Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract.

Background: The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. Purpose: We sought to evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP). Methods: C57BL/6J mice were subjected to total abdominal irradiation (11-14 Gy single fraction) under conventional irradiation (low DPP and low MDR, CONV) and various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. The effects of DPP were evaluated for DPPs of 1-6 Gy while the total dose and MDR were kept constant; the effects of MDR were evaluated for the range 0.3- 1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay. Results: Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to better sparing of regenerating crypts, with a more prominent effect seen at 12 and 14 Gy TAI. However, at fixed DPPs >4 Gy, similar sparing of crypts was demonstrated irrespective of MDR (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV for all MDRs from 0.3 Gy/s to 104 Gy/s, but at a lower DPP of 0.93 Gy, increasing MDR produced a greater survival effect. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model. Conclusions: This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.

What Complexity Science Predicts About the Potential of Artificial Intelligence/Machine Learning to Improve Primary Care.

Primary care physicians are likely both excited and apprehensive at the prospects for artificial intelligence (AI) and machine learning (ML). Complexity science may provide insight into which AI/ML applications will most likely affect primary care in the future. AI/ML has successfully diagnosed some diseases from digital images, helped with administrative tasks such as writing notes in the electronic record by converting voice to text, and organized information from multiple sources within a health care system. AI/ML has less successfully recommended treatments for patients with complicated single diseases such as cancer; or improved diagnosing, patient shared decision making, and treating patients with multiple comorbidities and social determinant challenges. AI/ML has magnified disparities in health equity, and almost nothing is known of the effect of AI/ML on primary care physician-patient relationships. An intervention in Victoria, Australia showed promise where an AI/ML tool was used only as an adjunct to complex medical decision making. Putting these findings in a complex adaptive system framework, AI/ML tools will likely work when its tasks are limited in scope, have clean data that are mostly linear and deterministic, and fit well into existing workflows. AI/ML has rarely improved comprehensive care, especially in primary care settings, where data have a significant number of errors and inconsistencies. Primary care should be intimately involved in AI/ML development, and its tools carefully tested before implementation; and unlike electronic health records, not just assumed that AI/ML tools will improve primary care work life, quality, safety, and person-centered clinical decision making.

Storylines of family medicine VIII: clinical approaches.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VIII: clinical approaches', authors address the following themes: 'Evaluation, diagnosis and management I-toward a working diagnosis', 'Evaluation, diagnosis and management II-process steps', 'Interweaving integrative medicine and family medicine', 'Halfway-the art of clinical judgment', 'Seamless integration in family medicine-team-based care', 'Technology-uncovering stories from noise' and 'Caring for patients with multiple long-term conditions'. May readers recognise in these essays the uniqueness of a family medicine approach to care.

Utility of intracranial pressure monitoring as a diagnostic tool in pediatric ventriculomegaly.

