Local Failure Research Articles

The Random RFPA Method for Modelling Rock Failure

Abstract The random rock failure process analysis (RRFPA) method was developed in this research to characterize the material spatial variability and uncertainty in rock failure modelling. The random field theory (RFT) was integrated with the traditional rock failure process analysis (RFPA) to model rock heterogeneity. In this approach, the variation of rock properties is represented as a function of relative distance, such that the influence of material intrinsic correlation on its fracturing behaviour can be appropriately captured. To validate the theory, 300 RRFPA simulations were conducted to investigate the failure characteristics of rock samples under compressive loading. The results showed that by incorporating a spectrum of material properties, the numerical outcomes exhibited distinct upper and lower bounds of stress across all testing scenarios, closely aligning with the experimental relationships. The histograms for uniaxial compressive strength and elastic modulus showed that both properties followed normal distributions, with the average values of 10.099 MPa and 1.818 GPa, respectively. The corresponding coefficients of variation were 0.450 and 0.038. The localized failure tended to result in a more rapid release of acoustic emission energy, but generated smaller cumulative energy compared to the overall failure pattern. In general, the maximum relative error of the RRFPA model was only 0.66% for uniaxial compressive strength, elastic modulus, and critical axial strain.

Abstract B024: CRISPR-Cas9 screening reveals a novel JAK1 dependent mechanism of radioresistance in head and neck squamous cell carcinoma

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide, and local failure of disease following treatment with radiation therapy remains a major challenge for improving patient outcomes. We therefore designed a CRISPR-Cas9 pooled genetic screen to identify signaling mechanisms that regulate HNSCC radiosensitivity. Using a kinome gRNA library (763 genes with 8 gRNAs each), Cal27 and Detroit562 cells were screened using fractionated exposure to ionizing radiation as a selection pressure. Deep sequencing results identified significant enrichment or depletion of gRNAs for DNA damage signaling (ATM and DNAPK) and NFKB signaling (IRAK4, IRAK1, IKKA, IKKB), pathways known to regulate cell survival after radiation. Surprisingly, the screen also identified significant depletion of Janus kinase signaling (JAK1 and TYK2) to be a cause of radiation resistance. Independent knockout (KO) of Janus Kinase 1 (JAK1) in both Cal27 and Detroit562 cells caused radioresistance in vitro and in vivo. JAK1 KO prolongs G2 cell cycle arrest in HNSCC after treatment with radiation or after thymidine synchronization. JAK1 KO cells also have enhanced Rad51 foci formation indicative of homologous recombination usage for DNA repair. Consistent with an enhanced mitotic arrest, JAK1 KO causes the appearance of cells with 4N and 8N DNA content after exposure to radiation as measured by flow cytometry with propidium iodide or following 5-ethynyl-2’deoxyuridine (EdU) labeling. HNSCC cells with JAK1 KO, or treated with the JAK1 specific inhibitor Abrocitinib, formed significantly fewer micronuclei after radiation treatment consistent with a reduction in mitotic errors. Consistent with these findings, live cell imaging demonstrated cells with JAK1 KO undergo fewer mitotic catastrophe events. Loss of JAK1 function did not alter CDK1, but delayed activation of Aurora Kinase A (AURKA) and Polo-like Kinase 1 (PLK1), identifying a cell cycle signaling pathway regulated by JAK1. Live cell imaging also showed a more than doubling of the time required from chromatin condensation to sister chromatid separation, suggesting an associated defect in kinetochore assembly. The effects of inhibiting Kif18a, a kinesin that regulates kinetochore tension, in combination with radiation was therefore tested. Kif18 inhibition significant radiosensitized JAK1 KO HNSCC in clonogenic survival and xenograft models. In summary we have elucidated a JAK1-dependent mechanism for the regulation of AURKA/PLK1 signaling, a protective G2 arrest, and radioresistance. Furthermore, we provide a mechanistic and targeted pharmacologic approach for overcoming therapeutic resistance and enhancing radiation therapy in HNSCC. Citation Format: Vanessa Kelley, Marta Baro, William Gasperi, Chatchai Phoomak, Hojin Lee, Joseph Contessa. CRISPR-Cas9 screening reveals a novel JAK1 dependent mechanism of radioresistance in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B024.

