Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch.

A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or ß3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis. They also showed altered fat distribution with markedly increased subcutaneous adiposity. Subcutaneous adipose tissue in mutant mice acquired many key properties of visceral fat, including decreased thermogenic and increased inflammatory gene expression and increased macrophage accumulation. Transplantation of subcutaneous fat into mice with diet-induced obesity showed a loss of metabolic benefit when tissues were derived from PRDM16 mutant animals. These findings indicate that PRDM16 and beige adipocytes are required for the "browning" of white fat and the healthful effects of subcutaneous adipose tissue.

Adipsin is an adipokine that improves ß cell function in diabetes.

A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic ß cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining ß cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with ß cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to ß cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM.

Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.

Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP:

TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis.

PGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases.

Mechanistic model for booster doses effectiveness in healthy, cancer, and immunosuppressed patients infected with SARS-CoV-2.

SARS-CoV-2 vaccines are effective at limiting disease severity, but effectiveness is lower among patients with cancer or immunosuppression. Effectiveness wanes with time and varies by vaccine type. Moreover, previously prescribed vaccines were based on the ancestral SARS-CoV-2 spike-protein that emerging variants may evade. Here, we describe a mechanistic mathematical model for vaccination-induced immunity. We validate it with available clinical data and use it to simulate the effectiveness of vaccines against viral variants with lower antigenicity, increased virulence, or enhanced cell binding for various vaccine platforms. The analysis includes the omicron variant as well as hypothetical future variants with even greater immune evasion of vaccine-induced antibodies and addresses the potential benefits of the new bivalent vaccines. We further account for concurrent cancer or underlying immunosuppression. The model confirms enhanced immunogenicity following booster vaccination in immunosuppressed patients but predicts ongoing booster requirements for these individuals to maintain protection. We further studied the impact of variants on immunosuppressed individuals as a function of the interval between multiple booster doses. Our model suggests possible strategies for future vaccinations and suggests tailored strategies for high-risk groups.

In silico dynamics of COVID-19 phenotypes for optimizing clinical management.

Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines, and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of comorbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age; comorbidities such as obesity, diabetes, and hypertension; and dysregulated immune response. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8+ T cells and sufficient control of the innate immune response. Furthermore, the best treatment-or combination of treatments-depends on the preinfection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.

Utility of Noncancerous Chest CT Features for Predicting Overall Survival and Noncancer Death in Patients With Stage I Lung Cancer Treated With Stereotactic Body Radiotherapy.

BACKGROUND. Noncancerous imaging markers can be readily derived from pre-treatment diagnostic and radiotherapy planning chest CT examinations. OBJECTIVE. The purpose of this article was to explore the ability of noncancerous features on chest CT to predict overall survival (OS) and noncancer-related death in patients with stage I lung cancer treated with stereotactic body radiation therapy (SBRT). METHODS. This retrospective study included 282 patients (168 female, 114 male; median age, 75 years) with stage I lung cancer treated with SBRT between January 2009 and June 2017. Pretreatment chest CT was used to quantify coronary artery calcium (CAC) score, pulmonary artery (PA)-to-aorta ratio, emphysema, and body composition in terms of the cross-sectional area and attenuation of skeletal muscle and subcutaneous adipose tissue at the T5, T8, and T10 vertebral levels. Associations of clinical and imaging features with OS were quantified using a multivariable Cox proportional hazards (PH) model. Penalized multivariable Cox PH models to predict OS were constructed using clinical features only and using both clinical and imaging features. The models' discriminatory ability was assessed by constructing time-varying ROC curves and computing AUC at prespecified times. RESULTS. After a median OS of 60.8 months (95% CI, 55.8-68.0), 148 (52.5%) patients had died, including 83 (56.1%) with noncancer deaths. Higher CAC score (11-399: hazard ratio [HR], 1.83 [95% CI, 1.15-2.91], p = .01; ≥ 400: HR, 1.63 [95% CI, 1.01-2.63], p = .04), higher PA-to-aorta ratio (HR, 1.33 [95% CI, 1.16-1.52], p < .001, per 0.1-unit increase), and lower thoracic skeletal muscle index (HR, 0.88 [95% CI, 0.79-0.98], p = .02, per 10-cm2/m2 increase) were independently associated with shorter OS. Discriminatory ability for 5-year OS was greater for the model including clinical and imaging features than for the model including clinical features only (AUC, 0.75 [95% CI, 0.68-0.83] vs 0.61 [95% CI, 0.53-0.70]; p < .01). The model's most important clinical or imaging feature according to mean standardized regression coefficients was the PA-to-aorta ratio. CONCLUSION. In patients undergoing SBRT for stage I lung cancer, higher CAC score, higher PA-to-aorta ratio, and lower thoracic skeletal muscle index independently predicted worse OS. CLINICAL IMPACT. Noncancerous imaging features on chest CT performed before SBRT improve survival prediction compared with clinical features alone.

