; non-US based speakers: affiliated with an institution outside the US; non-MD speakers. Univariable and multivariable analyses were employed to assess factors associated with the selection of presenters for invited faculty roles. Results: A total of 3337 presentations (1649 from 2022, 1688 from 2023) were included. 71.6% of the speakers were US-based, 56.6% were male and 40.5% were full professors. The highest proportion of podium presentations was by AMGs (48.5%), followed by non-US based (28.3%), IMGs (14.1%), and non-MD (9.1%) speakers. 57% of IMG presentations consisted of original research compared to 48.7% for AMGs (Table). Notably, compared to AMGs, IMGs were significantly less likely to be included in invited faculty roles (odds ratio [OR] 0.72 [95% CI 0.58 – 0.88], p <0.01), a finding that remained significant after accounting for gender and academic rank (adjusted OR 0.75 [0.61 – 0.94], p= 0.01). Conclusions: Relative to IMGs’ original research output, IMGs appear to receive less invitations for ASCO Annual Meeting invited faculty roles compared to AMGs. Our findings suggest potential under-representation and under-recognition of IMGs in these roles, despite their contributions to the oncology workforce in the US. [Table: see text]

BACKGROUND AND OBJECTIVES: Repeat stereotactic radiosurgery (SRS) for residual arteriovenous malformations (AVMs) can be considered as a salvage approach after failure of initial SRS. There are no published guidelines regarding patient selection, timing, or SRS parameters to guide clinical practice. This systematic review aimed to review outcomes and complications from the published literature to inform practice recommendations provided on behalf of the International Stereotactic Radiosurgery Society. METHODS: We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of MEDLINE, Scopus, Web of Science, and Embase was conducted. Fourteen studies with 925 patients met the inclusion criteria. Patients were treated between 1985 and 2022. All studies were retrospective, except for one prospective cohort. RESULTS: The median patient age at repeat SRS ranged from 32 to 60 years. Four studies (630 patients) reported detailed information on Spetzler–Martin grade at the time of repeat SRS; 12.54% of patients had Spetzler–Martin grade I AVMs (79/630 patients), 46.51% had grade II (293/630), 34.92% had grade III (220/630), 5.08% had grade IV (32/630), and 0.95% had grade V (6/630). The median prescription doses varied between 15 and 25 Gy (mean, 13.06-22.8 Gy). The pooled overall obliteration rate at the last follow-up after repeat SRS was 59% (95% CI 51%-67%) with a median follow-up between 21 and 50 months. The pooled hemorrhage incidence at the last follow-up was 5% (95% CI 4%-7%), and the pooled overall radiation-induced change incidence was 12% (95% CI 7%-20%). CONCLUSION: For an incompletely obliterated AVM, repeat radiosurgery after 3 to 5 years of follow-up from the first SRS provides a reasonable benefit to the risk profile. After repeat SRS, obliteration is achieved in the majority of patients. The risk of hemorrhage or radiation-induced change appears low, and International Stereotactic Radiosurgery Society recommendations are presented.

Objective To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short‐term surgical complications requiring a return to the operating room and 30‐day mortality utilizing data from the Multi‐Institutional Study on Tracheotomy (MIST). Methods A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications. Results Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy ( p = 0.001). Morbidly obese patients (BMI ≥35 kg/m 2 ) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%–75%]: 11.0 days [7–17 days] versus 9.0 days [5–14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days ( p = 0.12) or mortality ( p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%–75%]: 10.0 days [6–15 days] versus 10.0 days [6–15 days]; p = 0.36). Conclusion BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days. Level of Evidence 3 Laryngoscope , 134:4674–4681, 2024