Abstract P017: Circulating tumor DNA kinetics identify prodynorphin signaling as a target to radiosensitize non-small cell lung cancer

Abstract Introduction: Definitive chemoradiation therapy (CRT) is essential for controlling locoregionally advanced non-small cell lung cancer (NSCLC); however, up to 30% of patients experience local recurrences within the radiation field. Analyzing favorable responders to treatment could enable identification of genetic alterations associated with radiosensitivity, but standard imaging cannot distinguish residual disease from inflammation and fibrosis during treatment to assess treatment response. We hypothesized that circulating tumor DNA (ctDNA) kinetics during CRT could identify genetic alterations associated with radiosensitivity that could be validated in preclinical models and harnessed to develop new combination therapies with radiotherapy (RT). Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) ctDNA analysis to pre-CRT and mid-treatment (mid-CRT) plasma samples from 61 patients with Stage II-III NSCLC. We identified ctDNA rapid responders as the 10 patients with the largest decrease in ctDNA concentration mid-CRT without local progression and determined the prevalence of genetic alterations in rapid responders versus slow responders using Fisher’s exact tests corrected for multiple hypothesis testing. To investigate the therapeutic potential of targeting PDYN during RT, we performed clonogenic assays on isogeneic PDYN CRISPR-Cas9 knockout and wildtype H1299 and SW1573 human NSCLC cell lines and H1299 cells treated with prodynorphin-neutralizing antibodies. Results: Mid-CRT log-fold change in ctDNA concentration was significantly associated with progression-free survival (P=0.02) in Stage II-III NSCLC. Mutations in PDYN, which encodes the opioid peptide precursor protein prodynorphin, were observed in 30% of ctDNA rapid responders and 0% of ctDNA slow responders (adjusted P=0.04). In NSCLC patients from TCGA treated with RT, the cumulative incidence of local failure was significantly lower in tumors with PDYN mutations (0% vs. 17% at 3 years, P<0.001). PDYN knockout (PDYNNULL) radiosensitized human NSCLC cancer cells by clonogenic assay, and extracellular administration of prodynorphin or its cleavage product dynophin A partially restored radioresistance in PDYNNULL cells. Prodynorphin cleavage products have been reported to signal through opioid receptors and to antagonize N-methyl-D-aspartate receptor (NMDAR) signaling. Although treatment of wildtype H1299 cells with opioid receptor antagonists did not affect radiosensitivity, the NMDAR antagonist MK-801 partially restored RT resistance in PDYNNULL cells. Finally, prodynorphin-neutralizing antibodies significantly reduced clonogenic survival of human NSCLC cells. Conclusions: ctDNA kinetics enable the identification of patients responding favorably to treatment and putative targets to enhance the efficacy of RT. Targeting prodynorphin may enhance the radiosensitivity of NSCLC by increasing NMDAR signaling. Citation Format: Ziwei Wang, Angela B. Hui, Ash A. Alizadeh, Maximilian Diehn, Everett J. Moding.Circulating tumor DNA kinetics identify prodynorphin signaling as a target to radiosensitize non-small cell lung cancer.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P017

