Mid-treatment adaptive planning during thoracic radiation using 68 Ventilation-Perfusion Positron emission tomography.

Four-Dimensional Gallium 68 Ventilation-Perfusion Positron Emission Tomography (68Ga-4D-V/Q PET/CT) allows for dynamic imaging of lung function. To date there has been no assessment of the feasibility of adapting radiation therapy plans to changes in lung function imaged at mid-treatment function using 68Ga-4D-V/Q PET/CT. This study assessed the potential reductions of dose to the functional lung when radiation therapy plans were adapted to avoid functional lung at the mid-treatment timepoint using volumetric arc radiotherapy (VMAT). Methods: A prospective clinical trial (U1111-1138-4421) was performed in patients undergoing conventionally fractionated radiation therapy for non-small cell lung cancer (NSCLC). A 68Ga-4D-V/Q PET/CT was acquired at baseline and in the 4th week of treatment. Functional lung target volumes using the ventilated and perfused lung were created. Baseline functional volumes were compared to the week 4 V/Q functional volumes to describe the change in function over time. For each patient, 3 VMAT plans were created and optimised to spare ventilated, perfused or anatomical lung. All key dosimetry metrics were then compared including dose to target volumes, dose to organs at risk and dose to the anatomical and functional sub-units of lung. Results: 25 patients had both baseline and 4 week mid treatment 68Ga-4D-V/Q PET/CT imaging. This resulted in a total of 75 adapted VMAT plans. The HPLung volume decreased in 16/25 patients with a mean of the change in volume (cc) -28 ± 515 cc [±SD, range -996 cc to 1496 cc]. The HVLung volume increased in 13/25 patients with mean of the change in volume (cc) + 112 ± 590 cc. [±SD, range -1424 cc to 950 cc]. The functional lung sparing technique was found to be feasible with no significant differences in dose to anatomically defined organs at risk. Most patients did derive a benefit with a reduction in functional volume receiving 20 Gy (fV20) and/or functional mean lung dose (fMLD) in either perfusion and/or ventilation. Patients with the most reduction in fV20 and fMLD were those with stage III NSCLC. Conclusion: Functional lung volumes change during treatment. Some patients benefit from using 68Ga-4D-V/Q PET/CT in the 4th week of radiation therapy to adapt radiation plans. In these patients, the role of mid-treatment adaptation requires further prospective investigation.

"Stabilise-reduce, stabilise-reduce": A survey of the common practices of deprescribing services and recommendations for future services.

BACKGROUND: Public Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development. METHODS: We identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis. RESULTS: Thirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering. CONCLUSION: We found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice.

Inhibition of the CCR6-CCL20 axis prevents regulatory T cell recruitment and sensitizes head and neck squamous cell carcinoma to radiation therapy.

BACKGROUND:  Radioresistance of HNSCCs remains a major challenge for effective tumor control. Combined radiotherapy (RT) and immunotherapy (IT) treatment improved survival for a subset of patients with inflamed tumors or tumors susceptible to RT-induced inflammation. To overcome radioresistance and improve treatment outcomes, an understanding of factors that suppress anti-tumor immunity is necessary. In this regard, regulatory T cells (Tregs) are critical mediators of immune suppression in HNSCCs. In this study, we investigated how radiation modulates Treg infiltration in tumors through the chemokine CCL20. We hypothesized that radiation induces CCL20 secretion resulting in Treg infiltration and suppression of anti-tumor immunity. METHODS:  Human and mouse HNSCC cell lines with different immune phenotypes were irradiated at doses of 2 or 10 Gy. Conditioned media, RNA and protein were collected for assessment of CCL20. qPCR was used to determine CCL20 gene expression. In vivo, MOC2 cells were implanted into the buccal cavity of mice and the effect of neutralizing CCL20 antibody was determined alone and in combination with RT. Blood samples were collected before and after RT for analysis of CCL20. Tumor samples were analyzed by flow cytometry to determine immune infiltrates, including CD8 T cells and Tregs. Mass-spectrometry was performed to analyze proteomic changes in the tumor microenvironment after anti-CCL20 treatment. RESULTS:  Cal27 and MOC2 HNSCCs had a gene signature associated with Treg infiltration, whereas SCC9 and MOC1 tumors displayed a gene signature associated with an inflamed TME. In vitro, tumor irradiation at 10 Gy significantly induced CCL20 in Cal27 and MOC2 cells relative to control. The increase in CCL20 was associated with increased Treg migration. Neutralization of CCL20 reversed radiation-induced migration of Treg cells in vitro and decreased intratumoral Tregs in vivo. Furthermore, inhibition of CCL20 resulted in a significant decrease in tumor growth compared to control in MOC2 tumors. This effect was further enhanced after combination with RT compared to either treatment alone. CONCLUSION:  Our results suggest that radiation promotes CCL20 secretion by tumor cells which is responsible for the attraction of Tregs. Inhibition of the CCR6-CCL20 axis prevents infiltration of Tregs in tumors and suppresses tumor growth resulting in improved response to radiation.

