Embryonically Active Piriform Cortex Neurons Promote Intracortical Recurrent Connectivity during Development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used Targeted Recombination in Active Populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing of these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Stereotactic body radiotherapy for centrally located inoperable early-stage NSCLC: EORTC 22113-08113 LungTech phase II trial results.

BACKGROUND: The international EORTC phase II single-arm LungTech trial 22113-08113 assessed safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance (RTQA) for any eligible patient, SBRT (8x7.5 Gy, ICRU 83) was delivered. The primary endpoint was freedom from local progression probability at three years after start of SBRT. RESULTS: The trial was closed earlier due to poor accrual related to repeated safety-related pauses in recruitment. Between 08/2015 and 12/2017, 39 patients from 6 European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range, 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Median follow-up was 3.6 years. The 3-year freedom from local progression and overall survival rates were 81.5% (90% CI: 62.7-91.4%) and 61.1% (90%CI: 44.1-74.4%), respectively. Cumulative incidence rates of local, regional and distant progression at 3 years were 6.7% (90% CI: 1.6-17.1%), 3.3% (90% CI: 0.4 - 12.4%) and 29.8% (90% CI: 16.8 - 44.1%), respectively. SBRT-related acute and late AEs ≥ G3 were reported in 6.5% (n=2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4 % (n=6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively. CONCLUSION: The LungTech trial suggests that SBRT with 8×7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints and post-SBRT interventions is crucial.

Optimal management of radiation pneumonitis: Findings of an international Delphi consensus study.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study. METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3. RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease. CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.

The Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) protocol to explore the feasibility of embedding behavioural modifications into the clinical pathway for patients undergoing radical radiotherapy for lung cancer.

Patients with curable non-surgical lung cancer are often current smokers, have co-existing medical comorbidities and are treated with curative radiotherapy. To maximise the benefits of modern radiotherapy, there is an urgent need to optimise the patient's health to improve survival and quality of life. METHODS AND ANALYSIS: The Yorkshire Cancer Research-funded Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) (L426) is a single-centre prospective feasibility study to assess embedding behavioural changes into the radical radiotherapy pathway of patients with lung cancer. Feasibility will be assessed by measuring acceptability, demand and implementation. The duration of the study is 24 months. PREHABS has two workstreams: the intervention study and the theory of change (ToC) study.Intervention study: PREHABS will commence at the R-IDEAL phase 2 trial (exploratory) based on existing evidence and includes support for smoking cessation, increasing activity and dietary well-being. Patients undergoing radical radiotherapy for lung cancer will be recruited from the oncology department at Leeds Teaching Hospitals NHS Trust (LTHT). ToC study: to maximise the acceptability and adherence to the PREHABS, we will use a ToC approach to qualitatively explore the key barriers and enablers of implementing a tailored programme of 'prehabilitation'. The PREHABS ToC study participants will be recruited from patients with lung cancer undergoing radical radiotherapy and staff from the LTHT oncology department. ANALYSIS: The primary endpoint analysis will report the number of participants and adherence to the study interventions. Secondary endpoints include continued engagement with study interventions post-treatment. The analysis will focus on descriptive statistics. Thematic analysis of the qualitative data from the ToC study will identify consensus on intervention optimisation and delivery. ETHICS AND DISSEMINATION: On 12 May 2021, the Cambridge East Ethics Committee granted ethical approval (21/EE/0048). The study is registered in the National Institute for Health and Care Research (NIHR) portfolio. The results will be disseminated through publication in peer-reviewed scientific journals and presented at conferences. TRIAL REGISTRATION NUMBER: NIHR portfolio 48420.

Electrophysiological Recordings from Identified Cell Types in the Olfactory Cortex of Awake Mice.

Neural circuits consist of a myriad of distinct cell types, each with specific intrinsic properties and patterns of synaptic connectivity, which transform neural input and convey this information to downstream targets. Understanding how different features of an odor stimulus are encoded and relayed to their appropriate targets will require selective identification and manipulation of these different elements of the circuit. Here, we describe methods to obtain dense, extracellular electrophysiological recordings of odor-evoked activity in olfactory (piriform) cortex of awake, head-fixed mice, and optogenetic tools and procedures to identify genetically defined cell types within this circuit.