Influence of occlusal loading on the longevity of dental bridges

Dental bridges are a cornerstone in restorative dentistry, offering functional and aesthetic solutions for patients with missing teeth. Their longevity is influenced by a complex interplay of biomechanical, material, and clinical factors. Occlusal loading, the force exerted during mastication and other functional activities, plays a critical role in determining the durability of these prostheses. Excessive or uneven occlusal forces can lead to mechanical failures such as fractures, debonding, or material fatigue. Advances in materials, particularly high-strength ceramics like zirconia, have improved the ability of bridges to withstand these stresses, providing enhanced resistance to wear and fracture. Design considerations, including connector dimensions and the use of computer-aided design and computer-aided manufacturing (CAD/CAM) technology, ensure more precise stress distribution, minimizing the risk of localized mechanical failures. Finite element analysis and digital occlusal analysis have further refined the understanding of stress patterns, enabling personalized approaches tailored to individual patient needs. Clinical studies have highlighted the importance of maintenance strategies, such as regular follow-ups and early repair of minor defects, in extending the lifespan of dental bridges. Patient-specific factors, such as parafunctional habits and periodontal health, significantly influence outcomes and necessitate individualized treatment planning. Emerging technologies, combined with material innovations, have shifted the focus toward optimizing the biomechanical performance of dental bridges. Trends reveal that integrating robust materials with advanced design techniques results in improved longevity and reduced failure rates. The interplay between clinical, material, and mechanical factors continues to evolve, offering new insights into enhancing the reliability and success of dental bridges over time.

Investigation of 3D steel frames with a reduced beam section and various web-opening shapes under internal column loss

ABSTRACT The sudden loss of columns due to abnormal loads demonstrates a remarkable example of a localized failure that might ultimately result in the progressive collapse of the complete steel-framed structures. In this study, finite element (FE) simulations are implemented by utilizing ABAQUS-Explicit to investigate the progressive collapse of two-storey steel reduced beam section (RBS) frames with web openings. The reliability and accuracy of the FE models are validated by comparing the obtained results with currently available experimental test results. A numerical investigation is conducted on twenty-eight RBS frames, each with a distinct web opening form (i.e. circular, square, and hexagon holes), different sizes of (D = 75, 90, and 105 mm), and varying distances of (25, 50, and 100 mm) from the center of the flange-reduced to the web opening. The failure modes, load-displacement characteristics, and development of catenary action are evaluated. The results showed that the specimens with square holes showed a greater degree of damage and lower load-carrying capacity compared with the specimens that have circle and hexagonal holes. In addition, an increased opening size resulted in a decrease in load-bearing capacity at small distances, thereby resulting in an increased capacity at a large distance.

Dynamic Failure Mechanism and Fractal Features of Fractured Rocks Under Quasi-Triaxial Static Pressures and Repeated Impact Loading

Mastering the dynamic mechanical behaviors of pre-stressed fractured rocks under repeated impact loads is crucial for safety management in rock engineering. To achieve this, repeated impact loading experiments were performed on produced fractured samples exposed to varying pre-applied axial and confining pressures using a split Hopkinson pressure bar test system in combination with a nuclear magnetic resonance imaging system, and the dynamic failure mechanism and fractal features were investigated. The results indicate that the dynamic stress–strain curves exemplify typical class II curves, and the strain rebound progressively diminishes with growing impact times. The impact times, axial pressure, and confining pressure all significantly affect the dynamic peak strength, average dynamic strength, dynamic deformation modulus, average dynamic deformation modulus, maximum strain, and impact resistance performance. Moreover, under low confining pressures, numerous shear cracks and tensile cracks develop, which are interconnected and converge to form large-scale macroscopic fracture surfaces. In contrast, specimens under a high confining pressure primarily experience tensile failure, accompanied by localized small-scale shear failure. Under low axial pressure, some shear cracks and tensile cracks emerge, while at high axial pressure, anti-wing cracks and secondary coplanar cracks occur, characterized predominantly by shear failure. In addition, as the confining pressure grows from 8 to 20 MPa, the fractal dimensions are 2.44, 2.32, 2.23, and 2.12, respectively. When the axial pressures are 8, 14, and 20 MPa, the fractal dimensions are 2.44, 2.46, and 2.52, respectively. Overall, the degree of fragmentation of the sample decreases with growing confining pressure and grows with rising axial pressure.