Lung-RADS Category 3 and 4 Nodules on Lung Cancer Screening in Clinical Practice.

BACKGROUND. Lung-RADS category 3 and 4 nodules account for most screening-detected lung cancers and are considered actionable nodules with management implications. The cancer frequency among such nodules is estimated in the Lung-RADS recommendations and has been investigated primarily by means of retrospectively assigned Lung-RADS classifications. OBJECTIVE. The purpose of this study was to assess the frequency of cancer among lung nodules assigned Lung-RADS category 3 or 4 at lung cancer screening (LCS) in clinical practice and to evaluate factors that affect the cancer frequency within each category. METHODS. This retrospective study was based on review of clinical radiology reports of 9148 consecutive low-dose CT LCS examinations performed for 4798 patients between June 2014 and January 2021 as part of an established LCS program. Unique nodules assigned Lung-RADS category 3 or 4 (4A, 4B, or 4X) that were clinically categorized as benign or malignant in a multidisciplinary conference that considered histologic analysis and follow-up imaging were selected for further analysis. Benign diagnoses based on stability required at least 12 months of follow-up imaging. Indeterminate nodules were excluded. Cancer frequencies were evaluated. RESULTS. Of the 9148 LCS examinations, 857 (9.4%) were assigned Lung-RADS category 3, and 721 (7.9%) were assigned category 4. The final analysis included 1297 unique nodules in 1139 patients (598 men, 541 women; mean age, 66.0 ± 6.3 years). A total of 1108 of 1297 (85.4%) nodules were deemed benign, and 189 of 1297 (14.6%) were deemed malignant. The frequencies of malignancy of category 3, 4A, 4B, and 4X nodules were 3.9%, 15.5%, 36.3%, and 76.8%. A total of 45 of 46 (97.8%) endobronchial nodules (all category 4A) were deemed benign on the basis of resolution. Cancer frequency was 13.1% for solid, 24.4% for part-solid, and 13.5% for ground-glass nodules. CONCLUSION. In the application of Lung-RADS to LCS clinical practice, the frequency of Lung-RADS category 3 and 4 nodules and the cancer frequency in these categories were higher than the prevalence and cancer risk estimated for category 3 and 4 nodules in the Lung-RADS recommendations and those reported in earlier studies in which category assignments were retrospective. Nearly all endobronchial category 4A nodules were benign. CLINICAL IMPACT. Future Lung-RADS iterations should consider the findings of this study from real-world practice to improve the clinical utility of the system.

Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy.

The peroxisome-proliferator receptor-γ (PPARγ) is expressed in multiple cancer types. Recently, our group has shown that PPARγ is phosphorylated on serine 273 (S273), which selectively modulates the transcriptional program controlled by this protein. PPARγ ligands, including thiazolidinediones (TZDs), block S273 phosphorylation. This activity is chemically separable from the canonical activation of the receptor by agonist ligands and, importantly, these noncanonical agonist ligands do not cause some of the known side effects of TZDs. Here, we show that phosphorylation of S273 of PPARγ occurs in cancer cells on exposure to DNA damaging agents. Blocking this phosphorylation genetically or pharmacologically increases accumulation of DNA damage, resulting in apoptotic cell death. A genetic signature of PPARγ phosphorylation is associated with worse outcomes in response to chemotherapy in human patients. Noncanonical agonist ligands sensitize lung cancer xenografts and genetically induced lung tumors to carboplatin therapy. Moreover, inhibition of this phosphorylation results in deregulation of p53 signaling, and biochemical studies show that PPARγ physically interacts with p53 in a manner dependent on S273 phosphorylation. These data implicate a role for PPARγ in modifying the p53 response to cytotoxic therapy, which can be modulated for therapeutic gain using these compounds.

Early experience with hippocampal avoidance whole brain radiation therapy and simultaneous integrated boost for brain metastases.

