BACKGROUND:Noninvasive quantitative assessment of marrow recovery after curative therapies such as total marrow irradiation (TMI) and bone marrow transplantation (BMT) remain poorly defined, particularly in sickle cell disease (SCD). PURPOSE:To evaluate MRI-derived proton density fat fraction (PDFF) as a biomarker of marrow recovery following organ-sparing total marrow irradiation-based transplantation (OS-TMI/BMT) in an SCD mouse model and to assess initial clinical feasibility in patients. STUDY TYPE:Exploratory preclinical study with descriptive pilot feasibility analysis in humans. SUBJECTS:Townes SCD mice (n = 10 controls, n = 8 treated) and 2 adults (male, 24 ± 1 years old) with SCD. FIELD STRENGTH/SEQUENCE:Preclinical 7-T small-bore MRI used a spoiled gradient echo (GRE) multi-echo sequence for PDFF and R2* mapping, while clinical 3-T MRI employed a spoiled GRE-based sequence. ASSESSMENT:Marrow recovery in an animal study was assessed using MRI-derived PDFF with ROI analysis, complemented by micro-CT and histologic evaluation. Translational feasibility was assessed with longitudinal PDFF MRI in 2 adults with severe SCD undergoing marrow transplantation. STATISTICAL TESTS:Parametric data were analyzed using t-tests and Pearson correlation, nonparametric data using Mann-Whitney U and Spearman correlation, and two-way ANOVA assessed group, region, and interaction effects, with significance set at p < 0.05. RESULTS:Right femur MRI showed partial restoration of adipose-rich marrow in the OS-TMI/BMT group versus controls, higher PDFF in the proximal metaphysis (42.5 ± 2.7 vs. 34.8 ± 6.5), midshaft diaphysis (44.8 ± 3.0 vs. 26.9 ± 7.0), and distal metaphysis (45.1 ± 2.6 vs. 36.2 ± 4.9). OS-TMI/BMT also improved trabecular structure, with increased trabecular thickness, reduced bone surface-to-volume ratio, lower structure model index and anisotropy, and increased distal bone volume density. In 2 patients, PDFF increased post-transplant, and 1-year biopsy showed trilineage hematopoiesis without fibrosis. DATA CONCLUSION:Marrow-selective transplantation was associated with partial normalization of the marrow and skeletal microenvironment in SCD. PDFF may provide a practical noninvasive approach for monitoring post-transplant marrow recovery. LEVEL OF EVIDENCE: 4: TECHNICAL EFFICACY:Stage 2.

Background and Objectives: Bladder cancer (BC) represents a significant global health burden, ranking as the tenth most commonly diagnosed malignancy worldwide, with an incidence rate of 5.6 per 100,000 person-years annually. The research team aimed to summarize evidence on specialized nursing-led interventions for bladder cancer management across the disease continuum. Materials and Methods: This scoping review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) methodology to search four databases from January 2018 to November 2025. Results: This concise but informative scoping review of 20 studies revealed substantial clinical and patient-reported benefits from specialized nursing interventions. Enhanced recovery after surgery (ERAS) protocols incorporating structured nursing care demonstrated a 35% reduction in postoperative complications. Integrated nursing interventions during postoperative intravesical therapy significantly improved patient satisfaction, treatment compliance, and self-efficacy while reducing anxiety and depression. Digital health platforms, including internet-based and mobile applications, proved effective in reducing caregiver burden, enhancing disease knowledge, and improving coping strategies. Preoperative stoma education and postoperative ostomy care management significantly improved self-efficacy, stoma care knowledge, and overall health-related quality of life. Psychosocial interventions, including cognitive behavioral therapy and mindfulness-based approaches, demonstrated significant improvements in quality of life and reductions in fear of recurrence, depression, and anxiety. However, a critical evidence gap exists regarding bladder cancer-specific mental health interventions. Conclusions: Specialized nursing-led care plays a critical role in strengthening clinical and assistive practice in bladder cancer. Evidence from this scoping review shows that nursing-led interventions significantly improve clinical outcomes, patient satisfaction, symptom management, and quality of life across all phases of bladder cancer care while reducing caregiver burden and enhancing psychological well-being for both patients and families, reinforcing the value of integrating specialized nursing roles into routine bladder cancer management.