Research on Concrete Crack Detection in Hydropower Station Burial Engineering Based on Quantum Particle Technology

Cracking in hydraulic buried engineering can cause localized damage or complete structural failure, potentially resulting in catastrophic project outcomes. Traditional methods for detecting cracks in hydraulic concrete buried engineering are often insufficient in terms of reliability and accuracy. With the development and application of particle-based technology, it has been widely used in the field of crack detection. This research investigates the support pier of the Yingxiuwan Hydropower Plant and the lock pier of the Yuzixi Hydropower Plant. Employing principles from quantum physics, quantum particle non-destructive detection technology is introduced to identify crack locations. A three-dimensional simulation model is constructed and verified accurately through integration with CT scanning techniques. The results demonstrate that particle detection technology effectively detects cracks in hydraulic concrete buried engineering, exhibiting minimal susceptibility to external interference. The particle detection data enable 3D visualization of cracks, accurately reflecting the conditions within embedded concrete components. This method provides a reliable and advanced technical solution for precise crack detection in concrete-embedded engineering and offers critical data for exploring crack propagation mechanisms.

Development of swelling pressure in paulownia and Norway spruce during moisture absorption

Wood hybrid materials have gained significant attention for advanced technical applications over the past decade. In contrast to other materials, wood’s hygroscopic nature causes swelling and shrinkage, leading to differential expansion in hybrid systems under varying humidity conditions. When wood’s swelling is restrained by surrounding materials, stresses develop within both the wood and its adjacent components. To study this phenomenon, swelling tests were conducted on kiln-dried paulownia (Paulownia elongata) and Norway spruce (Picea abies) in a climate chamber at 20 °C and 98% relative humidity, with expansion restricted in one direction. Moisture absorption initially exhibited a steep, linear increase, levelling off after approximately 2 h. Swelling pressures rose sharply, peaking after 30 h for paulownia and 19 h for spruce, before gradually decreasing due to increased moisture content and relaxation. The measured stresses were lower than the compressive strengths of both wood species at their respective moisture contents. Microscopic examinations showed no cellular damage in paulownia during moisture absorption due to swelling pressure. In contrast, spruce wood displayed cell wall deformations and ray’s kinking in the early wood region of radial samples, as well as cell wall bending in tangential samples. This indicates that maximum stress is determined by the localised failure of the wood’s cellular structure rather than its overall properties. Such local effects were more pronounced in spruce than in paulownia due to their different structure. As a result, paulownia shows excellent potential for use in hybrid structures due to its low swelling and shrinkage properties and uniform structure.

Planning for success but facing uncertainty: lessons learned from a native oyster, Ostrea lurida, restoration project in the Salish Sea

Overexploitation and degradation of water quality nearly depleted Olympia oyster stocks in Puget Sound, Washington, USA by the early 1900s. With an intended goal of creating self-sustaining Olympia oyster populations in a target region in Puget Sound, the Swinomish Indian Tribal Community began reestablishing Olympia oysters at two different sites, Kiket and Lone Tree, from 2015-2017. One of our primary objectives was to quantify the biological successes or failures of our reestablished populations. Our results provide a guide for the evolution of project-specific, evidence-based restoration plans that could allow for further use of adaptive management and conservation aquaculture. Following the creation of experimental plots and restoration beds across two sites using 735 m² of shell habitat, including 245 m² of seeded cultch, we measured temporal change in oyster length and density as proxies for growth, recruitment, and survival. Significant growth was observed each year in each lagoon. Despite the known presence of brooding oysters and competent larvae in the region, we found no evidence of recruitment at either site through six years of monitoring. Survival decreased significantly each year and at each site. Thus, while we quantify evidence of growth and reproduction, we are not meeting the success metrics of recruitment or survival therefore hindering the chances of long-term success. We hypothesize that our restoration efforts are hampered by the relatively small population size within our restored areas, insufficient amounts of appropriate surrounding habitat, and lower water residence time. Our study suggests managers need to consistently monitor restoration projects due to site-specific differences and to determine if local failure is a possibility. Low survival and recruitment do not necessitate termination of projects. However, these measurements do suggest that projects like ours need to consider expanding use of conservation aquaculture as a tool or employing adaptive management by developing and implementing novel strategies to increase naturally-occurring adult populations and available habitat.

