Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Assessing nutrition literacy and nutrition counseling proficiency following an interdisciplinary culinary medicine elective.

CONTEXT: Culinary medicine (CM) is a growing field of education that aims to bridge the gap between the clinical need for nutritional counseling and the lack of education on the topic. Healthcare professionals can aid in nutrition-related noncommunicable disease (NCD) prevention by improving a patient's dietary behavior. However, the presence of nutrition education in healthcare curricula is lacking. Early evidence indicates that CM could address this gap. OBJECTIVES: The objectives of this study are to determine if the provision of an interdisciplinary CM elective will improve student knowledge and confidence with counseling on nutrition and culinary principles, and to improve personal dietary habits of students. METHODS: This was a one-group pretest-posttest quasi-experimental design. First- and second-year osteopathic medical students (OMS) and nurse practitioner students were recruited to participate in a CM elective via email. Participants were excluded if they were not in good academic standing at their respective institutions. Twelve individuals (n=8 medical; n=4 nursing) were enrolled in the course. Participants completed pre- and postcourse surveys to determine changes in nutrition literacy (Nutrition Literacy Assessment Instrument [NLit42]), nutrition counseling proficiency (Nutrition Survey for Family Practitioners), and dietary quality (Automated Self-Administered 24-h dietary assessment tool; ASA24®). A two-sided, paired t test was conducted to determine changes in outcome variables. RESULTS: All 12 participants completed the precourse assessments, and 8 participants completed the postcourse assessments. Culinary activity attendance was 94.5 %. Participants exhibited a statistically significant increase in their overall nutrition literacy scores after completing the CM elective (p=0.006). Literacy subcategories indicated that the improvement came from the participant's ability to understand household measurements (p=0.005) better. Increases in self-reported proficiency were observed for participants' confidence to counsel on nutrition and prevention/wellness (p=0.02) and macronutrients in health and food safety (p=0.01). No statistically significant changes in the personal dietary pattern or quality were observed. CONCLUSIONS: The interdisciplinary CM elective improved nutrition literacy and some aspects of counseling proficiency. Although small shifts in dietary variables were observed, the elective did not statistically improve participants' dietary pattern. However, some changes that were observed may lead to clinically relevant outcomes if maintained long-term. These findings are encouraging. Implementing CM as an educational tool could improve healthcare practitioners' ability to understand and counsel patients on nutrition to prevent the nutrition-related NCDs.

The future of cancer care in the UK-time for a radical and sustainable National Cancer Plan.

Cancer affects one in two people in the UK and the incidence is set to increase. The UK National Health Service is facing major workforce deficits and cancer services have struggled to recover after the COVID-19 pandemic, with waiting times for cancer care becoming the worst on record. There are severe and widening disparities across the country and survival rates remain unacceptably poor for many cancers. This is at a time when cancer care has become increasingly complex, specialised, and expensive. The current crisis has deep historic roots, and to be reversed, the scale of the challenge must be acknowledged and a fundamental reset is required. The loss of a dedicated National Cancer Control Plan in England and Wales, poor operationalisation of plans elsewhere in the UK, and the closure of the National Cancer Research Institute have all added to a sense of strategic misdirection. The UK finds itself at a crossroads, where the political decisions of governments, the cancer community, and research funders will determine whether we can, together, achieve equitable, affordable, and high-quality cancer care for patients that is commensurate with our wealth, and position our outcomes among the best in the world. In this Policy Review, we describe the challenges and opportunities that are needed to develop radical, yet sustainable plans, which are comprehensive, evidence-based, integrated, patient-outcome focused, and deliver value for money.

One versus three weeks hypofractionated whole breast radiotherapy for early breast cancer treatment: the FAST-Forward phase III RCT.

Background: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations: A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients.

Looking Back: International Practice Patterns in Breast Radiation Oncology From a Case-Based Survey Across 54 Countries During the First Surge of the COVID-19 Pandemic.