Background:[18F] 3'-deoxy-3'-fluorothymidine positron emission tomography (FLT-PET) is valuable for detecting acute myeloid leukemia (AML) and monitoring stem cell engraftment after hematopoietic stem cell transplant (HCT) by assessing cellular proliferation in marrow-rich tissues. Reliable marrow quantification is difficult to achieve, and manual segmentation is impractical in clinical workflows. Most automated tools focus on solid tumors and lack clinical validation for skeletal FLT-PET/CT. This study evaluates deep learning whole-body segmentation and cortical-trabecular marrow quantification on FLT-PET/CT in AML with HCT. Results:Twenty refractory AML patients undergoing total marrow and lymphoid irradiation (TMLI) and transplantation were analyzed. From 134 predefined regions, five representative ROIs (spleen, liver, T6, L1, L3) validated agreement with manual segmentation. Automated and manual count measurements showed strong agreement, with a high correlation (r > 0.98, p < 0.0001). Consistent hotspot detection by both methods supports the AI tool's accuracy and clinical applicability. Small liver/spleen differences and larger positive vertebral trabecular biases were observed. AI cut processing time by ~ 95%, markedly improving efficiency. Conclusion:This study provides a technical validation of an AI-driven multi-organ segmentation platform for FLT-PET/CT in AML and HCT, including separate cortical bone and trabecular marrow compartments. The automated approach demonstrated high agreement, excellent reproducibility, and substantial efficiency gains in skeletal marrow and organ quantification. These findings establish a scalable framework for future studies that will correlate FLT-based bone marrow metrics with clinical response and transplant outcomes. Trial registration:ClinicalTrials.gov NCT03422731. Registered 6 February 2018, https//www.cancer.gov/research/participate/clinicaltrialssearch/v?id=NCI201701778.

Background: Melanoma outcomes have improved in recent years as a result of modern systemic therapies. A major molecular feature of melanoma is abnormal telomerase activation; this is most often caused by telomerase reverse transcriptase (TERT) promoter mutations, which occur in 50–82% of cases and are the most common noncoding alteration in this cancer. Telomerase maintains telomere length, allowing melanoma cells to avoid senescence and continue dividing. However, how telomerase activity influences melanoma cell doubling time remains unclear, and the pathways linking TERT expression to faster cell-cycle progression require further study. Although telomerase inhibitors show promise in preclinical models, their clinical use is limited by delayed cytotoxicity and resistance. Materials and Methods: A scoping review was conducted using Scopus, ScienceDirect, MEDLINE/PubMed, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Keywords included “telomerase,” “melanoma,” “cancer,” “cell proliferation,” and “doubling time,” using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Telomerase-related biomarkers were found to correlate with disease stage and survival. Suggested therapeutic strategies include enzyme inhibitors, cytotoxic nucleotide incorporation, telomere destabilization, and immunotherapies such as peptide or dendritic cell vaccines, etc. Conclusions: Understanding both telomere-dependent and -independent TERT functions is essential for developing effective biomarkers and therapies that overcome resistance and slow melanoma progression.

Sickle cell disease (SCD) is associated with chronic bone marrow stress, altered hematopoiesis, and reduced adiposity. Whether marrow-selective conditioning followed by transplantation normalizes these abnormalities remains unclear. We investigated bone marrow remodeling in Townes mice by comparing SCD control (SCD-Con) with mice that received total marrow irradiation (TMI) followed by bone marrow transplantation (SCD-TMI-BMT). Multiparametric micro-MRI at 7 T quantified proton density water fraction (PDWF), proton density fat fraction (PDFF), and R2*(1/T2*), and micro-CT assessed trabecular structure in the femur. SCD-Con marrow showed higher water content (elevated PDWF), reduced adiposity (lower PDFF), and imaging features consistent with erythroid hyperplasia and elevated iron burden (shorter T2* with reciprocal increase in R2*). In contrast, SCD-TMI-BMT mice demonstrated smaller R2*, reduced PDWF, and partial restoration of adiposity, accompanied by reciprocal shifts in R2*, consistent with decreased cellular iron and marrow remodeling. Micro-CT revealed an improved trabecular architecture after BMT compared to SCD control. MRI imaging biomarkers aligned with histologic evidence of reduced cellularity and larger adipocyte voids. In conclusion, a TMI-BMT SCD model promotes partial normalization of the marrow microenvironment. Multiparametric MRI with micro-CT provides a practical, non-invasive framework for monitoring marrow remodeling and skeletal health after curative therapy.