Properties of Modern Flowable Fill Incorporating Rapid-Setting Cements: Laboratory and Field Studies of Dry Placement Method

Timely maintenance and rehabilitation is critical to ensuring the long-term sustainability of transportation infrastructure. Full-depth pavement repairs represent a significant investment of both time and money, but such repairs become necessary where localized pavement failures have occurred as a result of inadequate performance of the underlying support system. Subsurface layers are traditionally repaired using compacted lifts of aggregate. While this approach is relatively inexpensive, it is labor-intensive, time-consuming, and can lead to premature repair failure if the layer is not adequately constructed. Rapid-setting (RS) flowable fill provides a backfilling material option that flows under gravity to fill subsurface voids, self-consolidates, and sets rapidly to facilitate the early placement of surfacing material. The dry placement method is a novel technique in which the blended RS flowable fill is placed in its dry state and water is added without mixing. The performance of three commercially available RS flowable fill materials placed using the dry method was investigated using both laboratory and accelerated full-scale vehicle trafficking. Results from these experiments indicate that reduced repair time and in-place cost, as compared to traditional repair techniques, can be achieved when flowable fill containing RS cement is employed using the dry placement method.

Local characterization of collagen architecture and mechanical properties of tissue engineered atherosclerotic plaque cap analogs.

Many cardiovascular events are triggered by fibrous cap rupture of an atherosclerotic plaque in arteries. However, cap rupture, including the impact of the cap's structural components, is poorly understood. To obtain better mechanistic insights in a biologically and mechanically controlled environment, we previously developed a tissue-engineered fibrous cap model. In the current study, we characterized the (local) structural and mechanical properties of these tissue-engineered cap analogs. Twenty-four collagenous cap analogs were cultured. The analogs were imaged with multiphoton microscopy with second-harmonic generation to obtain local collagen fiber orientation and dispersion. Then, the analogs were mechanically tested under uniaxial tensile loading until failure, and the local deformation (strain) and failure characteristics were analyzed. Our results demonstrated that the tissue-engineered analogs mimic the dominant (circumferential) fiber direction of human plaques. The analogs also exhibited a physiological strain stiffening response, similar to human fibrous plaque caps. Ruptures in the analogs initiated in and propagated towards local high-strain regions. The local strain values at the rupture sites were similar to the ones reported for carotid human fibrous plaque tissue. Finally, the study revealed that the rupture propagation path in the analogs followed the local fiber direction. STATEMENT OF SIGNIFICANCE: Many cardiovascular events are triggered by mechanical rupture of atherosclerotic plaque caps. Yet, cap rupture mechanics is poorly understood. This is mainly due to the scarcity of plaques for high-throughput testing and the structural complexity of plaques. To overcome this, we previously developed tissue-engineered cap analogs. The current study characterizes (local) structural and mechanical properties of these cap analogs. Our findings show that: (1) cap analogs closely mimic human fibrous caps, including fiber orientation and strain stiffening responses; (2) structural and mechanical properties of cap analogs are associated, which provides critical information for understanding plaque rupture; and (3) cap ruptures commonly start in and propagate towards high-strain areas, indicating the potential use of strain measurements for cap rupture risk assessment.

B7-H3 CAR-T cell therapy combined with irradiation is effective in targeting bulk and radiation-resistant chordoma cancer cells

BackgroundChordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment,...

Unveiling the Emerging Role of Xanthine Oxidase in Acute Pancreatitis: Beyond Reactive Oxygen Species.

Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that catalyzes hypoxanthine and xanthine to produce urate and is accompanied by the generation of reactive oxygen species (ROS) in purine catabolism. Considerable preclinical and clinical studies have been conducted over many decades to investigate the role of XO in the pathogenesis of AP and its potential targeting therapeutic value. There is no doubt that the ROS generated by irreversibly activated XO participates in the local pancreas and multiple organ failure during AP. However, the optimal timing and doses for therapeutic interventions targeting XO in animal studies and the clinic, as well as the additional molecular mechanisms through which XO contributes to disease onset and progression, including metabolic regulation, remain to be elucidated. This review summarized the benefits and contradictions of using XO inhibitors in animal models, offered mechanisms other than ROS, and discussed the difficulties faced in clinical trials. We hope to provide a perspective on the future worthwhile basic and clinical research on XO by analyzing its chemical and biological characteristics, as well as the progress of its regulatory mechanisms in AP.

