Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

Evaluation of the impact of artificial intelligence-assisted image interpretation on the diagnostic performance of clinicians in identifying pneumothoraces on plain chest X-ray: a multi-case multi-reader study.

BACKGROUND: Artificial intelligence (AI)-assisted image interpretation is a fast-developing area of clinical innovation. Most research to date has focused on the performance of AI-assisted algorithms in comparison with that of radiologists rather than evaluating the algorithms' impact on the clinicians who often undertake initial image interpretation in routine clinical practice. This study assessed the impact of AI-assisted image interpretation on the diagnostic performance of frontline acute care clinicians for the detection of pneumothoraces (PTX). METHODS: A multicentre blinded multi-case multi-reader study was conducted between October 2021 and January 2022. The online study recruited 18 clinician readers from six different clinical specialties, with differing levels of seniority, across four English hospitals. The study included 395 plain CXR images, 189 positive for PTX and 206 negative. The reference standard was the consensus opinion of two thoracic radiologists with a third acting as arbitrator. General Electric Healthcare Critical Care Suite (GEHC CCS) PTX algorithm was applied to the final dataset. Readers individually interpreted the dataset without AI assistance, recording the presence or absence of a PTX and a confidence rating. Following a 'washout' period, this process was repeated including the AI output. RESULTS: Analysis of the performance of the algorithm for detecting or ruling out a PTX revealed an overall AUROC of 0.939. Overall reader sensitivity increased by 11.4% (95% CI 4.8, 18.0, p=0.002) from 66.8% (95% CI 57.3, 76.2) unaided to 78.1% aided (95% CI 72.2, 84.0, p=0.002), specificity 93.9% (95% CI 90.9, 97.0) without AI to 95.8% (95% CI 93.7, 97.9, p=0.247). The junior reader subgroup showed the largest improvement at 21.7% (95% CI 10.9, 32.6), increasing from 56.0% (95% CI 37.7, 74.3) to 77.7% (95% CI 65.8, 89.7, p<0.01). CONCLUSION: The study indicates that AI-assisted image interpretation significantly enhances the diagnostic accuracy of clinicians in detecting PTX, particularly benefiting less experienced practitioners. While overall interpretation time remained unchanged, the use of AI improved diagnostic confidence and sensitivity, especially among junior clinicians. These findings underscore the potential of AI to support less skilled clinicians in acute care settings.

ERS/ESTS statement on the management of pleural infection in adults.

Pleural infection is a common condition encountered by respiratory physicians and thoracic surgeons alike. The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) established a multidisciplinary collaboration of clinicians with expertise in managing pleural infection with the aim of producing a comprehensive review of the scientific literature. Six areas of interest were identified: 1) epidemiology of pleural infection, 2) optimal antibiotic strategy, 3) diagnostic parameters for chest tube drainage, 4) status of intrapleural therapies, 5) role of surgery and 6) current place of outcome prediction in management. The literature revealed that recently updated epidemiological data continue to show an overall upwards trend in incidence, but there is an urgent need for a more comprehensive characterisation of the burden of pleural infection in specific populations such as immunocompromised hosts. There is a sparsity of regular analyses and documentation of microbiological patterns at a local level to inform geographical variation, and ongoing research efforts are needed to improve antibiotic stewardship. The evidence remains in favour of a small-bore chest tube optimally placed under image guidance as an appropriate initial intervention for most cases of pleural infection. With a growing body of data suggesting delays to treatment are key contributors to poor outcomes, this suggests that earlier consideration of combination intrapleural enzyme therapy (IET) with concurrent surgical consultation should remain a priority. Since publication of the MIST-2 study, there has been considerable data supporting safety and efficacy of IET, but further studies are needed to optimise dosing using individualised biomarkers of treatment failure. Pending further prospective evaluation, the MIST-2 regimen remains the most evidence based. Several studies have externally validated the RAPID score, but it requires incorporating into prospective intervention studies prior to adopting into clinical practice.