Background/Objectives:Bone marrow (BM) adipocytes are critical in progressing solid tumor metastases and hematological malignancies across pediatric to aging populations. Single-point biopsies remain the gold standard for monitoring BM diseases, including hematologic malignancies, but are limited in capturing the full complexity of loco-regional and global BM microenvironments. Non-invasive imaging techniques like Magnetic Resonance Imaging (MRI), could offer valuable alternatives for real-time evaluation of BM diseases in both preclinical translational and clinical studies. Methods:We developed a preclinical proton density fat fraction (PDFF) MRI technique for quantitative BM composition assessment, focusing on fat fraction (FF) within mouse femurs. We validated this method using aging mice and young mice subjected to 10 Gy X-ray irradiation, compared with young unirradiated mice as controls. Water-fat phantoms (0% to 100% fat content) were used to optimize the imaging sequence, and immunohistochemical (IHC) staining with H&E validates equivalent adipose content in the femur BM regions. Results:Significant differences in FF were observed across age groups (p = 0.001 for histology and p = 0.0002 for PDFF) and between irradiated and control mice (p = 0.005 for histology and p = 0.002 for PDFF). A strong correlation (R 2 ∼ 0.84) between FF values from PDFF and histology validates the accuracy of the technique. Conclusions:These findings demonstrate the potential of PDFF MRI as a non-invasive real-time imaging biomarker for quantifying BM fat fraction in preclinical mice model studies, particularly in evaluating the effects of aging, disease progression, and irradiation therapy in pediatric and translational oncology research.

Background: Bone marrow (BM) adipocytes play a critical role in the progression of both solid tumor metastases and expansion of hematological malignancies across a spectrum of ages, from pediatric to aging populations. Single-point biopsies remain the gold standard for monitoring BM diseases, including hematologic malignancies, but these are limited in capturing the full complexity of loco-regional and global BM microenvironments. Non-invasive imaging techniques such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), and Positron Emission Tomography (PET) could provide valuable alternatives for real-time evaluation in both preclinical translational and clinical studies. Methods: We developed a preclinical proton density fat fraction (PDFF) MRI technique for the quantitative assessment of BM composition, focusing on the fat fraction (FF) within mouse femurs. We validated this method using aging mice and young mice subjected to 10 Gy X-ray irradiation, compared to young control mice. Water–fat phantoms with varying fat percentages (0% to 100%) were used to optimize the imaging sequence, and immunohistochemical (IHC) staining with H&E validated equivalent adipose content in the femur BM region. Results: Significant differences in FF were observed across age groups (p = 0.001 for histology and p < 0.001 for PDFF) and between irradiated and control mice (p = 0.005 for histology and p = 0.002 for PDFF). A strong correlation (R2~0.84) between FF values from PDFF-MRI and histology validated the accuracy of the technique. Conclusions: These findings highlight PDFF-MRI’s potential as a non-invasive, real-time, in vivo biomarker for quantitatively assessing the BM fat fraction in preclinical studies, particularly in studies evaluating the effects of aging, disease progression, and cytotoxic cancer therapies, including chemotherapy and radiation.