Shape-Dependent Behavior of Intact Rock Under Creep Loading

Abstract Many underground mining operations require the design of pillars that their long-term structural integrity under creep loading is essential for sustainable operation of mines and safety of personnel. Characterizing the mechanical behavior of rocks at different shapes over the long-term can assist in efficient design of underground pillars. Over the past 4 decades, a large number of studies have examined the shape effect and long-term behavior of rocks separately, while consideration of these two together is essential. Accordingly, a comprehensive investigation is needed to assess the influence of shape on the mechanical behavior of intact rocks under long term or creep loading. Thus, in this work, an extensive laboratory experiments were conducted on a shaly sandstone, known as “Gosford” sandstone, with various length-to-diameter or “slenderness” ratios under both quasi-static and creep compressive loadings. The uniaxial compressive tests were performed on a number of cylindrical samples with constant diameter of 54 mm and varying slenderness ratios of 0.5, 1, 2, and 4. Also, a set of single and multi-step creep experiments were carried out on the samples with different slenderness ratios. Eighteen cylindrical samples were subjected to single-step creep loading at the slenderness ratios of 1, 2, and 4 and their corresponding instantaneous strains, apparent secondary creep strain rates, axial creep strains at the failure and times to failure were analyzed. The results showed that a decrease in the slenderness ratio led to an increase in the uniaxial compressive strength (UCS) of tested samples under quasi-static loading. Also, under single-step creep loading, the samples with the slenderness ratios of 2 and 4 exhibited classical creep behavior including distinct primary, secondary, and tertiary phases, whereas samples with the 1:1 ratio demonstrated localized failure. The multi-step creep tests endorsed these findings in which, the samples with smaller slenderness ratios resulted in larger cumulative strains and higher apparent secondary creep strain rate at the various creep stress ratios (the ratio of applied stress over the mean UCS). Finally, it was concluded that the resulting failure patterns from the tested samples are highly shape dependent under both quasi-static and creep loading conditions.

Localized Deformation Analysis of a 3D Micropolar Modified Cam‐Clay Model

ABSTRACTIn classical continuum constitutive models, the loss of ellipticity of the governing rate equilibrium equations entails localizing deformations and mesh sensitivity in finite element simulations. Extensions of such models, rooted in the micromorphic continuum, aim at remedying mesh sensitivity by introducing length scales into the constitutive formulation. The micropolar continuum constitutes a special case of the micromorphic continuum and is commonly employed for remedying mesh sensitivity accompanying shear band failure. However, localizing deformations in the micropolar continuum remains largely unexplored. This study aims to investigate the conditions for localizing deformations in the micropolar continuum and to highlight their implications for 2D and 3D finite element simulations. To this end, we propose a micropolar extension of the modified Cam‐clay model formulated in a three‐dimensional infinitesimal elastoplastic framework and establish its localization characteristics following a method recently presented for the classical Cauchy–Boltzmann continuum. Investigations at the constitutive level highlight the stabilizing effect of the micropolar extension, which is increased both by the presence of couple stresses as well as by increasing the Cosserat couple modulus. Simulations at the structural level exhibit good agreement with the results obtained at the constitutive level and indicate that the Cosserat couple modulus required for adequately regularizing the structural response depends on the level of modal dilatancy. Even though localized failure is commonly regarded to be restricted to opening modes, we find mesh‐sensitive structural behavior also in cases where the expected maximum modal dilatancy is far from unity.