Patterns of chemotherapy use and outcomes in advanced non-small cell lung cancer by age in England: A retrospective analysis of the population-based Systemic Anti-Cancer Treatment (SACT) dataset.

INTRODUCTION: We described the patterns of chemotherapy use and outcomes in patients diagnosed with stage III or IV non-small cell lung cancer (NSCLC) by age in England. MATERIALS AND METHODS: In this retrospective population-based study, we included 20,716 (62% stage IV) patients with NSCLC diagnosed from 2014 to 2017 treated with chemotherapy. We used the Systemic Anti-Cancer Treatment (SACT) dataset to describe changes in treatment plan and estimated 30 and 90-day mortality rates and median, 6-, and 12-month overall survival (OS) using Kaplan Meier estimator for patients aged <75 and ≥ 75 by stage. Using flexible hazard regression models we assessed the impact of age, stage, treatment intent (stage III), and performance status on survival. RESULTS: Patients aged ≥75 years were less likely to receive two or more regimens, more likely to have their treatment modified because of comorbidities and their doses reduced compared to younger patients. However, early mortality rates and overall survival were similar across ages, apart from the oldest patients with stage III disease. DISCUSSION: This observational study demonstrates that age is associated with treatment patterns in an older population with advanced NSCLC in England. Although this reflects a pre-immunotherapy period, given the median age of NSCLC patients and increasingly older population, these results suggest older patients (>75 yrs) may benefit from more intense treatments.

Neuroscience: Seq-ing maps in the olfactory cortex.

Many cortical brain regions are spatially organized to optimize sensory representation. Such topographic maps have so far been elusive in the olfactory cortex. A high-throughput tracing study reveals that the neural circuits connecting olfactory regions are indeed topographically organized.

Online Symptom Monitoring During Pelvic Radiation Therapy: Randomized Pilot Trial of the eRAPID Intervention.

PURPOSE: Radiation therapy (RT) and chemoRT for pelvic cancers increase survival but are associated with serious treatment-related symptoms. Electronic-patient self-Reporting of Adverse-events: Patient Information and aDvice (eRAPID) is a secure online system for patients to self-report symptoms, generating immediate advice for hospital contact or self-management. This pilot study aimed to establish feasibility and acceptability of the system. METHODS AND MATERIALS: In a prospective 2-center randomized parallel-group pilot study, patients undergoing radical pelvic RT for prostate cancer (prostateRT) or chemoRT for lower gastrointestinal and gynecological cancers were randomized to usual care (UC) or eRAPID (weekly online symptom reporting for 12, 18, and 24 weeks). Primary outcomes were recruitment/attrition, study completion, and patient adherence. Secondary outcomes were effect on hospital services and performance of patient outcome measures. Missing data, floor/ceiling effects, and mean change scores were examined for Functional Assessment of Cancer Therapy (FACT-G), European Organisation for Research and Treatment of Cancer, Quality of Life (EORTC QLQ C-30), self-efficacy, and EuroQol (EQ5D). RESULTS: From 228 patients approached, 167 (73.2%) were consented and randomized (83, eRAPID; 84, UC; 87, prostateRT; 80, chemoRT); 150 of 167 completed 24 study weeks. Only 16 patients (9.6%) withdrew (10, eRAPID; 6, UC). In the eRAPID arm, completion rates were higher in patients treated with prostateRT compared with chemoRT (week 1, 93% vs 69%; week 2, 93% vs 68%; week 12, 69% vs 55%). Overall, over 50% of online reports triggered self-management advice for milder adverse events. Unscheduled hospital contact was low, with no difference between eRAPID and UC. Return rates for outcome measures were excellent in prostateRT (97%-91%; 6-24 weeks) but lower in chemoRT (95%-55%; 6-24 weeks). Missing data were low (1%-4.1%), ceiling effects were evident in EQ5D-5L, self-efficacy-scale, and FACT-Physical Wellbeing. At 6 weeks, the chemoRT-eRAPID group showed less deterioration in FACT-G, EORTC QLQ-C30, and EQ5D-Visual Analogue Scale than UC, after baseline adjustment. CONCLUSIONS: eRAPID was successfully added to UC at 2 cancer centers in different patient populations. Acceptability and feasibility were confirmed with excellent adherence by prostate patients, but lower by those undergoing chemoRT for gynecological cancers.