Gas6 induces inflammation and reduces plaque burden but worsens behavior in a sex-dependent manner in the APP/PS1 model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the leading cause of dementia worldwide. TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) are known for their role in engagement of phagocytosis and modulation of inflammation, and recent evidence suggests a complex relationship between Axl, Mer, and microglial phagocytosis of amyloid plaques in AD. Gas6, the primary CNS TAM ligand, reduces neuroinflammation and improves outcomes in murine models of CNS disease. Therefore, we hypothesized that AAV-mediated overexpression of Gas6 would alleviate plaque pathology, reduce neuroinflammation, and improve behavior in the APP/PS1 model of Alzheimer's disease. METHODS: Adeno-associated viral vectors were used to overexpress Gas6 in the APP/PS1 model of Alzheimer's disease. Nine-month-old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, which expresses a non-functional Gas6 protein. One month after injections, mice underwent a battery of behavioral tasks to assess cognitive function and brains were processed for immunohistochemical and transcriptional analyses. RESULTS: Gas6 overexpression reduced plaque burden in male APP/PS1 mice. However, contrary to our hypothesis, Gas6 increased pro-inflammatory microglial gene expression and worsened contextual fear conditioning compared to control-treated mice. Gas6 overexpression appeared to have no effect on phagocytic mechanisms in vitro or in vivo as measured by CD68 immunohistochemistry, microglial methoxy-04 uptake, and primary microglial uptake of fluorescent fibrillar amyloid beta. CONCLUSION: Our data describes a triad of worsened behavior, reduced plaque number, and an increase in proinflammatory signaling in a sex-specific manner. While Gas6 has historically induced anti-inflammatory signatures in the peripheral nervous system, our data suggest an alternative, proinflammatory role in the context of Alzheimer's disease pathology.

The association between cancer-related fatigue and diabetes from pre-chemotherapy to 6 months post-chemotherapy.

PURPOSE: To quantify the relationship between diabetes and fatigue from pre-chemotherapy to 6 months post-chemotherapy for women with breast cancer compared to women without a history of cancer (controls). METHODS: This was a secondary analysis from a nationwide prospective longitudinal study of female patients with breast cancer undergoing chemotherapy and controls. Diabetes diagnosis (yes/no) was obtained at baseline, and cancer-related fatigue was measured using the Multidimensional Fatigue Symptom Inventory (MFSI) pre-, post-, and 6 months post-chemotherapy in patients; controls were assessed at equivalent time points. Repeated measures mixed effects models estimated the association between fatigue and diabetes controlling for cancer (yes/no), body mass index, exercise and smoking habits, baseline anxiety and depressive symptoms, menopausal status, marital status, race, and education. RESULTS: Among 439 patients and 235 controls (52.8 ± 10.5 years old), diabetes was twice as prevalent among patients as controls (11.6% vs. 6.8%). At baseline, diabetes was associated with worse fatigue (4.1 ± 1.7 points, p = 0.017). Also, diabetes was associated with clinically meaningful worse fatigue throughout the study period among all participants (5.2 ± 1.9 points, p = 0.008) and patients alone (4.5 ± 2.0, p = 0.023). For the MFSI subdomains among patients, diabetes was associated with worse general (p = 0.005) and mental fatigue (p = 0.026). CONCLUSIONS: Diabetes was twice as prevalent in women with breast cancer compared to controls, and diabetes was associated with more severe cancer-related fatigue in patients before and after chemotherapy and at 6 months post-chemotherapy. Interventions that address diabetes management may also help address cancer-related fatigue during chemotherapy treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01382082, first posted June 27, 2011.

Patients' and healthcare professionals' views on a pre- and post-operative rehabilitation programme (SOLACE) for lung cancer: A qualitative study.