OBJECTIVE: Intracranial pressure (ICP) monitoring is commonly utilized for identifying pathologic ICP in cases of traumatic brain injury; however, its utility in hydrocephalic children has not been elucidated. Although patients with typical (pressure-active) hydrocephalus present with clear signs and/or symptoms and the need for cerebrospinal fluid (CSF) diversion is often clear, others may have arrested or pressure-compensated hydrocephalus with pathologic ICP elevation masked by ambiguous signs or are completely asymptomatic. Without treatment these pathologic ICP elevations may affect neurologic development or crescendo over time leading to neurological decline. The purpose of this study is to investigate the utility of ICP monitoring as a diagnostic tool in this relatively common patient population and identify ventriculomegaly patients with and without pathologic ICP, thus improving accuracy of identifying those with and without surgical needs. METHODS: 36 patients (≤ 17 years old) underwent 41 inpatient ICP recording sessions between 2016 and 2022 and were retrospectively reviewed. This included patients with a history of severe, nonprogressive ventriculomegaly and normal fundoscopic examinations lacking traditional signs and symptoms concerning for elevated ICP. Nighttime pathological plateau waves were defined as sustained elevations of ICP ≥ 2x baseline for a duration of ≥ 5 minutes. RESULTS: The mean age of patients was 5.5 years old (range 0-17 years old). 46.3% of patients had prior endoscopic third ventriculostomy (ETV), 14.6% had prior ventriculoperitoneal shunt (VPS), and 39% were without prior surgical intervention. Roughly half (51.2%) of patients had congenital ventriculomegaly while other patients had ventriculomegaly due to other pathologies such as germinal matrix hemorrhage/intraventricular hemorrhage (GMH/IVH) (29.3%), stroke (4.9%), cerebral infections/meningitis (2.4%), or unknown etiology (12.2%). The average procedure time was 19.1 ± 10.5 minutes, and mean length of stay was 2.8 ± 0.7 days. Pathologic ICP was demonstrated in 12 cases (29.3%), 4 (33.3%) of which were asymptomatic. Pathologic ICP was found in 7 of 19 (36.8%) in the prior ETV group, 1 of 6 (16.7%) in prior shunt group, and 4 of 16 (25%) in the non-surgical group (p = 0.649). Among those with pathologic ICP, 6 (50%) cases received an ETV, 5 (41.7%) cases underwent VPS placement, and 1 (8.3%) case underwent a VPS revision. There were no infectious complications or cases of hemorrhage. 4 patients required repositioning of the ICP monitor due to dislodgement. CONCLUSION: Inpatient ICP monitoring is a safe and effective diagnostic tool for evaluating the presence of pathologic ICP in severe, persistent non-progressive ventriculomegaly. The use of ICP monitoring may aid in identifying patients with pressure-compensated hydrocephalus who demonstrate pathologic ICP where surgical intervention may be warranted, while preventing unnecessary CSF diversion in those without pathology.

Artificial Intelligence-Generated Draft Replies to Patient Inbox Messages.

Importance: The emergence and promise of generative artificial intelligence (AI) represent a turning point for health care. Rigorous evaluation of generative AI deployment in clinical practice is needed to inform strategic decision-making. Objective: To evaluate the implementation of a large language model used to draft responses to patient messages in the electronic inbox. Design, Setting, and Participants: A 5-week, prospective, single-group quality improvement study was conducted from July 10 through August 13, 2023, at a single academic medical center (Stanford Health Care). All attending physicians, advanced practice practitioners, clinic nurses, and clinical pharmacists from the Divisions of Primary Care and Gastroenterology and Hepatology were enrolled in the pilot. Intervention: Draft replies to patient portal messages generated by a Health Insurance Portability and Accountability Act-compliant electronic health record-integrated large language model. Main Outcomes and Measures: The primary outcome was AI-generated draft reply utilization as a percentage of total patient message replies. Secondary outcomes included changes in time measures and clinician experience as assessed by survey. Results: A total of 197 clinicians were enrolled in the pilot; 35 clinicians who were prepilot beta users, out of office, or not tied to a specific ambulatory clinic were excluded, leaving 162 clinicians included in the analysis. The survey analysis cohort consisted of 73 participants (45.1%) who completed both the presurvey and postsurvey. In gastroenterology and hepatology, there were 58 physicians and APPs and 10 nurses. In primary care, there were 83 physicians and APPs, 4 nurses, and 8 clinical pharmacists. The mean AI-generated draft response utilization rate across clinicians was 20%. There was no change in reply action time, write time, or read time between the prepilot and pilot periods. There were statistically significant reductions in the 4-item physician task load score derivative (mean [SD], 61.31 [17.23] presurvey vs 47.26 [17.11] postsurvey; paired difference, -13.87; 95% CI, -17.38 to -9.50; P < .001) and work exhaustion scores (mean [SD], 1.95 [0.79] presurvey vs 1.62 [0.68] postsurvey; paired difference, -0.33; 95% CI, -0.50 to -0.17; P < .001). Conclusions and Relevance: In this quality improvement study of an early implementation of generative AI, there was notable adoption, usability, and improvement in assessments of burden and burnout. There was no improvement in time. Further code-to-bedside testing is needed to guide future development and organizational strategy.

BTN1A1 is a novel immune checkpoint mutually exclusive to PD-L1.

BACKGROUND: While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized. METHODS: BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, followed by the development of a BTN1A1-specific antibody that was administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition. RESULTS: BTN1A1 was confirmed to suppress T-cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of Janus-activated kinase/signal transducer and activator of transcription signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice. CONCLUSION: Together, these results confirm that the potential of BTN1A1 is a bona fide immune checkpoint and a viable immunotherapeutic target for the treatment of individuals with anti-PD-1/PD-L1 refractory or resistant disease, opening new avenues to improving survival outcomes for patients with a range of cancers.

AI-guided histopathology predicts brain metastasis in lung cancer patients.

Brain metastases can occur in nearly half of patients with early and locally advanced (stage I-III) non-small cell lung cancer (NSCLC). There are no reliable histopathologic or molecular means to identify those who are likely to develop brain metastases. We sought to determine if deep learning (DL) could be applied to routine H&E-stained primary tumor tissue sections from stage I-III NSCLC patients to predict the development of brain metastasis. Diagnostic slides from 158 patients with stage I-III NSCLC followed for at least 5 years for the development of brain metastases (Met+, 65 patients) versus no progression (Met-, 93 patients) were subjected to whole-slide imaging. Three separate iterations were performed by first selecting 118 cases (45 Met+, 73 Met-) to train and validate the DL algorithm, while 40 separate cases (20 Met+, 20 Met-) were used as the test set. The DL algorithm results were compared to a blinded review by four expert pathologists. The DL-based algorithm was able to distinguish the eventual development of brain metastases with an accuracy of 87% (p < 0.0001) compared with an average of 57.3% by the four pathologists and appears to be particularly useful in predicting brain metastases in stage I patients. The DL algorithm appears to focus on a complex set of histologic features. DL-based algorithms using routine H&E-stained slides may identify patients who are likely to develop brain metastases from those who will remain disease free over extended (>5 year) follow-up and may thus be spared systemic therapy. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effectiveness of an Artificial Intelligence-Enabled Intervention for Detecting Clinical Deterioration.

Importance: Inpatient clinical deterioration is associated with substantial morbidity and mortality but may be easily missed by clinicians. Early warning scores have been developed to alert clinicians to patients at high risk of clinical deterioration, but there is limited evidence for their effectiveness. Objective: To evaluate the effectiveness of an artificial intelligence deterioration model-enabled intervention to reduce the risk of escalations in care among hospitalized patients using a study design that facilitates stronger causal inference. Design, Setting, and Participants: This cohort study used a regression discontinuity design that controlled for confounding and was based on Epic Deterioration Index (EDI; Epic Systems Corporation) prediction model scores. Compared with other observational research, the regression discontinuity design facilitates causal analysis. Hospitalized adults were included from 4 general internal medicine units in 1 academic hospital from January 17, 2021, through November 16, 2022. Exposure: An artificial intelligence deterioration model-enabled intervention, consisting of alerts based on an EDI score threshold with an associated collaborative workflow among nurses and physicians. Main Outcomes and Measures: The primary outcome was escalations in care, including rapid response team activation, transfer to the intensive care unit, or cardiopulmonary arrest during hospitalization. Results: During the study, 9938 patients were admitted to 1 of the 4 units, with 963 patients (median [IQR] age, 76.1 [64.2-86.2] years; 498 males [52.3%]) included within the primary regression discontinuity analysis. The median (IQR) Elixhauser Comorbidity Index score in the primary analysis cohort was 10 (0-24). The intervention was associated with a -10.4-percentage point (95% CI, -20.1 to -0.8 percentage points; P = .03) absolute risk reduction in the primary outcome for patients at the EDI score threshold. There was no evidence of a discontinuity in measured confounders at the EDI score threshold. Conclusions and Relevance: Using a regression discontinuity design, this cohort study found that the implementation of an artificial intelligence deterioration model-enabled intervention was associated with a significantly decreased risk of escalations in care among inpatients. These results provide evidence for the effectiveness of this intervention and support its further expansion and testing in other care settings.

Survival outcomes and toxicity of adjuvant immunotherapy after definitive concurrent chemotherapy with proton beam radiation therapy for patients with inoperable locally advanced non-small cell lung carcinoma.

INTRODUCTION: Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC. MATERIALS AND METHODS: We analyzed 354 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009 to 2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT + IO patients. Survival was estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards regression evaluated the effect of IO on disease outcomes. RESULTS: Median age was 70 years; 71 (20%) received CPBT + IO and 283 (80%) received CPBT only. After PSM, 71 CPBT patients were matched with 71 CPBT + IO patients. Three-year survival rates for CPBT + IO vs CPBT were: OS 67% vs 30% (P < 0.001) and PFS 59% vs 35% (P = 0.017). Three-year LRFS (P = 0.137) and DMFS (P = 0.086) did not differ. Receipt of adjuvant IO was a strong predictor of OS (HR 0.40, P = 0.001) and PFS (HR 0.56, P = 0.030), but not LRFS (HR 0.61, P = 0.121) or DMFS (HR 0.61, P = 0.136). There was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT + IO vs 17% CPBT, P = 0.037). CONCLUSION: This study, one of the first to investigate CPBT followed by IO for inoperable LA-NSCLC, showed that IO conferred survival benefits with no increased rates of toxicity.

Thrombectomy in Stroke Patients With Low Alberta Stroke Program Early Computed Tomography Score: Is Modified Thrombolysis in Cerebral Infarction (mTICI) 2c/3 Superior to mTICI 2b?

BACKGROUND AND PURPOSE: Outcomes following mechanical thrombectomy (MT) are strongly correlated with successful recanalization, traditionally defined as modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b. This retrospective cohort study aimed to compare the outcomes of patients with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS; 2-5) who achieved mTICI 2b versus those who achieved mTICI 2c/3 after MT. METHODS: This study utilized data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combined databases from 32 thrombectomy-capable stroke centers between 2013 and 2023. The study included only patients with low ASPECTS who achieved mTICI 2b, 2c, or 3 after MT for internal carotid artery or middle cerebral artery (M1) stroke. RESULTS: Of the 10,229 patients who underwent MT, 234 met the inclusion criteria. Of those, 98 (41.9%) achieved mTICI 2b, and 136 (58.1%) achieved mTICI 2c/3. There were no significant differences in baseline characteristics between the two groups. The 90-day favorable outcome (modified Rankin Scale score: 0-3) was significantly better in the mTICI 2c/3 group than in the mTICI 2b group (adjusted odds ratio 2.35; 95% confidence interval [CI] 1.18-4.81; P=0.02). Binomial logistic regression revealed that achieving mTICI 2c/3 was significantly associated with higher odds of a favorable 90-day outcome (odds ratio 2.14; 95% CI 1.07-4.41; P=0.04). CONCLUSION: In patients with low ASPECTS, achieving an mTICI 2c/3 score after MT is associated with a more favorable 90-day outcome. These findings suggest that mTICI 2c/3 is a better target for MT than mTICI 2b in patients with low ASPECTS.

Building Pandemic-Resilient Primary Care Systems: Lessons Learned From COVID-19.

On January 30, 2023, the Biden Administration announced its intention to end the existing COVID-19 public health emergency declaration. The transition to a "postpandemic" landscape presents a unique opportunity to sustain and strengthen pandemic-era changes in care delivery. With this in mind, we present 3 critical lessons learned from a primary care perspective during the COVID-19 pandemic. First, clinical workflows must support both in-person and internet-based care delivery. Second, the integration of asynchronous care delivery is critical. Third, planning for the future means planning for everyone, including those with potentially limited access to health care due to barriers in technology and communication. While these lessons are neither unique to primary care settings nor all-encompassing, they establish a grounded foundation on which to construct higher-quality, more resilient, and more equitable health systems.

The LRRK2 kinase substrates RAB8a and RAB10 contribute complementary but distinct disease-relevant phenotypes in human neurons.

Mutations in the LRRK2 gene cause familial Parkinson's disease presenting with pleomorphic neuropathology that can involve α-synuclein or tau accumulation. LRRK2 mutations are thought to converge upon a pathogenic increase in LRRK2 kinase activity. A subset of small RAB GTPases has been identified as LRRK2 substrates, with LRRK2-dependent phosphorylation resulting in RAB inactivation. We used CRISPR-Cas9 genome editing to generate a novel series of isogenic iPSC lines deficient in the two most well-validated LRRK2 substrates, RAB8a and RAB10, from deeply phenotyped healthy control lines. Thorough characterization of NGN2-induced neurons revealed opposing effects of RAB8a and RAB10 deficiency on lysosomal pH and Golgi organization, with isolated effects of RAB8a and RAB10 ablation on α-synuclein and tau, respectively. Our data demonstrate largely antagonistic effects of genetic RAB8a or RAB10 inactivation, which provide discrete insight into the pathologic features of their biochemical inactivation by pathogenic LRRK2 mutation in human disease.

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation in Unresectable EGFR-Mutant NSCLC: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. METHODS: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used. RESULTS: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3). CONCLUSIONS: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. METHODS AND MATERIALS: Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P = .003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P = .002), and planning treatment volume (P = .033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P = .011). CONCLUSIONS: This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

Metformin in Conjunction With Stereotactic Radiotherapy for Early-stage Non-small Cell Lung Cancer: Long-term Results of a Prospective Phase II Clinical Trial.

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC. PATIENTS AND METHODS: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure (LF), progression-free survival (PFS), overall survival (OS), and Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicities. RESULTS: There were 14 patients randomized to the metformin arm and one to the placebo. Median follow-up was four years. In the metformin group, the median PFS was 4.65 years [95% confidence interval (CI)=0.31-5.93] and median survival was 4.97 years (95%CI=3.05-4.61). Five year PFS was 27.8% (95%CI=5.3-57.3%) and OS was 46.0% (95%CI=16.0-71.9%). The one patient randomized to placebo was alive and without progression at five years. There were no LFs in the primary SBRT treatment volumes and no CTCAE version 4 Grade ≥3 adverse events. CONCLUSION: Outcomes of SBRT and metformin for early-stage NSCLC were similar to historic controls. These findings along with the results of the NRG-LU001 and OCOG randomized trials do not support the therapeutic use of metformin for NSCLC.

Endovascular Treatment of Small Anterior Communicating Artery Aneurysms: Safety and Efficacy in a Contemporary Cohort.

BACKGROUND AND OBJECTIVES: Endovascular treatment (EVT) of small anterior communicating artery (ACoA) aneurysms accompanies a high risk of intraprocedural rupture (IR) because of anatomic location and aneurysm orientation. In this study, we aimed to investigate the safety and efficacy of EVT for small ACoA aneurysms in a contemporary cohort. METHODS: ACoA aneurysms treated at the Medical University of South Carolina between April 2012 and March 2022 were retrospectively analyzed. Periprocedural baseline characteristics, aneurysm size, and clinical and radiological outcomes were collected. Aneurysms were dichotomized into <4 and ≥4 mm in maximum size. The IR rate, favorable occlusion rate (Raymond-Roy I and II), and the favorable outcome defined as modified Rankin Scale 0-2 were compared. RESULTS: A total of 174 patients were identified, of whom 111 (63.8%) were female, and the median age was 57.7 (interquartile range 50.6-69.6) years. 98 (56.3%) aneurysms were ruptured, and 53 (30.5%) were <4 mm. IR was not observed in unruptured ACoA aneurysms, and there was no significant difference in the IR rates between <4 mm and ≥4 mm ruptured aneurysms (6.5% vs 4.5%, P = .65). Favorable occlusion rate and favorable outcome were observed in 94.7% and 78.2% of patients, respectively. CONCLUSION: EVT of small ACoA aneurysms is safe and effective.

Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models.

Background: Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC. Methods: Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, radiotherapy duration, chemotherapy, mean heart and lung doses, and thoracic vertebrae V20Gy. MDACC predictors for grade 4 lymphopenia were age, baseline lymphocyte count, planning target volume (PTV), and BMI. The external performance of both models was assessed. Results: Among 100 patients, 78 patients (78%) developed grade ≥3 lymphopenia, with grade 4 lymphopenia in 17 (17%). For predicting grade ≥3 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.77 and 0.79, respectively. For predicting grade 4 lymphopenia, c-statistics were 0.69 and 0.80, respectively. Calibration for the Christie and MDACC models demonstrated moderate and good agreement, respectively. Conclusion: The PTV-based MDACC prediction model for severe RIL demonstrated superior external performance in NSCLC patients compared to the dosimetry-based Christie model. As such, the MDACC model can aid in identifying patients at high risk for severe lymphopenia. However, to optimize radiotherapy planning, further improvement and external validation of dosimetry-based models is desired.

Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition.

Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation. Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS). Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.