A Randomized Controlled Trial of an Exercise Maintenance Intervention in Men and Women After Cardiac Rehabilitation (ECO-PCR Trial).

BACKGROUND: Exercise maintenance interventions are needed for cardiac rehabilitation (CR) graduates to maintain moderate and vigorous-intensity physical activity (MVPA). We tested an exercise facilitator intervention (EFI) to promote exercise maintenance compared with usual care (UC) separately in men and women. METHODS: This was a 3-site, randomized (1:1), parallel-group, superiority trial (ECO-PCR). CR graduates were stratified by site and sex and randomly allocated (concealed). EFI participants received a face-to-face introductory session, 5 small-group counseling teleconferences, and 3 personal calls from a trained facilitator over 50 weeks. In-person assessments were undertaken at baseline and 26 and 52 weeks after randomization. The primary outcome was weekly minutes of MVPA, measured by accelerometer. Secondary outcomes were exercise capacity, risk factors, quality of life, and enrollment in community-based exercise programs. Effects were tested with the use of linear mixed models. RESULTS: A total of 449 CR graduates (135 women, 314 men) were randomised (n = 226 EFI, n = 223 UC). In the intention-to-treat analysis for men and for women, there were no significant effects for treatment or time on MVPA. In a planned secondary analysis that considered only those adherent to EFI (completed ≥ 66% of sessions; per-protocol), bouted MVPA (ie, in sustained bouts of ≥ 10 min) was higher in women in the EFI group (mean = 132.6 ± 135.2 min/wk at 52 weeks) compared with UC (111.8 ± 113.1; P = 0.013). Regarding secondary outcomes, in women, a treatment group main effect was observed for blood pressure (P = 0.011) and exercise capacity (P = 0.019; both per-protocol) favouring EFI; no other differences were observed. CONCLUSIONS: In this trial of CR completers, an EFI showed promise for women, but was ineffective in men.

The 'patient voice': patients who experience antidepressant withdrawal symptoms are often dismissed, or misdiagnosed with relapse, or a new medical condition.

BACKGROUND: Stopping antidepressants commonly causes withdrawal symptoms, which can be severe and long-lasting. National Institute for Health and Care Excellence (NICE) guidance has been recently updated to reflect this; however, for many years withdrawal (discontinuation) symptoms were characterised as 'usually mild and self-limiting over a week'. Consequently, withdrawal symptoms might have been misdiagnosed as relapse of an underlying condition, or new onset of another medical illness, but this has never been studied. METHOD: This paper outlines the themes emerging from 158 respondents to an open invitation to describe the experience of prescribed psychotropic medication withdrawal for petitions sent to British parliaments. The accounts include polypharmacy (mostly antidepressants and benzodiazepines) but we focus on antidepressants because of the relative lack of awareness about their withdrawal effects compared with benzodiazepines. Mixed method analysis was used, including a 'lean thinking' approach to evaluate common failure points. RESULTS: The themes identified include: a lack of information given to patients about the risk of antidepressant withdrawal; doctors failing to recognise the symptoms of withdrawal; doctors being poorly informed about the best method of tapering prescribed medications; patients being diagnosed with relapse of the underlying condition or medical illnesses other than withdrawal; patients seeking advice outside of mainstream healthcare, including from online forums; and significant effects on functioning for those experiencing withdrawal. DISCUSSION: Several points for improvement emerge: the need for updating of guidelines to help prescribers recognise antidepressant withdrawal symptoms and to improve informed consent processes; greater availability of non-pharmacological options for managing distress; greater availability of best practice for tapering medications such as antidepressants; and the vital importance of patient feedback. Although the patients captured in this analysis might represent medication withdrawal experiences that are more severe than average, they highlight the current inadequacy of health care systems to recognise and manage prescribed drug withdrawal, and patient feedback in general.