AIMS AND OBJECTIVES: To explore patients' and healthcare professionals' views and experiences of a pre- and post-operative rehabilitation intervention (SOLACE), for patients undergoing surgery for early-stage lung cancer. BACKGROUND: Considerable post-operative complications can occur after surgery. A specialist lung cancer service (SOLACE) was developed to optimise health and fitness levels prior to and following lung cancer resections, as well as reducing morbidity and mortality, and improving the physical and psychological well-being of patients. DESIGN: The design was an exploratory, descriptive qualitative interview study. METHODS: Seventeen lung cancer patients and eight healthcare professionals were recruited from a large teaching hospital in South England. Data were collected through semi-structured telephone and face-to-face interviews. Transcribed interview data were analysed thematically. The COREQ checklist was used to report on the study process. RESULTS: The SOLACE service was positively perceived by patients and healthcare professionals. Patients valued the provision of tailored support/advice and peer support and reported benefits to their health and well-being. Barriers to patient uptake of the classes included time constraints, motivation and access for patients who lived at a distance. CONCLUSIONS: There is benefit in providing a personalised approach through a pre- and post-operative rehabilitation service for lung cancer patients. Virtual support may address equality of access to service for those who live at a distance from the hospital. RELEVANCE TO CLINICAL PRACTICE: Introduction of a pre- and post-operative rehabilitation service provided by specialist peri-operative rehabilitation nurses and practitioners can yield positive outcomes for patients undergoing surgical treatment of early-stage lung cancer. Engagement of key healthcare professionals, consideration of virtual follow-up services and making patients aware of services could maximise patient uptake. Further consideration is needed of the best way to promote patient self-management and long-term continuation of patient rehabilitation in the community.

The longitudinal relationship between immune cell profiles and frailty in patients with breast cancer receiving chemotherapy.

BACKGROUND: Frailty is associated with an increased risk of chemotherapy toxicity. Cellular markers of inflammation can help identify patients with frailty characteristics. However, the role of cellular markers of inflammation in identifying patients at risk of developing chemotherapy-induced frailty and their clinical utility are not fully understood. METHODS: This study was a secondary analysis of a large nationwide cohort study of women with stage I-IIIC breast cancer (n = 581, mean age 53.4; range 22-81). Measures were completed pre-chemotherapy (T1), post-chemotherapy (T2), and 6 months post-chemotherapy (T3). Frailty was assessed at all three time points using a modified Fried score consisting of four self-reported measures (weakness, exhaustion, physical activity, and walking speed; 0-4, 1 point for each). Immune cell counts as well as neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ratio (LMR) were obtained at T1 and T2 time points. Separate linear regressions were used to evaluate the associations of (1) cell counts at T1 with frailty at T1, T2, and T3 and (2) change in cell counts (T2-T1) with frailty at T2 and T3. We controlled for relevant covariates and frailty at the T1 time point. RESULTS: From T1 to T2, the mean frailty score increased (1.3 vs 2.0; p < 0.01) and returned to T1 levels by the T3 time point (1.3 vs 1.3; p = 0.85). At the T1 time point, there was a positive association between cellular markers of inflammation and frailty: WBC (ß = 0.04; p < 0.05), neutrophils (ß = 0.04; p < 0.05), and NLR (ß = 0.04; p < 0.01). From T1 to T2, a greater increase in cellular markers of inflammation was associated with frailty at T2 (WBC: ß = 0.02, p < 0.05; neutrophils: ß = 0.03, p < 0.05; NLR: ß = 0.03; p < 0.01). These associations remained significant after controlling for the receipt of growth factors with chemotherapy and the time between when laboratory data was provided and the start or end of chemotherapy. CONCLUSIONS: In patients with breast cancer undergoing chemotherapy, cellular markers of inflammation are associated with frailty. Immune cell counts may help clinicians identify patients at risk of frailty during chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01382082.

The Relationship Between Frailty and Emotional Health in Older Patients with Advanced Cancer.