Melanoma survival has improved markedly in the past decade with new systemic agents. A key molecular hallmark is aberrant telomerase activation, largely driven by telomerase reverse transcriptase (TERT) promoter mutations (which are present in 50–82% of cases). These mutations represent the most frequent noncoding alteration in melanoma. Telomerase activation results in replicative immortality by maintaining telomere length, so cancer cells bypass senescence and apoptosis. However, the relationship between telomerase activity and melanoma cell population doubling time remains poorly defined. Pathways linking telomerase expression to accelerated cell cycle progression require further study. While telomerase inhibitors show preclinical promise, clinical application is limited by delayed cytotoxicity and resistance mechanisms. No review has yet mapped evidence connecting telomerase activity with melanoma proliferation kinetics and doubling time. Materials and Methods: A scoping review was conducted using Scopus, ScienceDirect, MEDLINE/PubMed, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Keywords included “telomerase,” “melanoma,” “cancer,” “cell proliferation,” and “doubling time.” The PRISMA framework guided our analysis of published studies. Results: Telomerase is clinically relevant for diagnosis, prognosis, and therapy. Biomarkers such as telomere length, telomerase activity, and TERRA expression correlate with disease stage and survival. Therapeutic strategies include enzyme inhibitors (e.g., Imetelstat), cytotoxic nucleotide incorporation, telomere destabilization, and immunotherapies such as peptide or dendritic cell vaccines, DNA vaccines, and CAR-T cells. Resistance often arises through alternative telomere maintenance mechanisms. Targeting extratelomeric TERT functions offers promise but remains complex. Conclusions: Telomerase drives melanoma progression through telomere-dependent and independent mechanisms, influencing proliferation, survival, metabolism, and genome stability. Clarifying these processes is essential for developing biomarkers and therapies that effectively target telomerase, overcome resistance, limit cancer progression and potentially provide another useful therapeutic option against melanoma.

Background: Traditional systemic myeloablative conditioning methods, such as total body irradiation (TBI) and chemotherapy, severely damage the gastrointestinal (GI) tract and induce graft-versus-host disease (GVHD), negatively impacting patient outcomes in allogeneic transplantation. This gut damage disrupts the microbiota, leading to dysbiosis. Despite numerous efforts, post-treatment interventions have achieved limited success so far. We developed a high-precision total marrow irradiation (TMI) in vivo model, enabling tissue specific dose delivery with higher dose of radiation being delivered to disease sites while sparing other at-risk organs. We previously showed that reducing radiation dose to the gut reduces MadCam1 expression on gut endothelial cells, consequently reducing α4β7 integrin-mediated T cell adhesion to the gut, which may result in less GVHD. Here, we investigated the impact of TMI radiation delivery on gut biodiversity and overall biological responses. Methods: Balb/c (H2d) mice were subjected to either 8 Gy (4Gy/fraction in 2 fractions in 6 hrs) of TBI or TMI with the latter limiting GI exposure to 4 Gy (n≥4, duplicate study). Twenty-four hours post-irradiation, the mice received T cell-depleted B6 (H2b) donor bone marrow cells and enriched spleen conventional T cells. We collected fecal samples pre-irradiation, then on days 7 and 14 post-bone marrow transplant (BMT) for microbiome analysis using shotgun metagenomics (Transnetyx) and analyzed on the One Codex platform. We assessed radiation-induced effects on GI using immunofluorescence and electron microscopy and evaluated GI structure-function by analyzing microvilli structure, gut permeability (FITC Dextran), and inflammatory cytokines analysis. Results: The average microvilli height is significantly (p=0.003) reduced in the TBI group (485.93 ± 24 nm) compared to the TMI group (631.69 ± 32.29 nm), suggesting TMI preserves GI structures better than TBI. In addition, FITC-dextran uptake in serum showed increased leakiness in TBI treated mice than TMI mice (Mean Fluorescence; 7.8X 105 vs 6.01X 105, p=0.0233) suggesting less damage to GI in TMI treatment. Fecal microbiome analysis showed radiation conditioning alters alpha diversity (species diversity) as indicated by a lower Shannon Diversity Index (SDI median: 1.2 vs ~1.0) at post-BMT time-points. However, higher gut microbiome diversity was detected in TMI than TBI-treated mice at Day 7 post-BMT (Median SDI 0.9 vs 1.1). Moreover, TMI-treated mice showed higher relative abundances of the bacterial genera Alistipes and Prevotella, along with their respective species, compared to TBI-treated mice. Fecal samples from TMI-treated mice showed 2-fold decrease (p=0.034) in Firmicutes/Bacteroidetes (F/B) ratio and increased SCFA receptors FFAR3/GPR41 (12%, p=0.03) compared to TBI, which could promote a better gut barrier integrity and reduce inflammation. TMI-treated mice displayed significantly lower systemic inflammatory cytokine levels (e.g. TNFa, IL-1α, IL-9, IFN-γ, and IL-17a) as measured by cytokine array, confirmed with Elisa for TNFa (Day 3 and day 7 post BMT, p=0.002, p=0.04, respectively), compared to TBI-treated mice. Reduction in inflammatory cytokines was correlated with a marked decrease in GVHD. Conclusions: This study demonstrates that our novel tissue-specific myeloablative conditioning regimen, TMI, effectively preserve gut microbiome diversity and integrity after BMT in the murine model, compared to traditional systemic conditioning methods. TMI's targeted radiation delivery minimizes collateral damage to the gut microbiota by reducing GI exposure, thereby alleviating GVHD through enhanced GI structure-function, increased microbiome diversity, reduced systemic inflammation, and altered immune modulation. These findings open new therapeutic avenues that leverage microbiome preservation to improve transplant outcomes. Future research will explore how TMI maintains the gut microbiome, focusing on the roles of different microbial species and their metabolites, and their influence on immune cell recruitment and activation. This understanding will enhance insights into the interactions between the gut microbiome and immune responses post-irradiation, guiding more effective and personalized therapeutic interventions and ongoing clinical trial planning.