Systematic endobronchial ultrasound-guided transbronchial needle aspiration improves radiotherapy planning in non-small cell lung cancer.

OBJECTIVES: Patients suitable for radical chemoradiotherapy for lung cancer routinely have radiotherapy (planning) volumes based on positron emission tomography (PET)-computed tomography (CT) imaging alone. Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) can identify PET-occult malignancy and benign PET-avid regions. We investigated the impact of EBUS-TBNA on curative-intent radiotherapy in non-small cell lung cancer (NSCLC). METHODS: A prospective multicentre trial was undertaken, investigating the impact of systematic EBUS-TBNA in addition to PET-CT for patients considered for radical chemoradiotherapy with NSCLC. A subset analysis of patients with discordant findings between PET-CT and EBUS-TBNA was performed. Radiotherapy plans investigated tumour coverage and dose to critical organs at risk (OARs) using PET-CT alone in comparison to PET-CT and EBUS-TBNA. RESULTS: Of 30 patients enrolled, 10 had discordant findings between PET-CT and EBUS-TBNA. EBUS-TBNA-derived plans allowed for reduction in dose to OARs in patients downstaged by EBUS-TBNA, and reduced the risk of geographic miss in treating PET-occult disease in four patients where EBUS-TBNA identified malignant involvement of PET-negative lymphadenopathy. With the addition of EBUS-TBNA to radiotherapy planning, reductions were noted of 5.7%, 3.7% and 12.5% for the risks of symptomatic pneumonitis, mean heart dose and mean oesophageal dose, respectively. CONCLUSIONS: This study demonstrates for the first time that systematic EBUS-TBNA prior to radical-intent radiotherapy significantly improves coverage of subclinical disease through detection of PET-occult metastases. Identification of false-positive lymph node involvement in highly selected cases may reduce radiation dose to critical structures, and risk of organ toxicity.

PET-detected pneumonitis following curative-intent chemoradiation in non-small cell lung cancer (NSCLC): recognizing patterns and assessing the impact on the predictive ability of FDG-PET/CT response assessment.

PURPOSE: Inflammatory FDG uptake in the lung (PET-pneumonitis) following curative-intent radiotherapy (RT)/chemo-RT (CRT) in non-small cell lung cancer (NSCLC) can pose a challenge in FDG-PET/CT response assessment. The aim of this study is to describe different patterns of PET-pneumonitis to guide the interpretation of FDG-PET/CT and investigate its association with tumor response and overall survival (OS). METHODS: Retrospective analysis was performed on 87 NSCLC patients in three prospective trials who were treated with radical RT (n = 7) or CRT (n = 80), with baseline and post-treatment FDG-PET/CT. Visual criteria were performed for post-treatment FDG-PET/CT response assessment. The grading of PET-pneumonitis was based on relative lung uptake intensity compared to organs of reference and classified as per Deauville score from grade 1-5. Distribution patterns of PET-pneumonitis were defined as follows: A) patchy/sub-pleural; B) diffuse (involving more than a segment); and C) peripheral (diffusely surrounding a photopenic region). RESULTS: Follow-up FDG-PET/CT scans were performed approximately 3 months (median, 89 days; interquartile range, 79-93) after RT. Overall, PET-pneumonitis was present in 62/87 (71%) of patients, with Deauville 2 or 3 in 12/62 (19%) and 4 or 5 in 50/62 (81%) of patients. The frequency of patterns A, B and C of PET-pneumonitis was 19/62 (31%), 20/62 (32%) and 23/62 (37%), respectively. No association was found between grade or pattern of PET-pneumonitis and overall response at follow-up PET/CT (p = 0.27 and p = 0.56, respectively). There was also no significant association between PET-pneumonitis and OS (hazard ratio [HR], 1.3; 95% confidence interval [CI], 0.6-2.5; p = 0.45). Early FDG-PET/CT response assessment, however, was prognostic for OS (HR, 1.7; 95% CI, 1.2-2.2; p < 0.001). CONCLUSION: PET-pneumonitis is common in early post-CRT/RT, but pattern recognition may assist in response assessment by FDG-PET/CT. While FDG-PET/CT is a powerful tool for response assessment and prognostication, PET-pneumonitis does not appear to confound early response assessment or to independently predict OS.