BACKGROUND: Aging-related deficits that eventually manifest as frailty may be associated with poor emotional health in older patients with advanced cancer. This study aimed to examine the relationship between frailty and emotional health in this population. METHODS: This was a secondary analysis of baseline data from a nationwide cluster randomized trial. Patients were aged ≥70 years with incurable stage III/IV solid tumors or lymphomas, had ≥1 geriatric assessment (GA) domain impairment, and had completed the Geriatric Depression Scale, Generalized Anxiety Disorder-7, and Distress Thermometer. Frailty was assessed using a Deficit Accumulation Index (DAI; range 0-1) based on GA, which did not include emotional health variables (depression and anxiety), and participants were stratified into robust, prefrail, and frail categories. Multivariate logistic regression models examined the association of frailty with emotional health outcomes. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were reported. RESULTS: Five hundred forty-one patients were included (mean age: 77 years; 70-96). DAI ranged from 0.04 to 0.94; 27% of patients were classified as robust, 42% prefrail, and 31% frail. Compared with robust patients, frail patients had an increased risk of screening positive for depression (aOR = 12.8; 95% CI = 6.1-27.0), anxiety (aOR = 6.6; 95% CI = 2.2-19.7), and emotional distress (aOR = 4.62; 95% CI = 2.9-8.3). Prefrail compared with robust patients also had an increased risk of screening positive for depression (aOR = 2.22; 95% CI = 1.0-4.8) and distress (aOR = 1.71; 95% CI = 1.0-2.8). CONCLUSION: In older patients with advanced cancer, frailty is associated with poorer emotional health, which indicates a need for an integrated care approach to treating these patients. IMPLICATIONS FOR PRACTICE: A relationship exists between frailty and poor emotional health in older adults with advanced cancer. Identifying areas of frailty can prompt screening for emotional health and guide delivery of appropriate interventions. Alternatively, attention to emotional health may also improve frailty.

Concomitant Laparoscopic and Thoracoscopic Resection of Recurrent High-Grade Ovarian Cancer.

STUDY OBJECTIVE: To describe the first case of combined endoscopic management of a thoracic and abdominal recurrence of ovarian cancer. DESIGN: An instructive video showing the combined thoracic and abdominal surgical procedure. SETTING: Department of Gynecological Oncology, Churchill Hospital, Oxford University, UK. PATIENTS: A 64-year-old woman undergoing endoscopic treatment for a third recurrence of ovarian cancer after a full surgical staging in 2007. The disease-free interval from the last recurrence was 31 months. INTERVENTION: The operation was performed by a multidisciplinary team of thoracic and gynecologic oncologist surgeons. Surgery started with thoracoscopic resection of a right enlarged paracardiac lymph node of 24 mm and a small wedge of the right lung, which was attached to the lymph node. At laparoscopy, 2 nodules of 3 and 5 mm were excised from the mesosigmoid and 1 nodule of 20 mm was resected from the right hemidiaphragm. MEASUREMENTS AND MAIN RESULTS: The total operative time was 251 minutes, and no intraoperative complication occurred. No conversion to open surgery was necessary. The estimated blood loss was 50 mL. There was no visible residual disease at the end of the surgery. The patient was discharged 4 days after surgery. The final pathology report confirmed the presence of endometrioid adenocarcinoma in all specimens removed. Adjuvant chemotherapy with carboplatin/paclitaxel was started 2 weeks later. At the 60-day follow-up, no complications were recorded. A computed tomographic scan performed after 6 cycles of chemotherapy did not reveal any evidence of relapse. CONCLUSIONS: The combined endoscopic approach might be feasible in selected patients.

Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.

Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.

Novel penalised likelihood reconstruction of PET in the assessment of histologically verified small pulmonary nodules.