Despite our increasing understanding of the biology and evolution of the cancer process, it is indisputable that the natural process of cancer creation has become increasingly difficult to cure, as more mutations are found with age. It is significantly more difficult to challenge the curative method when there is heterogeneity within the tumor, as it hampers clinical and genetic categorization. With advances in diagnostic technologies and screening leading to progressive tumor shrinkage, it becomes more difficult over time to evaluate the effects of treatment on overall survival. New treatments are often authorized based on early evidence, such as tumor response; disease-free, progression-free, meta-static-free, and event-free survival; and, less frequently, based on clinical endpoints, such as overall survival or quality of life, when standard guidelines are not available to approve pharmaceuticals. These clearances usually happen quite rapidly. Although approval takes longer, relative survival demonstrates the genuine worth of a novel medication. Pressure is being applied by pharmaceutical companies and patient groups to approve “new” treatments based on one of the above-listed measures, with results that are frequently insignificantly beneficial and frequently have no impact on quality of life.

BACKGROUND:Breast cancer treatment has seen tremendous progress since the early 1980s, with the first findings of new chemotherapy and hormone therapies. Screening started in the same period.METHODS:A review of population data (SEER and the literature) shows an increase in recurrence-free survival until 2000 and it stagnates afterwards.RESULTS:Over the period 1980-2000, the 15% survival gain was presented by pharma as a contribution of new molecules. The contribution of screening during that same period was not implemented by them, although screening has been accepted as a routine procedure in the States since the 1980s and everywhere else since 2000.CONCLUSIONS:Interpretation of breast cancer outcome has largely focused on drugs, whereas other factors, such as screening, prevention, biologics, and genetics, were largely neglected. More attention should now be paid to examining the strategy based on realistic global data.

EDITORIAL article Front. Oncol., 19 July 2023Sec. Radiation Oncology Volume 13 - 2023 | https://doi.org/10.3389/fonc.2023.1240530

BackgroundTomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT).MethodsIn a single center 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a composite four-items measure of the time to 10% alteration in any of patient-reported outcomes, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat.ResultsAt 12 years median follow-up, overall and disease-free survivals between randomized arms were comparable, while survival time free from alteration significantly improved with H-IGRT which showed a gain of restricted mean survival time of 1.46 years over CRT, P=0.041.DiscussionThe finding establishes TomoBreast as a proof-of-concept that hypofractionated image-guided radiation-therapy can improve the sparing of lung-heart function in breast cancer adjuvant therapy without loss in disease-free survival. Hypofractionation is advantageous, conditional on using an advanced radiation technique. Multicenter validation may be warranted.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00459628. Registered 12 April 2007.