PURPOSE: Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. MATERIALS AND METHODS: We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. RESULTS: A total of 32 patients (median age, 63.5 years, range 45.3-78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4 months and 19.6 months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). CONCLUSION: HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

Role of Epidermal Growth Factor Receptor (EGFR) Inhibitors and Radiation in the Management of Brain Metastases from EGFR Mutant Lung Cancers.

The growth of genotype-directed targeted therapies, such as inhibitors of the epidermal growth factor receptor (EGFR), has revolutionized treatment for some patients with oncogene-addicted lung cancer. However, as systemic control for these patients has improved, brain metastases remain an important source of morbidity and mortality. Traditional treatment for brain metastases has been radiotherapy, either whole-brain radiation or stereotactic radiosurgery. The growing availability of drugs that can cross the blood-brain barrier and have activity in the central nervous system (CNS) has led to many studies investigating whether targeted therapy can be used in combination with or in lieu of radiation. In this review, we summarize the key literature about the incidence and nature of EGFR-mutant brain metastases (EGFR BMs), the data about the activity of EGFR inhibitors in the CNS, and whether they can be used as front-line therapy for brain metastases. Although initial use of tyrosine kinase inhibitors for EGFR BMs can often be an effective treatment strategy, multidisciplinary evaluation is critical, and prospective studies are needed to clarify which patients may benefit from early radiotherapy. IMPLICATIONS FOR PRACTICE: Management of brain metastases in epidermal growth factor receptor (EGFR) mutant lung cancer is a common clinical problem. The question of whether to start initial therapy with an EGFR inhibitor or radiotherapy (either whole-brain radiotherapy or stereotactic radiosurgery) is controversial. The development of novel EGFR inhibitors with enhanced central nervous system (CNS) penetration is an important advance in the treatment of CNS disease. Multidisciplinary evaluation and evaluation of extracranial disease status are critical to choosing the best treatment option for each patient.

Assessment of multi-criteria optimization (MCO) for volumetric modulated arc therapy (VMAT) in hippocampal avoidance whole brain radiation therapy (HA-WBRT).

This study compared the dosimetric performance of (a) volumetric modulated arc therapy (VMAT) with standard optimization (STD) and (b) multi-criteria optimization (MCO) to (c) intensity modulated radiation therapy (IMRT) with MCO for hippocampal avoidance whole brain radiation therapy (HA-WBRT) in RayStation treatment planning system (TPS). Ten HA-WBRT patients previously treated with MCO-IMRT or MCO-VMAT on an Elekta Infinity accelerator with Agility multileaf collimators (5-mm leaves) were re-planned for the other two modalities. All patients received 30 Gy in 15 fractions to the planning target volume (PTV), namely, PTV30 expanded with a 2-mm margin from the whole brain excluding hippocampus with margin. The patients all had metastatic lesions (up to 12) of variable sizes and proximity to the hippocampus, treated with an additional 7.5 Gy from a simultaneous integrated boost (SIB) to PTV37.5. The IMRT plans used eight to eleven non-coplanar fields, whereas the VMAT plans used two coplanar full arcs and a vertex half arc. The averaged target coverage, dose to organs-at-risk (OARs) and monitor unit provided by the three modalities were compared, and a Wilcoxon signed-rank test was performed. MCO-VMAT provided statistically significant reduction of D100 of hippocampus compared to STD-VMAT, and Dmax of cochleas compared to MCO-IMRT. With statistical significance, MCO-VMAT improved V30 of PTV30 by 14.2% and 4.8%, respectively, compared to MCO-IMRT and STD-VMAT. It also raised D95 of PTV37.5 by 0.4 Gy compared to both MCO-IMRT and STD-VMAT. Improved plan quality parameters such as a decrease in overall plan Dmax and total monitor units (MU) were also observed for MCO-VMAT. MCO-VMAT is found to be the optimal modality for HA-WBRT in terms of PTV coverage, OAR sparing and delivery efficiency, compared to MCO-IMRT or STD-VMAT.

Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer.