PURPOSE: The COVID-19 pandemic has profoundly affected cancer care worldwide, including radiation therapy (RT) for breast cancer (BC), because of risk-based resource allocation. We report the evolution of international breast RT practices during the beginning of the pandemic, focusing on differences in treatment recommendations between countries. MATERIALS AND METHODS: Between July and November 2020, a 58-question survey was distributed to radiation oncologists (ROs) through international professional societies. Changes in RT decision making during the first surge of the pandemic were evaluated across six hypothetical scenarios, including the management of ductal carcinoma in situ (DCIS), early-stage, locally advanced, and metastatic BC. The significance of changes in responses before and during the pandemic was examined using chi-square and McNemar-Bowker tests. RESULTS: One thousand one hundred three ROs from 54 countries completed the survey. Incomplete responses (254) were excluded from the analysis. Most respondents were from the United States (285), Japan (117), Italy (63), Canada (58), and Brazil (56). Twenty-one percent (230) of respondents reported treating at least one patient with BC who was COVID-19-positive. Approximately 60% of respondents reported no change in treatment recommendation during the pandemic, except for patients with metastatic disease, for which 57.7% (636/1,103; P < .0005) changed their palliative practice. Among respondents who noted a change in their recommendation during the first surge of the pandemic, omitting, delaying, and adopting short-course RT were the most frequent changes, with most transitioning to moderate hypofractionation for DCIS and early-stage BC. CONCLUSION: Early in the COVID-19 pandemic, significant changes in global RT practice patterns for BC were introduced. The impact of published results from the FAST FORWARD trial supporting ultrahypofractionation likely confounded the interpretation of the pandemic's independent influence on RT delivery.

Development and validation of models predicting treatment patterns in women with urinary urgency and/or urgency incontinence: A Symptoms of Lower Urinary Tract Dysfunction Research Network observational cohort study.

PURPOSE: To develop a tool to predict a woman's treatment pattern for bothersome urinary urgency (UU) and/or UU incontinence over 1 year after presenting for care at urology or urogynecology clinics. METHODS: The Symptoms of Lower Urinary Tract Dysfunction Research Network observational cohort study enrolled adult women with bothersome UU and/or UU incontinence using the lower urinary tract symptoms (LUTS) Tool who were seeking care for LUTS. Treatments for UU and/or urgency incontinence were ordered from least to most invasive. Ordinal logistic and Cox proportional hazard regression models were fit to predict the most invasive level of treatment during follow-up and overactive bladder (OAB) medication discontinuation, respectively. Binary logistic regression was performed to predict sling treatment during the study follow-up. Clinical tools were then created using the models listed above to predict treatment pattern over 12 months. RESULTS: Among 349 women, 281 reported UU incontinence, and 68 reported UU at baseline. The highest level of treatment during the study was as follows: 20% no treatment, 24% behavioral treatments, 23% physical therapy, 26% OAB medication, 1% percutaneous tibial nerve stimulation, 3% onabotulinumtoxin A, and 3% sacral neuromodulation. Slings were placed in 10% (n = 36) of participants before baseline and in 11% (n = 40) during study follow-up. Baseline factors associated with predicting the most invasive level of treatment included baseline level of treatment, hypertension, UU incontinence severity, stress urinary incontinence (SUI) severity, and anticholinergic burden score. Less severe baseline depression and less severe UU incontinence were associated with OAB medication discontinuation. UU and SUI severity were associated with sling placement during the study period. Three tools are available to predict: (1) highest level of treatment; (2) OAB medication discontinuation; and (3) sling placement. CONCLUSIONS: OAB treatment prediction tools developed in this study can help providers individualize treatment plans and identify not only patients at risk for treatment discontinuation but also patients who may not be escalated to potentially beneficial OAB treatments, with the goal to improve clinical outcomes for patients suffering from this chronic and often debilitating condition.

Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK.

Safety profile of cyclin-dependent kinase (CDK) 4/6 inhibitors with concurrent radiation therapy: A systematic review and meta-analysis.

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings.

Proton Beam Therapy for Early Breast Cancer: A Systematic Review and Meta-analysis of Clinical Outcomes.

PURPOSE: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking. METHODS AND MATERIALS: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis. RESULTS: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). CONCLUSIONS: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy.

Memory T cells possess an innate-like function in local protection from mucosal infection.

Mucosal infections pose a significant global health burden. Antigen-specific tissue-resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8+ T cells may also provide innate-like protection against antigenically unrelated pathogens independent of T cell receptor engagement. Whether bystander T cell activation is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated whether innate-like memory CD8+ T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory CD8+ T cells may mediate protection despite the lack of antigen specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen-nonspecific CD8+ T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8+ T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory CD8+ T cells from mice and humans. Altogether, our findings suggest that local bystander activation of CD8+ memory T cells contributes a fast and effective innate-like response to infection in mucosal tissue.

Pre-operative Radiotherapy And Deep Inferior Epigastric Artery Perforator (DIEP) flAp study (PRADA): Aesthetic outcome and patient satisfaction at one year.