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Introduction: The trafficking of immune cells in the GI is crucial for tissue immunity and can be targeted for the treatment of immune-related GI damage. Flow cytometry, as the primary technique to identify immune cells in organs such as the GI, has made substantial progress, offering valuable insights into a variety of immune cell subtypes and their microenvironments. However, one major limitation is the destruction of tissue samples during processing, lacking spatial information on immune cells in their microenvironment. Furthermore, there is a lack of information about how stress-induced tissue damage affects T-cell trafficking. In particular, the pre-HCT conditioning regime is essential for identifying the extent of organ damage and donor immune cell trafficking to the GI microenvironment and the subsequent occurrence of Graft vs Host Disease (GVHD). To address this need, it is necessary to develop a real-time imaging method for characterizing immune cells in the GI in an allogeneic bone marrow transplant (BMT) system. Here, we report developing a temperature-controlled Two-photon microscopy (TPM) setup investigating the pattern of T cell trafficking in the GI in real time and how modulating radiation dose affects immune cell trafficking in the preclinical mouse GVHD model of allogeneic BMT. Method: BALB/c Host mice were treated with 8 Gy TBI in 2 fractions, 6 h apart. For the GI dose reduction study (GI-4 Gy), Total Marrow Irradiation (TMI 8:4; 8 Gy to Bone marrow, 4 Gy to rest of the body including GI) was used as described (Darren et al. 2021). Donor B6 T cell Depleted bone marrow cells along with 1 million enriched tdtomato+ T cells were transplanted, and 7 days later, live T cell trafficking in GI was monitored by TPM (Prairie Ultima microscope). Vessels were labeled with QTracker 655, and TPM parameters were set as described (J Brooks et al. 2021). For imaging, a temperature-controlled externalized intestine's intravital imaging (EIII) window was developed (Fig 1.A) and was first evaluated to visualize the three-dimensional basis of Jejunum. It allows continuous blood flow while effectively controlling peristalsis, cardiac and respiratory motion artifacts with minimal tissue damage, delay in tissue degradation. A section of the intestine (Jejunum) was externalized from anesthetized mice and fixed on the EIII window's surface using n-butyl cyanoacrylate veterinary adhesive. The luminal surface was exposed by making an incision along the intestine, carefully avoiding the vascular plexus. The spatial distribution of vessels and tdtomato+ T-cells (green) at different z-stacks was evaluated by imaging through both serosa and luminal sides. GI samples were fixed in 10% NBF, OCT embedded, cryosection (5-10 m), and Anti-MAdCAM1 immunofluorescence (IF) performed using a standard protocol. Results: EIII window usage significantly reduced peristaltic movement, enabling T cells imaging at different depths from serosa to villi crypt (Fig 1.A-B). T cells reside preferentially in the lower crypt region and are affected by the radiation dose given to GI (Fig 1.D-G). T-cell localization at the crypt base region (~ 100µ from serosa) was significantly higher in TBI (8 Gy GI dose) mice than in TMI (4 Gy GI dose). Fig. 1 (F-G) shows T cell distribution at the top, middle, and base of the villi, and in the crypt, during luminal side imaging. Further, microvascular structures were affected at higher radiation dose, as seen by reduced vessel density in 8 Gy over 4 Gy treatments or control (Fig 1.C). Thus, ~50% dose reduction improved vasculature and reduced T cell trafficking. Histological analysis of intestinal tissue with lysozyme and anti-MAdCAM1 staining for confocal imaging further shows reduced crypt damage and T cell trafficking in lower radiation (Fig 1.H). Summary: TPM enabled us to visualize T cells in real-time within the GVHD mouse intestine. Radiation-induced tissue damage-dependent T-cell trafficking was evident in the mouse GI with GVHD and validated through the target receptor of MAdCAM1 endothelial cell expression. The spatial heterogeneity of T cells emphasizes the preferential niche of immune trafficking and associated GI environment and thus, the need for cautious interpretation of GVHD biopsies and warrants further studies on their spatial localization in immune cell-mediated GI diseases.