A Risk Model to Predict the Delivery of Adjuvant Chemotherapy Following Lung Resection in Patients With Pathologically Positive Lymph Nodes.

To investigate factors associated with the ability to receive adjuvant chemotherapy in patients with pathological N1 and N2 stage after anatomic lung resections for non-small cell lung cancer (NSCLC). Multicenter retrospective analysis on 707 consecutive patients found pathologic N1 (pN1) or N2 (pN2) disease following anatomic lung resections for NSCLC (2014-2019). Multiple imputation logistic regression was used to identify factors associated with adjuvant chemotherapy and to develop a model to predict the probability of starting this treatment. The model was externally validated in a population of 253 patients. In the derivation set, 442 patients were pN1 and 265 pN2. 58% received at least 1 cycle of adjuvant chemotherapy. The variables significantly associated with the probability of starting chemotherapy after multivariable regression analysis were: younger age (p < 0.0001), Body Mass Index (BMI) (p = 0.031), Forced Expiratory Volume in 1 second (FEV1) (p = 0.037), better performance status (PS) (p < 0.0001), absence of chronic kidney disease (CKD) (p = 0.016), resection lesser than pneumonectomy (p = 0.010). The logit of the prediction model was: 6.58 -0.112 x age +0.039 x BMI +0.009 x FEV1 -0.650 x PS -1.388 x CKD -0.550 x pneumonectomy. The predicted rate of adjuvant chemotherapy in the validation set was 59.2 and similar to the observed 1 (59%, p = 0.87) confirming the model performance in external setting. This study identified several factors associated with the probability of initiating adjuvant chemotherapy after lung resection in node-positive patients. This information can be used during preoperative multidisciplinary meetings and patients counseling to support decision-making process regarding the timing of systemic treatment.

Heart dose and cardiac comorbidities influence death with a cardiac cause following hypofractionated radiotherapy for lung cancer.

Background: There is increasing evidence of cardiac toxicity of thoracic radiotherapy however, it is difficult to draw conclusions on cardiac dose constraints due to the heterogeneity of published studies. Moreover, few studies record data on cause of death. The aim of this paper is to investigate the relationship between conventional cardiac dosimetric parameters and death with cardiac causes using data from the UK national cause of death registry. Methods: Data on cancer diagnosis, treatment and cause of death following radical lung cancer radiotherapy were obtained from Public Health England for all patients treated at the Christie NHS Foundation Trust between 1/1/10 and 31/12/16. Individuals with metastatic disease and those who received multiple courses of thoracic radiotherapy where excluded. All patients who received > 45Gy in 20 fractions were included. Cardiac cause of death was defined as the following ICD-10 codes on death certificate: I20-I25; I30-I32; I34-I37; I40-I52. Cardiac V5Gy, V30Gy, V50Gy and mean heart dose (MHD) were extracted. Cumulative incidence of death with cardiac causes were plotted for each cardiac dosimetric parameter. Multi-variable Fine and Gray competing risk analysis was used to model predictors for cardiac death with non-cardiac death as a competing risk. Results: Cardiac dosimetric parameters were available for 967 individuals, 110 died with a cardiac cause (11.4%). Patients with a cardiac comorbidity had an increased risk of death with a cardiac cause compared with those without a cardiac comorbidity (2-year cumulative incidence 21.3% v 6.2%, p<0.001). In patients with a pre-existing cardiac comorbidity, heart V30Gy ≥ 15% was associated with higher cumulative incidence of death with a cardiac cause compared to patients with heart V30Gy <15% (2-year rate 25.8% v 17.3%, p=0.05). In patients without a cardiac comorbidity, after adjusting for tumour and cardiac risk factors, MHD (aHR 1.07, 1.01-1.13, p=0.021), heart V5Gy (aHR 1.01, 1-1.13, p=0.05) and heart V30Gy (aHR 1.04, 1-1.07, p=0.039) were associated with cardiac death. Conclusion: The effect of cardiac radiation dose on cardiac-related death following thoracic radiotherapy is different in patients with and without cardiac comorbidities. Therefore patients' cardiovascular risk factors should be identified and managed alongside radiotherapy for lung cancer.