OBJECTIVES: Investigate the effect of a novel Bayesian penalised likelihood (BPL) reconstruction algorithm on analysis of pulmonary nodules examined with 18F-FDG PET/CT, and to determine its effect on small, sub-10-mm nodules. METHODS: 18F-FDG PET/CTs performed for nodule evaluation in 104 patients (121 nodules) were retrospectively reconstructed using the new algorithm, and compared to time-of-flight ordered subset expectation maximisation (OSEM) reconstruction. Nodule and background parameters were analysed semi-quantitatively and visually. RESULTS: BPL compared to OSEM resulted in statistically significant increases in nodule SUVmax (mean 5.3 to 8.1, p < 0.00001), signal-to-background (mean 3.6 to 5.3, p < 0.00001) and signal-to-noise (mean 24 to 41, p < 0.00001). Mean percentage increase in SUVmax (%ΔSUVmax) was significantly higher in nodules ≤10 mm (n = 31, mean 73%) compared to >10 mm (n = 90, mean 42 %) (p = 0.025). Increase in signal-to-noise was higher in nodules ≤10 mm (224%, mean 12 to 27) compared to >10 mm (165%, mean 28 to 46). When applying optimum SUVmax thresholds for detecting malignancy, the sensitivity and accuracy increased using BPL, with the greatest improvements in nodules ≤10 mm. CONCLUSION: BPL results in a significant increase in signal-to-background and signal-to-noise compared to OSEM. When semi-quantitative analyses to diagnose malignancy are applied, higher SUVmax thresholds may be warranted owing to the SUVmax increase compared to OSEM. KEY POINTS: • Novel Bayesian penalised likelihood PET reconstruction was applied for lung nodule evaluation. • This was compared to current standard of care OSEM reconstruction. • The novel reconstruction generated significant increases in lung nodule signal-to-background and signal-to-noise. • These increases were highest in small, sub-10-mm pulmonary nodules. • Higher SUV max thresholds may be warranted when using semi-quantitative analyses to diagnose malignancy.

18F-FDG PET/CT assessment of histopathologically confirmed mediastinal lymph nodes in non-small cell lung cancer using a penalised likelihood reconstruction.

PURPOSE: To investigate whether using a Bayesian penalised likelihood reconstruction (BPL) improves signal-to-background (SBR), signal-to-noise (SNR) and SUVmax when evaluating mediastinal nodal disease in non-small cell lung cancer (NSCLC) compared to ordered subset expectation maximum (OSEM) reconstruction. MATERIALS AND METHODS: 18F-FDG PET/CT scans for NSCLC staging in 47 patients (112 nodal stations with histopathological confirmation) were reconstructed using BPL and compared to OSEM. Node and multiple background SUV parameters were analysed semi-quantitatively and visually. RESULTS: Comparing BPL to OSEM, there were significant increases in SUVmax (mean 3.2-4.0, p<0.0001), SBR (mean 2.2-2.6, p<0.0001) and SNR (mean 27.7-40.9, p<0.0001). Mean background SNR on OSEM was 10.4 (range 7.6-14.0), increasing to 12.4 (range 8.2-16.7, p<0.0001). Changes in background SUVs were minimal (largest mean difference 0.17 for liver SUVmean, p<0.001). There was no significant difference between either algorithm on receiver operating characteristic analysis (p=0.26), although on visual analysis, there was an increase in sensitivity and small decrease in specificity and accuracy on BPL. CONCLUSION: BPL increases SBR, SNR and SUVmax of mediastinal nodes in NSCLC compared to OSEM, but did not improve the accuracy for determining nodal involvement. KEY POINTS: • Penalised likelihood PET reconstruction was applied for assessing mediastinal nodes in NSCLC. • The new reconstruction generated significant increases in signal-to-background, signal-to-noise and SUVmax. • This led to an improvement in visual sensitivity using the new algorithm. • Higher SUV max thresholds may be appropriate for semi-quantitative analyses with penalised likelihood.

Benefits of Resistance Training During Pregnancy for Maternal and Fetal Health: A Brief Overview.

Research demonstrates resistance training is not only safe but also beneficial for pregnant women. However, exercise recommendations for pregnant women still minimize the importance of resistance exercise and provide minimal guidance. With a large increase in strength-focused sports among women, it is critical to re-evaluate the risk/benefit ratio of these exercises and ensure the latest recommendations reflect the latest clinical research. The purpose of this review is to highlight the safety and benefits of resistance training for both maternal and fetal health, particularly focusing on recent work. Relevant research involving resistance training during pregnancy was accessed and analyzed via a quasi-systematic search. Results demonstrate that appropriate prenatal resistance training can help alleviate some of the common symptoms of pregnancy, such as fatigue, back pain, and poor mental health. Resistance exercise can assist with glucose control in gestational diabetes mellitus, as well as decrease the risk of infant macrosomia and childhood metabolic dysfunction associated with uncontrolled gestational diabetes. Resistance training can also increase the likelihood of a vaginal delivery, which is beneficial for both mother and baby. Concerning fetal health, resistance training increases uterine blood flow, decreases the risk of neonatal macrosomia, and improves cognitive function and metabolic health in childhood. As with all forms of exercise, pregnant women should avoid resistance exercises that involve the supine position for extended bouts of time, trauma (or risk of trauma) to the abdomen, ballistic movements, movements that rely heavily on balance, and conditions that prohibit appropriate temperature control. With these considerations in mind, resistance training's benefits far surpass the lack of risk to the fetus. Resistance training is a safe and effective way to improve and maintain physical fitness during pregnancy and represents no risk to fetal health and development. Thus, healthcare providers should recommend resistance training for pregnant women.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Should all patients receive extended thromboprophylaxis after resection of primary lung cancer?