Radiotherapy and immunotherapy: a synergistic effect in cancer care.

Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers. Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre-existing active immune microenvironment that can be reactivated by ICIs. It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine. Radiotherapy increases expression of tumour-associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens. By its ability to overcome some tumour immune escape mechanisms, radiation provides a non-pharmacological and cost-effective approach to potentially improve the systemic response to immune checkpoints inhibitors.

What 18F-FDG PET Response-Assessment Method Best Predicts Survival After Curative-Intent Chemoradiation in Non-Small Cell Lung Cancer: EORTC, PERCIST, Peter Mac Criteria, or Deauville Criteria?

The optimal methodology for defining response with 18F-FDG PET after curative-intent chemoradiation for non-small cell lung cancer (NSCLC) is unknown. We compared survival outcomes according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC), PERCIST 1.0, the Peter Mac metabolic visual criteria, and the Deauville criteria, respectively. Methods: Three prospective trials of chemoradiation for NSCLC, involving baseline and posttreatment 18F-FDG PET/CT imaging, were conducted between 2004 and 2016. Responses were categorized as complete metabolic response (CMR), partial metabolic response, stable metabolic disease, or progressive metabolic disease. Cox proportional-hazards models and log-rank tests assessed the impact of each response on overall survival (OS). Results: Eighty-seven patients underwent 18F-FDG PET/CT before and after radical chemoradiation for NSCLC. Follow-up 18F-FDG PET/CT scans were performed at a median of 89 d (interquartile range, 79-93 d) after radiotherapy. Median follow-up and OS after PET response imaging were 49 and 28 mo, respectively. Interobserver agreements for EORTC, PERCIST, Peter Mac, and Deauville had κ values of 0.76, 0.76, 0.87, and 0.84, respectively. All 4 response criteria were significantly associated with OS. Peter Mac and Deauville showed better fit than EORTC and PERCIST and distinguished better between CMR and non-CMR. Conclusion: All 4 response criteria were highly predictive of OS, but visual criteria showed greater interobserver agreement and stronger discrimination between CMR and non-CMR, highlighting the importance of visual assessment to recognize radiation pneumonitis, changes in lung configuration, and patterns of response.

Adjuvant therapy in stage III endometrial cancer confined to the pelvis.

OBJECTIVE: To review outcomes of patients with stage III endometrial cancer confined to the pelvis treated with adjuvant pelvic radiotherapy (RT) or sequential chemoradiotherapy (CRT). METHODS: Between 1990 and 2012, 144 patients diagnosed with stage IIIA, B or C1 endometrial cancer were treated in our institution. All were treated with total hysterectomy, bilateral salpingo-oophorectomy ±â€¯lymph node dissection. Post-operatively, 67 patients received adjuvant RT alone, 37 CRT, 21 chemotherapy alone and 19 had no adjuvant therapy. This analysis focuses on the 104 patients treated with RT or CRT. RESULTS: The median follow-up was 61 months. Forty-six patients (44%) were stage IIIA, 6 (6%) were stage IIIB and 52 (50%) stage IIIC1. The 5-year overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) for patients treated by RT alone vs. CRT were, respectively, 67% vs. 61% (p = 0.55); 67% vs. 51% (p = 0.35); and 76% vs. 65% (p = 0.21). Grade 3 disease was an independent predictor for worse OS (HR = 6.01, p = 0.001), DFS (HR = 3.16, p = 0.03), and DSS (HR = 3.77, p = 0.02). In patients with grade 3 disease (n = 49), the 5-year OS was superior for the CRT (42% vs. 56%, p = 0.007). CONCLUSIONS: In patients with stage III endometrial cancer confined to the pelvis, the addition of adjuvant chemotherapy with RT significantly improved OS in grade 3 disease. Grade 3 histology is a strong predictor for poor outcome. Further randomized studies aiming specifically at stage III disease are warranted.

Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer.

Bladder cancer is considered as primarily a disease of the elderly, typically aged in their 70s or 80s and often with associated medical comorbidities. Unfortunately, fewer elderly patients receive radical treatment for muscle-invasive bladder cancer (MIBC) that their younger counterparts. Over the last decades, several studies have shown that the use of trimodality therapy consisting of transurethral bladder resection followed by concomitant chemotherapy and radiation therapy results in comparable outcomes to radical cystectomy, considered the gold standard for this disease. In this review, we revised the literature on bladder-preservation treatments using the trimodality approach in the elderly population with MIBC.

Hypofractionated intensity modulated radiation therapy in combined modality treatment for bladder preservation in elderly patients with invasive bladder cancer.

PURPOSE/OBJECTIVE(S): To review our experience with bladder-preserving trimodality treatment (TMT) using hypofractionated intensity modulated radiation therapy (IMRT) for the treatment of elderly patients with muscle-invasive bladder cancer. METHODS AND MATERIALS: Retrospective study of elderly patients treated with TMT using hypofractionated IMRT (50 Gy in 20 fractions) with concomitant weekly radiosensitizing chemotherapy. Eligibility criteria were as follows: age ≥70 years, a proven diagnosis of muscle-invasive transitional cell bladder carcinoma, stage T2-T3N0M0 disease, and receipt of TMT with curative intent. Response rate was assessed by cystoscopic evaluation and bladder biopsy. RESULTS: 24 patients with a median age of 79 years were eligible. A complete response was confirmed in 83% of the patients. Of the remaining patients, 1 of them underwent salvage cystectomy, and no disease was found in the bladder on histopathologic assessment. After a median follow-up time of 28 months, of the patients with a complete response, 2 patients had muscle-invasive recurrence, 1 experienced locoregional failure, and 3 experienced distant metastasis. The overall and cancer-specific survival rates at 3 years were 61% and 71%, respectively. Of the surviving patients, 75% have a disease-free and functioning bladder. All patients completed hypofractionated IMRT, and 19 patients tolerated all 4 cycles of chemotherapy. Acute grade 3 gastrointestinal or genitourinary toxicities occurred in only 4% of the patients, and acute grade 3 or 4 hematologic toxicities, liver toxicities, or both were experienced by 17% of the cohort. No patient experienced grade 4 gastrointestinal or genitourinary toxicity. CONCLUSIONS: Hypofractionated IMRT with concurrent radiosensitizing chemotherapy appears to be an effective and well-tolerated curative treatment strategy in the elderly population and should be considered for patients who are not candidates for cystectomy or who wish to avoid cystectomy.

Radiodiagnostic imaging in pregnancy and the risk of childhood malignancy: raising the bar.

Eduardo Franco and Guy-Anne Turgeon discuss new findings from Joel Ray and colleagues on the cancer risk following prenatal exposure to radiodiagnostic imaging, and where new research needs to be focused.

2D-3D registration of coronary angiograms for cardiac procedure planning and guidance.

We present a completely automated 2D-3D registration technique that accurately maps a patient-specific heart model, created from preoperative images, to the patient's orientation in the operating room. This mapping is based on the registration of preoperatively acquired 3D vascular data with intraoperatively acquired angiograms. Registration using both single and dual-plane angiograms is explored using simulated but realistic datasets that were created from clinical images. Heart deformations and cardiac phase mismatches are taken into account in our validation using a digital 4D human heart model. In an ideal situation where the pre- and intraoperative images were acquired at identical time points within the cardiac cycle, the single-plane and the dual-plane registrations resulted in 3D root-mean-square (rms) errors of 1.60 +/- 0.21 and 0.53 +/- 0.08 mm, respectively. When a 10% timing offset was added between the pre- and the intraoperative acquisitions, the single-plane registration approach resulted in inaccurate registrations in the out-of-plane axis, whereas the dual-plane registration exhibited a 98% success rate with a 3D rms error of 1.33 +/- 0.28 mm. When all potential sources of error were included, namely, the anatomical background, timing offset, and typical errors in the vascular tree reconstruction, the dual-plane registration performed at 94% with an accuracy of 2.19 +/- 0.77 mm.