INTRODUCTION: The optimal combination of radiotherapy and breast reconstruction has not yet been defined. Post-mastectomy radiotherapy (PMRT) has deleterious effects on breast reconstruction, leading to caution amongst surgeons. Pre-operative radiotherapy (PRT) is a growing area of interest, is demonstrated to be safe, and spares autologous flaps from radiotherapy. This study evaluates the aesthetic outcome of PRT and deep inferior epigastric artery perforator (DIEP) flap reconstruction within the Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp (PRADA) cohort. METHODS: PRADA was an observational cohort study designed to evaluate the feasibility and safety of PRT for women undergoing neoadjuvant chemotherapy and DIEP reconstruction. Panel evaluation of 3D surface images (3D-SIs) and patient-reported outcome measures (BREAST-Q) for a subset of women in the study were compared with those of a DIEP-PMRT cohort who had undergone DIEP reconstruction and PMRT. RESULTS: Seventeen out of 33 women from the PRADA study participated in this planned substudy. Twenty-eight women formed the DIEP-PMRT cohort (median follow-up 23 months). The median (inter-quartile range [IQR]) 'satisfaction with breasts' score at 12 months for the PRADA cohort was significantly better than the DIEP-PMRT cohort (77 [72-87] versus 64 [54-71], respectively), p=0.01). Median [IQR] panel evaluation (5-point scale) was also significantly better for the PRADA cohort than for the DIEP-PMRT cohort (4.3 [3.9-4.6] versus 3.6 [2.8-4] p=0.003). CONCLUSIONS: Aesthetic outcome for the PRADA cohort was reported to be 'good' or 'excellent' in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP-PMRT at 23 months. Switching surgery-radiotherapy sequencing leads to similar breast aesthetic outcomes and warrants further large-scale, multi-centre evaluation in a randomised trial.

Treatment patterns in women with urinary urgency and/or urgency urinary incontinence in the symptoms of Lower Urinary Tract Dysfunction Research Network Observational Cohort Study.

BACKGROUND: Limited epidemiological data exist describing how patients engage with various treatments for overactive bladder (OAB). To improve care for patients with OAB, it is essential to gain a better understanding of how patients interface with OAB treatments longitudinally, that is, how often patients change treatments and the pattern of this treatment change in terms of escalation and de-escalation. OBJECTIVES: To describe treatment patterns for women with bothersome urinary urgency (UU) and/or urgency urinary incontinence (UUI) presenting to specialty care over 1 year. STUDY DESIGN: The Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study enrolled adult women with bothersome UU and/or UUI seeking care for lower urinary tract symptoms (LUTS) between January 2015 and September 2016. An ordinal logistic regression model was fitted to describe the probabilities of escalating or de-escalating level of treatment during 1-year follow-up. RESULTS: Among 349 women, 281 reported UUI and 68 reported UU at baseline. At the end of 1 year of treatment by a urologist or urogynecologist, the highest level of treatment received by participants was 5% expectant management, 36% behavioral treatments (BT), 26% physical therapy (PT), 26% OAB medications, 1% percutaneous tibial nerve stimulation, 3% intradetrusor onabotulinum toxin A injection, and 3% sacral neuromodulation. Participants using BT or PT at baseline were more likely to be de-escalated to no treatment than participants on OAB medications at baseline, who tended to stay on medications. Predictors of the highest level of treatment included starting level of treatment, hypertension, UUI severity, stress urinary incontinence, and anticholinergic burden score. CONCLUSIONS: Treatment patterns for UU and UUI are diverse. Even for patients with significant bother from OAB presenting to specialty clinics, further treatment often only involves conservative or medical therapies. This study highlights the need for improved treatment algorithms to escalate patients with persistent symptoms, or to adjust care in those who have been unsuccessfully treated.

Characterization of the GU microbiome in women with self-perceived bladder health over the life course.

BACKGROUND: A variety of factors influence bladder health, including environmental factors, life experiences, biologic foundations, and coexistent medical conditions. A biologically diverse microbial community exists in the urine that is likely influenced by the microbial inhabitants of the vagina. The relationship between the genitourinary (GU) microbiome and self-perceived bladder health is unknown. OBJECTIVE: To longitudinally define the GU microbiome in women with self-percieved bladder health sampled across multiple time points over a year. STUDY DESIGN: Women with no reported lower urinary tract dysfunction or symptoms (LUTS) were recruited from six clinical sites and assessed every 6 weeks for 1 year. Voided urine and vaginal samples were longitudinally collected. Self-perceived bladder health was assessed with select items from the LURN comprehensive assessment of self-reported urinary symptoms (CASUS) tool. We defined four life phases as follows: young (18-34 years, nulliparous), midlife (35-45 years, menstruating), transitional (46-60 years, perimenopausal), mature (>60 years, not using vaginal and/or systemic hormone replacement therapy). DNA was extracted from samples, and the V4 region of the 16S rRNA gene was amplified with region-specific primers. The 16S rRNA sequencing on an Illumina NovaSeq. Microbial beta-diversity was calculated using DEICODE to identify microbial taxa that cluster in the samples. Longitudinal volatility analysis was performed using the gemelli plugin. Log-abundance ratios of microbial features were explored and visualized in Qurro. RESULTS: Fifty-four (N = 16 young, N = 16 midlife, N = 15 transitional, N = 7 mature) women were enrolled and provided baseline data. Most women in each life phase (93%-98%) continued to report self-perceived bladder health throughout the 1-year follow-up as assessed by CASUS items. Temporal-based microbial diversity of urinary and vaginal microbiome remained relatively stable over 1 year in all subjects. The GU microbiomes of mature women were distinct and microbially diverse from that of young, midlife, and transitional women, with genera of Gardnerella, Cupriavidus, and Dialister contributory to the microbial features of the mature microbiome. The mature GU microbiome was statistically different (p < 0.0001) from the midlife, transitional, and young microbiome for the log ratio of Gardnerella and Cupriavidus (in the numerator) and Lactobacillus (in the denominator) for voided samples and Gardnerella and Dialister (in the numerator) and Lactobacillus (in the denominator) for vaginal samples. Differences in the GU microbiome were also demonstrated via longitudinal beta-diversity between women developing urinary frequency as reported by CASUS responses or objectively on bladder diary compared to women without urinary frequency. CONCLUSION: In women with a self-perceived healthy bladder, the GU microbiome remained stable in all age groups over a 1 year period. Differences were seen with respect to life phase, where mature women were distinct from all other groups, and with respect to self-reported LUTS.

Cost-effectiveness of 5 fraction and partial breast radiotherapy for early breast cancer in the UK: model-based multi-trial analysis.

PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

Parents' talk about conceptual categories with infants: stability, variability, and implications for expressive language development.

Children's exposure to talk about conceptual categories plays a powerful role in shaping their conceptual development. However, it remains unclear when parents begin to talk about categories with young children and whether such talk relates to children's language skills. This study examines relations between parents' talk about conceptual categories and infants' expressive language development. Forty-seven parent-infant dyads were videotaped playing together at child age 10, 12, 14, and 16 months. Transcripts of interactions were analyzed to identify parents' talk about conceptual categories. Children's expressive language development was assessed at 18 months. Findings indicate that parents indeed talked about conceptual categories with infants and that talk was stable across time, with college-educated parents producing more than non-college-educated parents. Further, parents' talk about conceptual categories between 10 and 16 months predicted children's 18-month expressive language. This study sheds new light on mechanisms through which early experiences may support children's language development.

Longitudinal urinary microbiome characteristics in women with urgency urinary incontinence undergoing sacral neuromodulation.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the stability of the urinary microbiome communities in women undergoing sacral neuromodulation (SNM) for urgency urinary incontinence (UUI). We hypothesized that clinical response to SNM therapy would be associated with changes in the urinary microbiome. METHODS: Women completed the Overactive Bladder Questionnaire Short-Form, the International Consultation on Incontinence Questionnaire Short Form, and the Female Sexual Function Index at baseline and 3 months post-SNM implantation. Transurethral urinary specimens were obtained for microbiome analysis at baseline and 3 months postoperatively. The V4 region of the 16S rRNA gene (515F-806R) was amplified with region-specific primers, and Amplicon Sequence Variants (ASVs) were identified with a closed-reference approach of taxonomic classification. Alpha-diversity was calculated using the phylogenetic (i.e., Faith's phylogenetic diversity) and nonphylogenetic metrics (i.e., Shannon diversity, and Pielou's evenness) using the QIIME2 plugin. Longitudinal paired volatility analysis was performed using the DEICODE and Gemelli plugin to account for host specificity across both time and space. RESULTS: Nineteen women who underwent SNM and provided both baseline and 3-month urine samples were included in this analysis. Women reported improvement in objective (number of UUI episodes) and subjective (symptom severity and health-related quality of life) measures. Ninety percent of the bacteria were classified as Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. No significant differences were observed in each subject's beta-diversity at 3 months compared with their baseline microbiome. CONCLUSIONS: Our descriptive pilot study of a cohort of women who had achieved objective and subjective improvements in UUI following SNM therapy demonstrates that the urinary microbiome remains relatively stable, despite variability amongst the cohort.

Extra-Virgin Olive Oil Enhances the Blood-Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial.

Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-ß (Aß) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aß42/Aß40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aß. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.