OBJECTIVE: The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and venous thromboembolism in patients undergoing early-stage lung cancer resection and the impact of change from short duration to extended thromboprophylaxis. METHODS: We reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer following a change in protocol from inpatient-only to extended thromboprophylaxis to 28 days. Propensity-score matching of control (routine inpatient pharmacologic thromboprophylaxis) and treatment group (extended pharmacologic thromboprophylaxis) was performed. Adjustment for covariates based on the Caprini risk assessment model was undertaken. Thromboembolic outcomes were compared between the 2 groups. RESULTS: Seven hundred fifty consecutive patients underwent resection of primary lung cancer at Oxford University Hospitals NHS Foundation Trust between January 2013 and December 2018. Six hundred patients were included for analysis and propensity-score matching resulted in 253 matched pairs. Extended prophylaxis was associated with a significant reduction in pulmonary emboli (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01). One patient (0.4%) developed a bleeding complication within the treatment cohort. Multivariable logistic regression model demonstrated that extended thromboprophylaxis was independently associated with a reduction in postoperative pulmonary emboli. CONCLUSIONS: Patients undergoing lung cancer resection surgery are at moderate-to-high risk of postoperative thromboembolic disease. Extended dalteparin for 28 days is safe and is associated with reduced incidence of pulmonary embolus in patients undergoing resection of early-stage primary lung cancer.

Relationships between cytokines and cognitive function from pre- to post-chemotherapy in patients with breast cancer.

Cancer-related cognitive decline (CRCD) is a clinically important problem and negatively affects daily functioning and quality of life. We conducted a pilot longitudinal study from pre- to post-chemotherapy in patients with breast cancer to assess changes in inflammation and cognition over time, as well as the impact of baseline cytokine level on post-chemotherapy cognitive scores. We found that concentrations of IL-6, MCP-1, sTNFRI, and sTNFRII significantly increased in patients, while IL-1ß significantly decreased (p < 0.05). After controlling for covariates, increases in IL-6 and MCP-1 were associated with worse executive function and verbal fluency in patients from pre- to post-chemotherapy (p < 0.05). Higher baseline IL-6 was associated with better performance on executive function and verbal fluency post chemotherapy (p < 0.05). Overall, these results suggest that chemotherapy-associated increases in cytokines/receptors is associated with worse cognitive function. Larger studies are needed to confirm these findings.

Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, coupled with the ongoing coronavirus disease 2019 (COVID-19) pandemic. mRNA lipid nanoparticle (LNP) vaccines have been developed, but their intramuscular delivery limits pulmonary bioavailability. Inhalation of nanoparticle therapeutics offers localized drug delivery that minimizes off targeted adverse effects and has greater patient compliance. However, LNP platforms require extensive reformulation for inhaled delivery. Lung-derived extracellular vesicles (Lung-Exo) offer a biological nanoparticle alternative that is naturally optimized for mRNA translation and delivery to pulmonary cells. We compared the biodistribution of Lung-Exo against commercially standard biological extracellular vesicles (HEK-Exo) and LNPs (Lipo), where Lung-Exo exhibited superior mRNA and protein cargo distribution to and retention in the bronchioles and parenchyma following nebulization administration. This suggests that inhaled Lung-Exo can deliver mRNA and protein drugs with enhanced pulmonary bioavailability and therapeutic efficacy.