Purpose: Previous studies in patients with breast cancer have shown acute radiation therapy-induced reductions of pulmonary diffusing capacity, essentially owing to lung volume restriction. We aimed to assess the long-term effect of 2 radiation therapy regimens, which differed in terms of radiation technique and dose fractionation, on lung function. Methods and Materials: From a randomized controlled trial comparing conventional 3-dimensional conformal radiation therapy (CR) and hypofractionated tomotherapy (TT), 84 patients with breast cancer (age at inclusion 54 +/- 10 [standard deviation] years) could be assessed at baseline, after 3 months, and after 1, 2, 3, and 10 years. Measurements included forced vital capacity, total lung capacity (TLC), and diffusing capacity (TLco). Results: Radiation therapy-induced lung function changes over 10 years (Delta) were similar for both treatment arms, and in a patient subgroup with negligible history of respiratory disease or smoking (n = 57) these averaged: Delta forced vital capacity = -13 (+/- 9) percent predicted; Delta TLco = -14 (+/- 12) percent predicted; and Delta TLC = -11 (+/- 9) percent predicted. The only significant correlation was between V20 (lung volume exposed to dose exceeding 20 Gy) and Delta TLco (rho = -0.36; P =.007). In this subgroup, as well as in the entire patient cohort, the incurred pulmonary restriction in terms of TLC and TLco showed a greater decline at 3 months for CR versus TT. However, at 10 years, no significant difference could be detected between CR and TT (P = .9 for TLC and P = .2 for TLco in the entire patient cohort). Of the patients with normal TLC and TLco at baseline (ie, above lower limits of normal), respectively 94% and 96% were still normal 10 years later. Conclusions: In women with breast cancer, conventional 3-dimensional conformal radiation therapy and hypofractionated tomotherapy induce similar restrictive lung patterns during the course of a 10-year period, despite some treatment-dependent differences in the first 3 months. The large majority of women with normal lung function at baseline maintained a normal lung function status 10 years after radiation therapy, irrespective of treatment arm. (C) 2022 Elsevier Inc. All rights reserved.

We investigated lung-heart toxicity and mortality in 123 women with stage I-II breast cancer enrolled in 2007–2011 in a prospective trial of adjuvant radiotherapy (TomoBreast). We were concerned whether the COVID-19 pandemic affected the outcomes. All patients were analyzed as a single cohort. Lung-heart status was reverse-scored as freedom from adverse-events (fAE) on a 1–5 scale. Left ventricular ejection fraction (LVEF) and pulmonary function tests were untransformed. Statistical analyses applied least-square regression to calendar-year aggregated data. The significance of outliers was determined using the Dixon and the Grubbs corrected tests. At 12.0 years median follow-up, 103 patients remained alive; 10-years overall survival was 87.8%. In 2007–2019, 15 patients died, of whom 11 were cancer-related deaths. In 2020, five patients died, none of whom from cancer. fAE and lung-heart function declined gradually over a decade through 2019, but deteriorated markedly in 2020: fAE dipped significantly from 4.6–4.6 to 4.3–4.2; LVEF dipped to 58.4% versus the expected 60.3% (PDixon = 0.021, PGrubbs = 0.054); forced vital capacity dipped to 2.4 L vs. 2.6 L (PDixon = 0.043, PGrubbs = 0.181); carbon-monoxide diffusing capacity dipped to 12.6 mL/min/mmHg vs. 15.2 (PDixon = 0.008, PGrubbs = 0.006). In conclusion, excess non-cancer mortality was observed in 2020. Deaths in that year totaled one-third of the deaths in the previous decade, and revealed observable lung-heart deterioration.

Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor (areg/egf). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients.

PurposeRecent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia.Methods and MaterialsWe developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIStissue) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).ResultsImplants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIStissue with the onset of AML and ALL. Two to 10 Gy TBI increased WIStissue and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIStissue was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart).ConclusionsL-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow.