Longitudinal brain volumetrics in glioma survivors.

OBJECTIVE: Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT. METHODS: This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models. RESULTS: The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36-18.9 years), and the median number of time points analyzed per patient was 12 (range 2-40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (ß = -0.06, p < 0.001) and use of RT (ß = -1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (ß = -0.08, p < 0.001), midline involvement (ß = 1.31, p = 0.006), and use of RT (ß = -1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (ß = -0.0027, p = 0.001), tumor resection (ß = -0.069, p < 0.001), use of chemotherapy (ß = -0.0597, p = 0.003), and use of RT (ß = -0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model. CONCLUSIONS: This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

Motiv8: a study protocol for a cluster-randomised feasibility trial of a weight management intervention for adults with severe mental illness in secure forensic services.

INTRODUCTION: People with severe mental illness have physical comorbidities which result in significant reductions in quality of life and premature mortality. Effective interventions are required that are suitable for people in secure forensic mental health services. We conducted pilot work of a multidisciplinary weight management intervention (Motiv8) which showed improvements in physical and mental health and high levels of satisfaction. We aim to test the feasibility of Motiv8 under cluster randomised conditions, with an aim to investigate the acceptability, feasibility and potential effectiveness of this intervention to supplement standard secure care. METHODS AND ANALYSIS: A randomised waitlist-controlled feasibility trial of a lifestyle intervention (Motiv8) + TAU compared with TAU (+ Motiv8 waitlist) for adults on secure mental health units will be conducted. Thirty-two people (4 cohorts) will be recruited from secure services in Greater Manchester Mental Health NHS Foundation Trust. Participants will be randomly allocated to Motiv8 or TAU + Motiv8 waitlist. All participants will receive Motiv8 during the trial. Assessor-blinded physical/mental health and lifestyle assessments will be conducted at baseline, 10 weeks (post-intervention/waitlist), and after 12 weeks (post-waitlist intervention/follow-up). Motiv8 is a multidisciplinary intervention including exercise sessions, cooking/nutrition classes, physical health education, psychology sessions, sleep hygiene, peer support and medication review by pharmacy. A nested qualitative study will be conducted with a subsample of participants (n = 10) to explore their experiences of taking part. The analysis will focus on feasibility outcomes and tabulated success indicators of the study (e.g. Recruitment rates, retention rates, follow-up retention and response rates, attendance at sessions, the experience of involvement in the trial and delivery of the intervention, assessment of safety, development of a manualised intervention). Thematic analysis will be conducted through qualitative interviews. The analysis will aim to inform the development of a definitive trial. ETHICS AND DISSEMINATION: The trial has been granted ethical approval from the NHS Health Research Authority and adopted onto the UK Clinical Research Network Portfolio. Findings will be disseminated via peer-reviewed publications, professional and public networks, conferences and clinical services. TRIAL REGISTRATION: ISRCTN13539285.

Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models.

The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including RPGR, CEP290, MYO7A, and USH2A. Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques.

Acute Toxicity of Total Body Irradiation Using Volumetric Arc Therapy With a Focus on the Effect of Lung Dose Rate.

Purpose: To report adverse effects of high dose total body irradiation (TBI) delivered using a volumetric arc therapy (VMAT) technique and to assess pulmonary toxicity at dose rates of 40 and 100 monitor units per minute (MU/min). Methods and Materials: This retrospective study included patients >18 years old who received ≥8 Gy TBI using a VMAT technique. The TBI dose was prescribed to a planning target volume consisting of a 0.5 cm retraction of the body with the lungs subtracted. The objective function specified planning target volume coverage goals of D100% ≥ 90% and Dmax <130%. A lung dose control structure consisting of a 1 cm retraction of the lung volume was limited to Dmean <75%. Treatments were initially delivered with a dose rate of 40 MU/min for the thoracic isocenters and 100 MU/min for the other isocenters. Beginning in January 2021, a dose rate of 100 MU/min was used for all isocenters. All treatments were administered in 2 Gy fractions delivered twice daily. Acute toxicity was assessed for 30 days after TBI. Results: A total of 29 patients were included in this analysis who received TBI between January 2019 and October 2021. Prescription dose ranged from 8 to 12 Gy. Mean lung dose was 7.9 Gy (SD, 1.4 Gy) for patients treated at 40 MU/min and for patients treated at 100 MU/min 7.1 Gy (SD, 1.3 Gy). Mucositis was the most common grade 3 toxicity and occurred in 10 (34%) patients. Only 1 instance of pneumonitis was observed and occurred in a patient who received a mean lung dose of 10.1 Gy delivered at 40 MU/min. Conclusions: In this cohort of patients who received high dose TBI using a VMAT technique, the composite rate of acute toxicity was not unexpectedly high. We did not observe an increase in lung toxicity after increasing the dose rate of the thoracic isocenters from 40 MU/min to 100 MU/min.

ONE SHOT - single shot radiotherapy for localized prostate cancer: 18-month results of a single arm, multicenter phase I/II trial.

PURPOSE: To assess in a prospective, multicenter, single-arm phase I/II study the early safety and efficacy profile of single fraction urethra-sparing stereotactic body radiotherapy (SBRT) for men with localized prostate cancer. MATERIAL AND METHODS: Patients with low- and intermediate-risk localized prostate cancer without significant tumor in the transitional zone were recruited. A single-fraction of 19 Gy was delivered to the prostate, with 17 Gy dose-reduction to the urethra. Intrafraction motion was monitored using intraprostatic electromagnetic transponders with intra-fraction correction of displacements exceeding 3 mm. Genitourinary (GU), gastrointestinal (GI), and sexual toxicity during the first 18 months were evaluated using the CTCAE v4.0 grading scale. Quality of life was assessed using the International Prostate Symptom Score, the Expanded Prostate Cancer Index composite 26 score, and the International Index of Erectile Function score. RESULTS: Among the 45 patients recruited in 5 centers between 2017 and 2022, 43 received the single fraction without protocol deviations, and 34 had a minimal follow-up of 18 months. The worst GU toxicity was observed at day-5 after SBRT (42.5 % and 20 % with grade 1 and 2, respectively), returning to baseline at week-12 and month-6 (<3% with grade 2), with a 12 % grade 2 flare at month 18. Gl toxicity was mild in the acute phase, with no grade ≥ 2 events (12 % grade 1 at month 6). Grade-3 proctitis was observed in one patient at month 12, with < 3 % grade 2 toxicity at month 18. Mean GU and GI bother scores showed a decline at day 5, a complete recovery at month 6, and a flare between month 12 and 18. Mean PSA dropped from 6.2 ng/ml to 1.2 ng/ml at month 18 and 0.7 ng/ml at month 24. After a median follow-up time of 26 months, 3 biochemical failures (7 %) were observed at month 17, 21 and 30. CONCLUSIONS: In this multicenter phase I/II trial, we demonstrated that a 19 Gy single-fraction urethra-sparing SBRT is feasible and associated with an acceptable toxicity rate, mostly returning to the baseline at week-12 and with a symptoms flare between months 12 and 18. Longer follow-up is needed to assess the potential long-term adverse effects and the disease control efficacy.

Availability of cancer survivorship support services across the National Cancer Institute Community Oncology Research Program network.

BACKGROUND: National cancer organizations recommend provision of nutrition, physical activity, and mental health supportive services to cancer survivors. However, the availability of these services across diverse community oncology settings remains unclear. METHODS: The National Cancer Institute Community Oncology Research Program (NCORP) is a national network of community oncology practices engaged in cancer research. The 2022 NCORP Landscape Assessment (5UG1CA189824) assessed individual practices' establishment of survivorship clinics and nutrition, physical activity, and mental health services, resources, and/or referrals. Descriptive statistics summarized and logistic regression quantified the association between services, practice, and patient characteristics. RESULTS: Of 46 NCORP community sites, 45 (98%) responded to the survey, representing 259 adult practice groups. A total of 41% had a survivorship clinic; 96% offered mental health, 94% nutrition, and 53% physical activity services, resources, and/or referrals. All 3 services were offered in various formats (eg, in-house, referrals, education) by 51% and in-house only by 25% of practices. Practices with advanced practice providers were more likely to have a survivorship clinic (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.04 to 9.76). Practices with at least 30% Medicare patients (OR = 2.54, 95% CI = 1.39 to 4.66) and more oncology providers (OR = 1.02, 95% CI = 1.01 to 1.04) were more likely to have all 3 services in any format. Practices with at least 30% Medicare patients (OR = 3.41, 95% CI = 1.50 to 7.77) and a survivorship clinic (OR = 2.84, 95% CI = 1.57 to 5.14) were more likely to have all 3 services in-house. CONCLUSIONS: Larger oncology practices and those caring for more survivors on Medicare provided more supportive services, resources, and/or referrals. Smaller practices and those without survivorship clinics may need strategies to address potential gaps in supportive services.

The fate of rice crop residues and context-dependent greenhouse gas emissions: Model-based insights from Eastern India.

Crop residue burning is a common practice in many parts of the world that causes air pollution and greenhouse gas (GHG) emissions. Regenerative practices that return residues to the soil offer a 'no burn' pathway for addressing air pollution while building soil organic carbon (SOC). Nevertheless, GHG emissions in rice-based agricultural systems are complex and difficult to anticipate, particularly in production contexts with highly variable hydrologic conditions. Here we predict long-term net GHG fluxes for four rice residue management strategies in the context of rice-wheat cropping systems in Eastern India: burning, soil incorporation, livestock fodder, and biochar. Estimations were based on a combination of Tier 1, 2, and 3 modelling approaches, including 100-year DNDC simulations across three representative soil hydrologic categories (i.e., dry, median, and wet). Overall, residue burning resulted in total direct GHG fluxes of 2.5, 6.1, and 8.7 Mg CO2-e in the dry, median, and wet hydrologic categories, respectively. Relative to emissions from burning (positive values indicate an increase) for the same dry to wet hydrologic categories, soil incorporation resulted in a -0.2, 1.8, or 3.1 Mg CO2-e change in emissions whereas use of residues for livestock fodder increased emissions by 2.0, 2.1, or 2.3 Mg CO2-e. Biochar reduced emissions relative to burning by 2.9 Mg CO2-e in all hydrologic categories. This study showed that the production environment has a controlling effect on methane and, therefore, net GHG balance. For example, wetter sites had 2.8-4.0 times greater CH4 emissions, on average, than dry sites when rice residues were returned to the soil. To effectively mitigate burning without undermining climate change mitigation goals, our results suggest that geographically-target approaches should be used in the rice-based systems of Eastern India to incentivize the adoption of regenerative 'no burn' residue management practices.

Simulated digestions of free oligosaccharides and mucin-type O-glycans reveal a potential role for Clostridium perfringens.

The development of a stable human gut microbiota occurs within the first year of life. Many open questions remain about how microfloral species are influenced by the composition of milk, in particular its content of human milk oligosaccharides (HMOs). The objective is to investigate the effect of the human HMO glycome on bacterial symbiosis and competition, based on the glycoside hydrolase (GH) enzyme activities known to be present in microbial species. We extracted from UniProt a list of all bacterial species catalysing glycoside hydrolase activities (EC 3.2.1.-), cross-referencing with the BRENDA database, and obtained a set of taxonomic lineages and CAZy family data. A set of 13 documented enzyme activities was selected and modelled within an enzyme simulator according to a method described previously in the context of biosynthesis. A diverse population of experimentally observed HMOs was fed to the simulator, and the enzymes matching specific bacterial species were recorded, based on their appearance of individual enzymes in the UniProt dataset. Pairs of bacterial species were identified that possessed complementary enzyme profiles enabling the digestion of the HMO glycome, from which potential symbioses could be inferred. Conversely, bacterial species having similar GH enzyme profiles were considered likely to be in competition for the same set of dietary HMOs within the gut of the newborn. We generated a set of putative biodegradative networks from the simulator output, which provides a visualisation of the ability of organisms to digest HMO and mucin-type O-glycans. B. bifidum, B. longum and C. perfringens species were predicted to have the most diverse GH activity and therefore to excel in their ability to digest these substrates. The expected cooperative role of Bifidobacteriales contrasts with the surprising capacities of the pathogen. These findings indicate that potential pathogens may associate in human gut based on their shared glycoside hydrolase digestive apparatus, and which, in the event of colonisation, might result in dysbiosis. The methods described can readily be adapted to other enzyme categories and species as well as being easily fine-tuneable if new degrading enzymes are identified and require inclusion in the model.

Characterization of Photon Intensity Modulated Radiation Therapy Robustness in Patients With Prostate Cancer as a Proposed Benchmark for Proton Therapy Robustness Evaluation.

PURPOSE: Robustness evaluation is increasingly used in particle therapy planning to assess clinical target volume (CTV) coverage in the setting of setup and range uncertainty. However, no clear standard exists as to an acceptable degree of plan robustness. The aim of this study is to quantify x-ray robustness parameters, as this could inform proton planning when held to a similar standard. METHODS AND MATERIALS: Consecutive patients with prostate adenocarcinoma treated with definitive x-irradiation to the prostate alone at a single institution in 2019 were retrospectively reviewed. CTV to planned target volume (PTV) margins of 7 mm in all directions, except 4 mm posteriorly, were used in the main cohort. Plans were normalized to PTV V100% ≥ 95%. Patient setup errors were simulated by shifting the isocenter relative to the patient in each of the cardinal directions. The magnitude of each shift equaled the magnitude of the CTV to PTV expansion in that direction. Range uncertainty was set to 0%. RESULTS: A total of 27 patients were evaluated. The mean (SD) nominal plan CTV V100% was 99.6% (1.1%). The mean (SD) worst-case shift CTV V100% was 97.2% (2.8%). The mean (SD) nominal and worst-case CTV V95% were 100% (0%) and 99.7% (0.5%), respectively. A worst-case CTV V100% > 90% and a worst-case CTV V95% > 99% were achieved in over 95% of plans. The mean (SD) nominal and worst-case rectal V70 Gy were 2.37 cc (1.00 cc) and 11.60 cc (3.16 cc), respectively. The mean (SD) nominal and worst-case bladder V60 Gy were 7.8% (4.8%) and 14.5% (9.3%), respectively. Paired 2-tailed t tests comparing the nominal to worst-case dose-volume histograms were significant for each dosimetric parameter (P < .01). CONCLUSIONS: X-ray planning uses PTV margins to inherently provide robustness to patient setup errors. Although the prostate remains well covered in various setup uncertainty scenarios, organs at risk routinely exceeded nominal treatment plan institutional constraints in the worst-case scenarios. Robustness metrics obtained from x-ray plans could serve as a benchmark for proton therapy robust optimization and evaluation.

Volumetric brain assessment of long-term head and neck cancer survivors.

BACKGROUND: Radiation therapy (RT) for locally advanced head and neck cancer (HNC) often exposes subcortical brain structures to radiation. We performed this study to assess region-specific brain volumetrics in a population of long term HNC survivors. METHODS AND MATERIALS: Forty HNC survivors were enrolled at a mean of 6.4 years from completion of RT. Patients underwent a research MRI protocol that included a 3D T1- weighted whole-brain scan on a 3 Tesla MRI scanner. Voxel based morphometry was performed using the Computational Anatomy Toolbox with the Neuromorphometrics atlas. Healthy controls from the Human Connectome Project were used as a comparison cohort. Study participants also completed a comprehensive neurocognitive assessment. RESULTS: The final study cohort consisted of 38 participants after excluding 2 participants due to image quality. HNC survivors displayed widespread reduction in gray matter (GM) brain region volumes that included bilateral medial frontal cortex, temporal lobe, hippocampus, supplemental motor area, and cerebellum. Greater radiation exposure was associated with reduced GM volume in the left ventral diencephalon (r = -0.512, p = 0.003). Associations between cognition and regional GM volumes were identified for motor coordination and bilateral cerebellum (left, r = 0.444, p = 0.009; right, r = 0.372, p = 0.030), confrontation naming and left amygdala (r = 0.382, p = 0.026), verbal memory and bilateral thalamus (left, r = 0.435, p = 0.010; right, r = 0.424, p = 0.012), right amygdala (r = 0.339, p = 0.050), and right putamen (r = 0.364, p = 0.034). CONCLUSIONS: Reductions in GM were observed within this cohort of primarily non-nasopharyngeal HNC survivors as compared to a control sample. GM volumes were associated with performance in multiple cognitive domains. Results of this exploratory study support the need for investigation of anatomic brain changes as an important translational corollary to cognitive problems among HNC survivors.

Riding the tides: Directions in mental health rehabilitation in NSW.

OBJECTIVE: This paper outlines the evolution of mental health rehabilitation in NSW, where allocation of health resources has repeatedly contradicted the policy intention to reorient services from inpatient to community-based services, leaving community rehabilitation the poor and disconnected cousin of inpatient services. The expanding role of community-managed organisations (CMOs) in psychosocial rehabilitation, the introduction of the National Disability Insurance Scheme (NDIS), and emerging service models have helped foster a maturing housing and social care environment, but present reality and the integration of health and social care services remains at a distance from best evidence practice. CONCLUSION: The challenge of the next decade of mental health reform is to embrace and consolidate greater service diversity and complexity. Understanding what factors influenced present reality is important in providing guardrails for the future, enabling the current wave of renewal and reinvestment in NSW to build on the strengths of past developments and steer a course around their weaknesses.

Crop establishment and diversification strategies for intensification of rice-based cropping systems in rice-fallow areas in Odisha.

Context or problem: In the Indian state of Odisha, rice-based system productivity is poor due to: (i) low rice yield in the monsoon (wet) season (2-4 t ha-1 compared to 6-8 t ha-1 in Punjab or Haryana); and (ii) limited cropping during the post-monsoon (dry) season (59% of the wet season rice area is left fallow in the dry season). Objective: Our study identifies strategies for increasing rice-based system productivity through: (i) alternative crop establishment methods in the wet season (Dry-Direct Seeded Rice or DSR, and mechanical puddled transplanted rice or PTR-M) to traditional methods such as broadcasting followed by post-emergence tillage (locally known as beushening) and manual random puddled transplanted rice (PTR-R); (ii) to identify rice-fallow areas suitable for pulse and oilseed cultivation in the dry season; and (iii) to evaluate the performance of short-duration pulses (green gram, Vigna radiata; black gram, Vigna mungo), and oilseeds (Brassica rapa var. toria, Helianthus annuus) in rice-fallow areas in the dry season. Methods: On-farm experiments were conducted between 2017 and 2019 in three districts of Odisha (Bhadrak, Cuttack and Mayurbhanj) to evaluate DSR compared to beushening and PTR-R; and PTR-M compared to PTR-R and manual line puddled transplanted rice (PTR-L) in the wet season. The data from Landsat-8 Operational Land Imager (OLI) and Sentinel-1satellite sensors was used to identify rice-fallow areas, and the daily SMAP (Soil Moisture Active Passive) L-band soil moisture was used for mapping suitable rice-fallow areas for growing pulses and oilseeds. Short duration crops were evaluated in suitable rice-fallow areas. Results: In the wet season, DSR (range -4 to + 53%) had a significant effect on rice yield over beushening. Similarly, PTR-M consistently increased rice yield by 16-26% over PTR-R, and by 5-23% over PTR-L. In the dry season, pulse crops (green gram and black gram) performed well compared to Indian mustard under rainfed cultivation. However, under irrigated conditions, dry-season rice yield was more productive than the rice equivalent yield of green gram, black gram and sunflower. We found that 1.03 M ha (i.e., ∼50%) of total rice-fallow areas of 2.1 M ha were suitable for growing short duration green gram and black gram in the dry season. Conclusions: We conclude that system productivity and cropping intensity can be increased by adoption of DSR and PTR-M in the wet season, and growing of green gram and black gram in the dry season. Implications: Odisha state can potentially produce an additional 0.67 million tonnes pulses if suitable rice-fallow areas are brought under green gram and black gram cultivation in the dry the season.

Analysis of treatment of muscle invasive bladder cancer using the national cancer database: Factors associated with receipt of aggressive therapy.

OBJECTIVES: To characterize the treatments received by muscle-invasive bladder cancer (MIBC) patients, analyze their use according to sociodemographic, clinical, pathologic, and facility variables, and identify possibilities for improvement in care, with the understanding that patients with MIBC face a potentially lethal disease, yet often do not receive guideline-concordant potentially curative therapies. MATERIALS AND METHODS: Using the National Cancer Data Base (NCDB), we analyzed 102,119 patients with MIBC diagnosed from 2009 to 2018. Treatments included cystectomy, radiation, chemotherapy (CT), or observation. Treatments including cystectomy or radiotherapy (RT) ≥50 Gy were considered aggressive therapy (AT). A multivariable generalized estimating equation model was used to assess the impact of the independent variables with receiving AT, using SAS version 9.4. RESULTS: The median age was 73 years, with 72.9% male, 84.3% White, and 7.1% Black. Stage distribution was 59.4% stage II, 23.0% stage III, and 17.6% stage IV. Overall, 55.2% of patients received AT, while 41.1% did not, with 26.6% receiving observation alone after transurethral resection of bladder tumor. 45.4% received cystectomy, 9.8% received RT, and 12.8% received CT as primary treatment. Notably, over 30% of patients ages 50 to 70 did not receive aggressive therapy. On multivariate analysis, factors associated with nonreceipt of AT included age >70 (OR < 0.79, P < 0.0001), Black race (OR 0.70, P < 0.0001), underinsured status (OR 0.62, P < 0.0001), high comorbidity (OR 0.74, P < 0.0001), and treatment at low volume (OR 0.72 P < 0.0001) or nonacademic cancer program (OR 0.54, P < 0.0001). Long-term trends included increases in utilization of perioperative CT (17.5% in 2009 to 46.7% in 2018, P < 0.001), and chemoradiation (5.4% in 2009 to 8.8% in 2018, P < 0.001). Using Cox regression analysis to control for confounding variables, receipt of aggressive therapy was associated with improved overall survival. CONCLUSIONS: Over a third of patients did not receive AT for MIBC, with many of these patients seemingly eligible by age and comorbidity status. Prospective studies are needed to determine why these patients do not receive AT. A better understanding of patient vs. access to care vs. provider factors will help to focus efforts to improve care for MIBC patients.

Stereotactic Body Radiation Therapy Salvage for Lymph Node Recurrent Prostate Cancer in the Era of PSMA PET Imaging.

PURPOSE OF REVIEW: Our understanding of patterns of prostate cancer recurrence after primary treatment of localized disease has significantly evolved since the development of positron emission tomography (PET) agents targeting prostate cancer. Previously, most biochemical recurrences were not associated with imaging correlates when restaging with computed tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy and, hence, were typically assumed to represent occult metastases. A rising prostate specific antigen (PSA) after previous local therapy prompting a PET scan showing uptake limited to regional lymph nodes is an increasingly common clinical scenario as advanced prostate cancer imaging becomes more widely utilized. The optimal management strategy for patients who have lymph node recurrent prostate cancer is both unclear and evolving, particularly in terms of local and regionally directed therapies. Stereotactic body radiation therapy (SBRT) utilizes ablative radiation doses with steep gradients to achieve local tumor control while sparing nearby normal tissues. SBRT is an attractive therapeutic modality due to its efficacy, favorable toxicity profile, and flexibility to administer elective doses to areas of potential occult involvement. The purpose of this review is to briefly describe how SBRT is being implemented in the era of PSMA PET for the management of solely lymph node recurrent prostate cancer. RECENT FINDINGS: SBRT has been shown to effectively control individual lymph node tumor deposits within the pelvis and retroperitoneum for prostate cancer and is well-tolerated with a favorable toxicity profile. However, a major limitation thus far has been the lack of prospective trials supporting the use of SBRT for oligometastatic nodal recurrent prostate cancer. As further trials are conducted, its exact role in the treatment paradigm of recurrent prostate cancer will be better established. Although PET-guided SBRT appears feasible and potentially beneficial, there is still considerable uncertainty about the use of elective nodal radiotherapy (ENRT) in patients with nodal recurrent oligometastatic prostate cancer. PSMA PET has undoubtedly advanced imaging of recurrent prostate cancer, revealing anatomic correlates for disease recurrence that previously went undetected. At the same time, SBRT continues to be explored in prostate cancer with feasibility, a favorable risk profile, and satisfactory oncologic outcomes. However, much of the existing literature comes from the pre-PSMA PET era and integration of this novel imaging approach has led to greater focus on new and ongoing clinical trials to rigorously evaluate this approach and compare to other established treatment modalities utilized for oligometastatic, nodal recurrence of prostate cancer.

Influence of conservation agriculture-based production systems on bacterial diversity and soil quality in rice-wheat-greengram cropping system in eastern Indo-Gangetic Plains of India.

Introduction: Conservation agriculture (CA) is gaining attention in the South Asia as an environmentally benign and sustainable food production system. The knowledge of the soil bacterial community composition along with other soil properties is essential for evaluating the CA-based management practices for achieving the soil environment sustainability and climate resilience in the rice-wheat-greengram system. The long-term effects of CA-based tillage-cum-crop establishment (TCE) methods on earthworm population, soil parameters as well as microbial diversity have not been well studied. Methods: Seven treatments (or scenarios) were laid down with the various tillage (wet, dry, or zero-tillage), establishment method (direct-or drill-seeding or transplantation) and residue management practices (mixed with the soil or kept on the soil surface). The soil samples were collected after 7 years of experimentation and analyzed for the soil quality and bacterial diversity to examine the effect of tillage-cum-crop establishment methods. Results and Discussion: Earthworm population (3.6 times), soil organic carbon (11.94%), macro (NPK) (14.50-23.57%) and micronutrients (Mn, and Cu) (13.25 and 29.57%) contents were appreciably higher under CA-based TCE methods than tillage-intensive farming practices. Significantly higher number of OTUs (1,192 ± 50) and Chao1 (1415.65 ± 14.34) values were observed in partial CA-based production system (p ≤ 0.05). Forty-two (42) bacterial phyla were identified across the scenarios, and Proteobacteria, Actinobacteria, and Firmicutes were the most dominant in all the scenarios. The CA-based scenarios harbor a high abundance of Proteobacteria (2-13%), whereas the conventional tillage-based scenarios were dominated by the bacterial phyla Acidobacteria and Chloroflexi and found statistically differed among the scenarios (p ≤ 0.05). Composition of the major phyla, i.e., Proteobacteria, Actinobacteria, and Firmicutes were associated differently with either CA or farmers-based tillage management practices. Overall, the present study indicates the importance of CA-based tillage-cum-crop establishment methods in shaping the bacterial diversity, earthworms population, soil organic carbon, and plant nutrient availability, which are crucial for sustainable agricultural production and resilience in agro-ecosystem.

Assessment of longitudinal changes in body composition of children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Studies examining changes in skeletal muscle and adipose tissue during treatment for cancer in children, adolescents, and young adults and their effect on the risk of chemotherapy toxicity (chemotoxicity) are limited. METHODS: Among 78 patients with lymphoma (79.5%) and rhabdomyosarcoma (20.5%), changes were measured in skeletal muscle (skeletal muscle index [SMI]; skeletal muscle density [SMD]) and adipose tissue (height-adjusted total adipose tissue [hTAT]) between baseline and first subsequent computed tomography scans at the third lumbar vertebral level by using commercially available software. Body mass index (BMI; operationalized as a percentile [BMI%ile]) and body surface area (BSA) were examined at each time point. The association of changes in body composition with chemotoxicities was examined by using linear regression. RESULTS: The median age at cancer diagnosis of this cohort (62.8% male; 55.1% non-Hispanic White) was 12.7 years (2.5-21.1 years). The median time between scans was 48 days (range, 8-207 days). By adjusting for demographics and disease characteristics, this study found that patients undergo a significant decline in SMD (ß ± standard error [SE] = -4.1 ± 1.4; p < .01). No significant changes in SMI (ß ± SE = -0.5 ± 1.0; p = .7), hTAT (ß ± SE = 5.5 ± 3.9; p = .2), BMI% (ß ± SE = 4.1 ± 4.8; p = .3), or BSA (ß ± SE = -0.02 ± 0.01; p = .3) were observed. Decline in SMD (per Hounsfield unit) was associated with a greater proportion of chemotherapy cycles with grade ≥3 nonhematologic toxicity (ß ± SE = 1.09 ± 0.51; p = .04). CONCLUSIONS: This study shows that children, adolescents, and young adults with lymphoma and rhabdomyosarcoma undergo a decline in SMD early during treatment, which is associated with a risk of chemotoxicities. Future studies should focus on interventions designed at preventing the loss of muscle during treatment. PLAIN LANGUAGE SUMMARY: We show that among children, adolescents, and young adults with lymphoma and rhabdomyosarcoma receiving chemotherapy, skeletal muscle density declines early during treatment. Additionally, a decline in skeletal muscle density is associated with a greater risk of nonhematologic chemotoxicities.

Understanding the Effect of Prescription Isodose in Single-Fraction Stereotactic Radiosurgery on Plan Quality and Clinical Outcomes for Solid Brain Metastases.

BACKGROUND AND OBJECTIVES: There is wide variation in treatment planning strategy for central nervous system (CNS) stereotactic radiosurgery. We sought to understand what relationships exist between intratumor maximum dose and local control (LC) or CNS toxicity, and dosimetric effects of constraining hotspots on plan quality of multiple metastases volumetric modulated arc therapy radiosurgery plans. METHODS: We captured brain metastases from 2015 to 2017 treated with single-isocenter volumetric modulated arc therapy radiosurgery. Included tumors received single-fraction stereotactic radiosurgery, had no previous surgery or radiation, and available follow-up imaging. Our criterion for local failure was 25% increase in tumor diameter on follow-up MRI or pathologic confirmation of tumor recurrence. We defined significant CNS toxicity as Radiation Therapy Oncology Group irreversible Grade 3 or higher. We performed univariate and multivariate analyses evaluating factors affecting LC. We examined 10 stereotactic radiosurgery plans with prescriptions of 18 Gy to all targets originally planned without constraints on the maximum dose within the tumor. We replanned each with a constraint of Dmax 120%. We compared V50%, mean brain dose, and Dmax between plans. RESULTS: Five hundred and thirty tumors in 116 patients were available for analysis. Median prescription dose was 18 Gy, and median prescription isodose line (IDL) was 73%. Kaplan-Meier estimate of 12-month LC only tumor volume (HR 1.43 [1.22-1.68] P < .001) was predictive of local failure on univariate analysis; prescription IDL and histology were not. In multivariate analysis, tumor volume impacted local failure (HR 1.43 [1.22-1.69] P < .001) but prescription IDL did not (HR 0.95 [0.86-1.05] P = .288). Only a single grade 3 and 2 grade 4 toxicities were observed; tumor volume was predictive of CNS toxicity (HR 1.58 [1.25-2.00]; P < .001), whereas prescription IDL was not (HR 1.01 [0.87-1.17] P = .940). CONCLUSION: The prescription isodose line had no impact on local tumor control or CNS toxicity. Penalizing radiosurgery hotspots resulted in worse radiosurgery plans with poorer gradient. Limiting maximum dose in gross tumor causes increased collateral exposure to surrounding tissue and should be avoided.

Benchmarking Automated Machine Learning-Enhanced Planning With Ethos Against Manual and Knowledge-Based Planning for Locally Advanced Lung Cancer.

Purpose: Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer. Methods and Materials: Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board-approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review. Results: Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage (P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics (P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics (P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were "per protocol" or met "variation acceptable" ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes. Conclusions: A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace.

Implementing conjunctive management of water resources for irrigation development: A framework applied to the Southern Plain of Western Nepal.

Climate variability and insufficient irrigation are primary constraints to stable and higher agricultural productivity and food security in Nepal. Agriculture is the largest global freshwater user, and integration of surface- and ground-water use is frequently presented as an strategy for increasing efficiency as well as climate change adaptation. However, conjunctive management (CM) planning often ignores demand-side requirements and a broader set of sustainable development considerations, including ecosystem health and economics of different development strategies. While there is generic understanding of conjunctive use, detailed technical knowhow to realize the CM is lacking in Nepal. This article presents a holistic framework through literature reviews, stakeholders consultations and expert interviews for assessing CM and implementation prospects from a systems-level perspective. We demonstrate the framework through a case study in Western Nepal, where climatic variability and a lack of irrigation are key impediments to increased agricultural productivity and sustainable development. Results show that knowledge of water resources availability is good and that of water demand low in the Western Terai. Additional and coordinated investments are required to improve knowledge gaps as well as access to irrigation. There is therefore a need to assess water resources availability, water access, use and productivity, to fill the knowledge gaps in order to pave pathways for CM. This paper also discusses some strategies to translate prospects of conjunctive management into implementation.