UNLABELLED: : Genotype-based selection of patients for targeted therapies has had a substantial impact on the treatment of non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs) directed at cancers driven by oncogenes, such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, often achieve dramatic responses and result in prolonged survival compared with chemotherapy. However, TKI resistance invariably develops. Disease progression can be limited to only one or a few sites and might not be symptomatic, raising the important question of whether this type of oligoprogression warrants a change in systemic therapy or consideration of local treatment. Recent clinical observations suggest a growing role for stereotactic body radiation therapy (SBRT) in the treatment of oligoprogressive and perhaps even oligopersistent disease (primary and/or metastases) in oncogene-driven NSCLC. SBRT might allow patients to continue with existing TKI treatments longer and delay the need to switch to other systemic options. We review the current data with regard to the use of SBRT for metastatic NSCLC and particularly oncogene-driven disease. Although there is great promise in the marriage of targeted therapies with SBRT, prospective data are urgently needed. In the meantime, such strategies are being used in carefully selected patients, with risk-adapted SBRT dose-fractionation regimens used to optimize the therapeutic index. IMPLICATIONS FOR PRACTICE: Stereotactic body radiation therapy (SBRT) or SBRT-like treatments are increasingly being used for oligoprogression in patients with oncogene-driven non-small cell lung cancer. This approach allows patients to extend the duration of tyrosine kinase inhibitor therapy and has the potential to prolong survival times. Careful patient selection and risk-adapted radiation dosing is of critical importance to minimize toxicity and preserve patient quality of life.

Fat cells directly sense temperature to activate thermogenesis.

Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and ß-adrenergic signaling, but here we report that cool temperature (27-33 °C) can directly activate a thermogenic gene program in adipocytes in a cell-autonomous manner. White and beige fat cells respond to cool temperatures, but classic brown fat cells do not. Importantly, this activation in isolated cells is independent of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway downstream of the ß-adrenergic receptors. These findings provide an unusual insight into the role of adipose tissues in thermoregulation, as well as an alternative way to target nonshivering thermogenesis for treatment of obesity and metabolic diseases.

Dynamic heterogeneity in COVID-19: Insights from a mathematical model.

Critical illness, such as severe COVID-19, is heterogenous in presentation and treatment response. However, it remains possible that clinical course may be influenced by dynamic and/or random events such that similar patients subject to similar injuries may yet follow different trajectories. We deployed a mechanistic mathematical model of COVID-19 to determine the range of possible clinical courses after SARS-CoV-2 infection, which may follow from specific changes in viral properties, immune properties, treatment modality and random external factors such as initial viral load. We find that treatment efficacy and baseline patient or viral features are not the sole determinant of outcome. We found patients with enhanced innate or adaptive immune responses can experience poor viral control, resolution of infection or non-infectious inflammatory injury depending on treatment efficacy and initial viral load. Hypoxemia may result from poor viral control or ongoing inflammation despite effective viral control. Adaptive immune responses may be inhibited by very early effective therapy, resulting in viral load rebound after cessation of therapy. Our model suggests individual disease course may be influenced by the interaction between external and patient-intrinsic factors. These data have implications for the reproducibility of clinical trial cohorts and timing of optimal treatment.

In silico clinical studies for optimal COVID-19 vaccination schedules in patients with cancer.

This study introduces a tailored COVID-19 model for patients with cancer, incorporating viral variants and immune-response dynamics. The model aims to optimize vaccination strategies, contributing to personalized healthcare for vulnerable groups.

Noninvasive Quantification of Radiation-Induced Lung Injury Using a Targeted Molecular Imaging Probe.

PURPOSE: Radiation-induced lung injury (RILI) is a progressive inflammatory process seen after irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Here, we sought to noninvasively quantify RILI using a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. METHODS AND MATERIALS: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe, to characterize the development of RILI and to assess disease mitigation after losartan treatment. The human analog probe 68Ga-CBP8, targeting type 1 collagen, was tested on excised human lung tissue containing RILI and was quantified via autoradiography. 68Ga-CBP8 positron emission tomography was used to assess RILI in vivo in 6 human subjects. RESULTS: Murine models demonstrated that probe signal correlated with progressive RILI severity over 6 months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding versus unirradiated control tissue, and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. CONCLUSIONS: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.

Paratesticular liposarcoma: unusual patterns of recurrence and importance of margins.

BACKGROUND: Paratesticular liposarcoma (LPS) is a rare entity for which optimal treatment has not been defined. We sought to determine recurrence patterns and prognostic factors. METHODS: A total of 25 patients with localized paratesticular LPS between 1987 and 2009 were reviewed. Actuarial local-recurrence-free survival (LRFS), disease-free-survival (DFS), and overall survival (OS) were determined using the Kaplan-Meier method. RESULTS: LPS histology was well differentiated for 10 patients (40 %), de-differentiated for 14 (56 %), and pleomorphic for 1 (4 %). Final margins were positive in 8 patients (32 %). Radiation therapy (RT) was given to 10 patients; fields included inguinal canal ± scrotum and low pelvis. LRFS rates at 3 and 5 years were 76 and 67 %. The 3-year LRFS rates were lower in patients with positive margins compared with those with negative margins (29 vs 100 %, p = .0005) and in patients with recurrent versus primary disease (38 vs 83 %, p = .04). Among patients who received surgery and RT, margins remained a significant predictor of local recurrence (p = .009). Interestingly, recurrences in 4 patients tracked along gonadal vessels, and only 1 patient had a distant recurrence. OS at 5 years was 100 %. CONCLUSIONS: For patients with localized paratesticular LPS, positive margins and presentation with recurrent disease are adverse prognostic factors for LRFS. LR for patients with positive margins is still high despite RT; thus aggressive surgery to attain negative margins should be attempted in all cases. The finding of regional recurrences along gonadal vessels should be validated, and imaging studies should be tailored to reflect potential patterns of disease at presentation and subsequent recurrence.

Incidence of Radiation Therapy Among Patients Enrolled in a Multidisciplinary Pulmonary Nodule and Lung Cancer Screening Clinic.

Importance: The number of pulmonary nodules discovered incidentally or through screening programs has increased markedly. Multidisciplinary review and management are recommended, but the involvement of radiation oncologists in this context has not been defined. Objective: To assess the role of stereotactic body radiation therapy among patients enrolled in a lung cancer screening program. Design, Setting, and Participants: This prospective cohort study was performed at a pulmonary nodule and lung cancer screening clinic from October 1, 2012, to September 31, 2019. Referrals were based on chest computed tomography with Lung Imaging Reporting and Data System category 4 finding or an incidental nodule 6 mm or larger. A multidisciplinary team of practitioners from radiology, thoracic surgery, pulmonology, medical oncology, and radiation oncology reviewed all nodules and coordinated workup and treatment as indicated. Exposures: Patients referred to the pulmonary nodule and lung cancer screening clinic with an incidental or screen-detected pulmonary nodule. Main Outcomes and Measures: The primary outcome was the proportion of patients undergoing therapeutic intervention with radiation therapy, stratified by the route of detection of their pulmonary nodules (incidental vs screen detected). Secondary outcomes were 2-year local control and metastasis-free survival. Results: Among 1150 total patients (median [IQR] age, 66.5 [59.3-73.7] years; 665 [57.8%] female; 1024 [89.0%] non-Hispanic White; 841 [73.1%] current or former smokers), 234 (20.3%) presented with screen-detected nodules and 916 (79.7%) with incidental nodules. For patients with screen-detected nodules requiring treatment, 41 (17.5%) received treatment, with 31 (75.6%) undergoing surgery and 10 (24.4%) receiving radiation therapy. Patients treated with radiation therapy were older (median [IQR] age, 73.8 [67.1 to 82.1] vs 67.6 [61.0 to 72.9] years; P < .001) and more likely to have history of tobacco use (67 [95.7%] vs 128 [76.6%]; P = .001) than those treated with surgery. Fifty-eight patients treated with radiation therapy (82.9%) were considered high risk for biopsy, and treatment recommendations were based on a clinical diagnosis of lung cancer after multidisciplinary review. All screened patients who received radiation therapy had stage I disease and were treated with stereotactic body radiation therapy. For all patients receiving stereotactic body radiation therapy, 2-year local control was 96.3% (95% CI, 91.1%-100%) and metastasis-free survival was 94.2% (95% CI, 87.7%-100%). Conclusions and Relevance: In this unique prospective cohort, 1 in 4 patients with screen-detected pulmonary nodules requiring intervention were treated with stereotactic body radiation therapy. This finding highlights the role of radiation therapy in a lung cancer screening population and the importance of including radiation oncologists in the multidisciplinary management of pulmonary nodules.

Heterogeneous immunogenicity of SARS-CoV-2 vaccines in cancer patients receiving radiotherapy.

The immunogenicity of SARS-CoV-2 vaccines in cancer patients receiving radiotherapy is unknown. This prospective cohort study demonstrates that anti-SARS-CoV-2 spike antibody and neutralization titers are reduced in a subset of thoracic radiotherapy patients, possibly due to immunosuppressive conditions. Antibody testing may be useful to identify candidates for additional vaccine doses.