Participation in community-based lung cancer screening: the Yorkshire Lung Screening Trial.

BACKGROUND: Screening with low-dose computed tomography (LDCT) reduces lung cancer mortality; however, the most effective strategy for optimising participation is unknown. Here we present data from the Yorkshire Lung Screening Trial, including response to invitation, screening eligibility and uptake of community-based LDCT screening. METHODS: Individuals aged 55-80 years, identified from primary care records as having ever smoked, were randomised prior to consent to invitation to telephone lung cancer risk assessment or usual care. The invitation strategy included general practitioner endorsement, pre-invitation and two reminder invitations. After telephone triage, those at higher risk were invited to a Lung Health Check (LHC) with immediate access to a mobile CT scanner. RESULTS: Of 44 943 individuals invited, 50.8% (n=22 815) responded and underwent telephone-based risk assessment (16.7% and 7.3% following first and second reminders, respectively). A lower response rate was associated with current smoking status (adjusted OR 0.44, 95% CI 0.42-0.46) and socioeconomic deprivation (adjusted OR 0.58, 95% CI 0.54-0.62 for the most versus the least deprived quintile). Of those responding, 34.4% (n=7853) were potentially eligible for screening and offered a LHC, of whom 86.8% (n=6819) attended. Lower uptake was associated with current smoking status (adjusted OR 0.73, 95% CI 0.62-0.87) and socioeconomic deprivation (adjusted OR 0.78, 95% CI 0.62-0.98). In total, 6650 individuals had a baseline LDCT scan, representing 99.7% of eligible LHC attendees. CONCLUSIONS: Telephone risk assessment followed by a community-based LHC is an effective strategy for lung cancer screening implementation. However, lower participation associated with current smoking status and socioeconomic deprivation underlines the importance of research to ensure equitable access to screening.

Shared Decision Making in Early-Stage Non-small Cell Lung Cancer: A Systematic Review.

BACKGROUND: The United Kingdom National Institute for Health and Care Excellence guidelines recommend that patients and professionals make shared decisions between surgery and stereotactic ablative radiotherapy (SABR) when treating early-stage non-small cell lung cancer (NSCLC). Variation by center suggests treatment decisions may be disproportionately influenced by clinician judgment and treatment availability rather than by patient preference. This systematic review critically evaluates studies of patient and clinician preferences for treatment of early-stage NSCLC. METHODS: Primary empirical research up to April 30, 2020, was identified from searches of MEDLINE, Embase, PsycInfo, and Web of Science databases. Data extracted included study characteristics and methods, preferences for NSCLC treatment, and involvement in decision making and risk of bias using the Mixed Methods Appraisal Tool. Findings were synthesized using descriptive data and narrative synthesis. RESULTS: Included in the review were 23 studies, of which 18 measured patient preferences, 4 clinician preferences, and 1 both clinician and patient preferences. Patients and clinicians were both most likely to prefer a collaborative role in treatment decisions. Most patients did not recall there being a choice between surgery or SABR options and thus experienced minimal decisional conflict. CONCLUSIONS: For professionals to support patients in making informed, value-based decisions about NSCLC treatments, better quality evidence is needed of the clinical and quality of life trade-offs for both surgery and SABR.

Factors influencing patient satisfaction after treatments for early-stage non-small cell lung cancer.

PURPOSE: Patient-reported outcome measures, including satisfaction with treatment decisions, provide important information in addition to clinical outcomes, survival and decision-making in lung cancer surgery. We investigated associations between preoperative clinical and socio-demographic factors and patient-reported satisfaction 6 weeks after radical treatment for early-stage non-small cell lung cancer (NSCLC). METHODS: We conducted a sub-group analysis of the prospective observational longitudinal study of 225 participants in two treatment groups-surgical (VATS) and radiotherapy (SABR). The Patient Satisfaction Questionnaire-18 (PSQ-18) was used to measure patient satisfaction 6 weeks after treatment. Clinical variables, Index of Multiple Deprivation decile and Decision self-efficacy scores were used in regression analysis. Variables with a p level < 0.1 were used as independent predictors in generalised linear logistic regression analyses. RESULTS: As expected, the two groups differed in pre-treatment clinical features. The SABR group experienced more grade 1-2 complications than the VATS group. No differences were found between the groups in any subscale of the PSQ-18 questionnaire. Patients experiencing complications or living in more deprived areas were more satisfied with care. Properative factors independently associated with patient satisfaction were the efficacy in decision-making and age. CONCLUSION: We showed that efficacy in treatment decision-making and age was the sole predictor of patient satisfaction with their care after radical treatment for early-stage NSCLC. Patients from more deprived areas and patients who suffered complications reported greater subsequent satisfaction. Involving patients in their care may improve satisfaction after treatment for early-stage NSCLC.

Parallel processing by distinct classes of principal neurons in the olfactory cortex.

Understanding how distinct neuron types in a neural circuit process and propagate information is essential for understanding what the circuit does and how it does it. The olfactory (piriform, PCx) cortex contains two main types of principal neurons, semilunar (SL) and superficial pyramidal (PYR) cells. SLs and PYRs have distinct morphologies, local connectivity, biophysical properties, and downstream projection targets. Odor processing in PCx is thought to occur in two sequential stages. First, SLs receive and integrate olfactory bulb input and then PYRs receive, transform, and transmit SL input. To test this model, we recorded from populations of optogenetically identified SLs and PYRs in awake, head-fixed mice. Notably, silencing SLs did not alter PYR odor responses, and SLs and PYRs exhibited differences in odor tuning properties and response discriminability that were consistent with their distinct embeddings within a sensory-associative cortex. Our results therefore suggest that SLs and PYRs form parallel channels for differentially processing odor information in and through PCx.

Quality of life after VATS lung resection and SABR for early-stage non-small cell lung cancer: A longitudinal study.

INTRODUCTION: Video-assisted thoracoscopic (VATS) lung resection is the recommended curative treatment for early-stage non-small cell lung cancer (NSCLC). Patients considered at high surgical risk, are treated with stereotactic ablative body radiotherapy (SABR) as a lower morbidity alternative. This study aims to investigate the impact of SABR and VATS resection on patients' quality of life (QoL) over the first year after treatment. METHODS: A prospective longitudinal observational study recruiting early-stage NSCLC patients from a single UK centre. QoL was assessed with EORTC QLQ-C30 and Lung Cancer Module LC13 at baseline, 6 weeks and 3, 6 and 12 months post-treatment. RESULTS: From 01.03.2017 till 01.03.2018, 244/281 patients (87%) consented to participate, 225 (95 SABR and 130 VATS) were included in the analysis. SABR patients had significantly worse baseline QoL scores than VATS patients, even after adjusting for preoperative clinical factors (C-30 Global Health mean: SABR = 53.8, VATS = 71.2; Physical Functioning mean: SABR = 57, VATS = 82.2; Fatigue mean: SABR = 43.5, VATS = 23.7; C30 Dyspnea mean: SABR = 49.5, VATS = 26.2). During the 12 months post SABR treatment patients' QoL scores remained stable. In the VATS group, there was a deterioration 6-weeks after treatment in Role, Physical, Social Functions, Global Health, Fatigue, C30/LC13 Dyspnoea, Pain, Appetite loss, Constipation, LC13 Pain in Chest and Arms. The scores improved by 12 months without reaching the preoperative values. CONCLUSIONS: Although QoL outcomes for SABR and VATS are not comparable due to different medical selection criteria, the QoL impact of the two treatments during the first year showed different trends which will inform patients and clinicians during decision-making discussions.

Causes of Death in People With Cardiovascular Disease: A UK Biobank Cohort Study.

Background Therapeutic advances have reduced cardiovascular death rates in people with cardiovascular diseases (CVD). We aimed to define the rates of cardiovascular and noncardiovascular death in people with specified CVDs or accruing cardiovascular multimorbidity. Methods and Results We studied 493 280 UK residents enrolled in the UK Biobank cohort study. The proportion of deaths attributed to cardiovascular, cancer, infection, or other causes were calculated in groups defined by 9 distinct self-reported CVDs at baseline, or by the number of these CVDs at baseline. Poisson regression analyses were then used to define adjusted incidence rate ratios for these causes of death, accounting for sociodemographic factors and comorbidity. Of 27 729 deaths, 20.4% were primarily attributed to CVD, 53.6% to cancer, 5.0% to infection, and 21.0% to other causes. As cardiovascular multimorbidity increased, the proportion of cardiovascular and infection-related deaths was greater, contrasting with cancer and other deaths. Compared with people without CVD, those with 3 or more CVDs experienced adjusted incidence rate ratios of 7.0 (6.2-7.8) for cardiovascular death, 4.4 (3.4-5.6) for infection death, 1.5 (1.4-1.7) for cancer death, and 2.0 (1.7-2.4) for other causes of death. There was substantial heterogeneity in causes of death, both in terms of crude proportions and adjusted incidence rate ratios, among the 9 studied baseline CVDs. Conclusions Noncardiovascular death is common in people with CVD, although its contribution varies widely between people with different CVDs. Holistic and personalized care are likely to be important tools for continuing to improve outcomes in people with CVD.

An International Expert Survey on the Indications and Practice of Radical Thoracic Reirradiation for Non-Small Cell Lung Cancer.

PURPOSE: Thoracic reirradiation for non-small cell lung cancer with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating non-small cell lung cancer with radiation therapy in the setting of prior thoracic irradiation. METHODS AND MATERIALS: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined during 4 rounds on the definition of reirradiation, selection of appropriate patients, pretreatment assessments, planning of radiation therapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents' comments and re-presented in subsequent rounds. RESULTS: Fifteen radiation oncologists participated in the 4 surveys between September 2019 and March 2020. The first 3 rounds had a 100% response rate, and the final round was completed by 93% of participants. Thirty-three out of 77 statements across all rounds achieved consensus. Key recommendations are as follows: (1) appropriate patients should have a good performance status and can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude reirradiation; (2) a full diagnostic workup should be performed in patients with suspected local recurrence and; (3) any reirradiation should be delivered using optimal image guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. CONCLUSIONS: These consensus statements provide practical guidance on appropriate patient selection for reirradiation, appropriate radiation therapy techniques, and cumulative dose constraints.

Chronic loss of inhibition in piriform cortex following brief, daily optogenetic stimulation.

It is well established that seizures beget seizures, yet the cellular processes that underlie progressive epileptogenesis remain unclear. Here, we use optogenetics to briefly activate targeted populations of mouse piriform cortex (PCx) principal neurons in vivo. After just 3 or 4 days of stimulation, previously subconvulsive stimuli trigger massive, generalized seizures. Highly recurrent allocortices are especially prone to "optokindling." Optokindling upsets the balance of recurrent excitation and feedback inhibition. To understand how this balance is disrupted, we then selectively reactivate the same neurons in vitro. Surprisingly, we find no evidence of heterosynaptic potentiation; instead, we observe a marked, pathway-specific decrease in feedback inhibition. We find no loss of inhibitory interneurons; rather, decreased GABA synthesis in feedback inhibitory neurons appears to underlie weakened inhibition. Optokindling will allow precise identification of the molecular processes by which brain activity patterns can progressively and pathologically disrupt the balance of cortical excitation and inhibition.

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

PURPOSE/OBJECTIVES: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes. MATERIAL AND METHODS: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes. RESULTS: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1. CONCLUSION: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.