Development of Local Ductile Failure Assessment Method and Its Application to Four Alloys Part I : Stress-Strain Relation And Analysis Without The Effect of Lode Angle

Development of Local Ductile Failure Assessment Method and Its Application to Four Alloys Part I : Stress-Strain Relation And Analysis Without The Effect of Lode Angle

Development of Local Ductile Failure Assessment Method And Its Application To Four Alloys Part II : Incorporation of The Effect of Lode Angle

Development of Local Ductile Failure Assessment Method And Its Application To Four Alloys Part II : Incorporation of The Effect of Lode Angle

Defining the Optimal Dose for 3-Dimensional Conformal Accelerated Partial Breast Irradiation: 15-Year Follow-Up of a Dose-Escalation Trial.

Randomized trials have demonstrated similar local tumor control in patients treated with accelerated partial-breast irradiation (APBI) compared with whole-breast irradiation. However, the optimal APBI dose for maximizing tumor control and minimizing toxicity is uncertain. We enrolled patients ≥18 years of age with grade 1 or 2 ductal carcinoma in situ or stage I invasive breast cancer and resection margins ≥2 mm between 2003 and 2011 to a sequential dose-escalation trial using 3-dimensional conformal external beam APBI giving twice daily 4 Gy fractions with total doses of 32 Gy, 36 Gy, and 40 Gy. Most were irradiated using mini-tangents plus en-face electrons or 3 to 4 coplanar photon beams; 19 patients in the 32 Gy dose cohort were treated with protons. The trial accrued 324 patients (99, 101, and 124 in 32 Gy, 36 Gy, and 40 Gy cohorts, respectively). The median follow-up was 15.2 years. The 15-year cumulative incidence of local failure in each dose cohort was 6.9%, 5%, and 3.9% in the 32 Gy, 36 Gy, and 40 Gy cohorts, respectively (log-rank P = .21) The 10-year cumulative incidence of local failure in each dose cohort was 5.2%, 5.2%, and 2.2%, respectively (log-rank P = .2). Ten-year rates of moderate or severe fibrosis by physician assessment in each cohort were 40%, 58%, and 67%, respectively (log-rank P < .01). The 10-year rates of fair or poor cosmesis by patient self-assessment were 25%, 30%, and 49% in each cohort, respectively (log-rank P < .01); physician assessment yielded similar 10-year rates of 21%, 39%, and 61%, respectively (log-rank P < .01). There were no significant differences in local failure rates between 32 Gy, 36 Gy, or 40 Gy delivered in twice daily 4 Gy fractions, but fibrosis and cosmetic outcomes were worse for patients treated to the 2 higher doses. Hence, our study did not show the benefit of administering more than 32 Gy using this fractionation scheme.

Neoadjuvant chemoradiotherapy in locally advanced and locally recurrent colon cancer

BackgroundWhile systemic management of high risk colon cancer is well addressed, advances in local management remain incremental. This study aims to identify a group of colon cancer patients where local management remains a challenge, and where intensifying local treatment with radiotherapy is potentially beneficial to minimise the risk of an R1 resection. MethodsPatients with select cT4 locally advanced primary colon (LAPC) (n=40) and locally recurrent colon (LRC) (n=48) adenocarcinomas who received neoadjuvant radiotherapy from 2005 to 2020 were studied. Radiotherapy prescription was 45-50.4 Gy in conventional fractionation. Estimated median follow-up time was 8.1 years and 6.3 years for the LAPC and LRC groups, respectively. ResultsThe most common primary site was the sigmoid colon (n=61). In the LAPC group, surgery was performed in 90% (n=36), 81% (n=29) of which were R0 resections, with pathologic downstaging occurring in 66.7% (n=24). In the LRC group, surgery was possible in 79.2% (n=38), 65.8% (n=25) of which were R0 resections. For the LAPC group, 13% (n=5) had local failures (hazard rate 3%, 95%CI 1-6%), 38% (n=14) had any disease progression (hazard rate 9%; 95%CI 5-14), and 55% (n=22) were alive at the end of the follow-up period (hazard rate 8%; 95%CI 5-13). For the LRC group, 35% (n=17) had local failures (5-year LFFS: 53%; 95%CI: 37-74), and 61% (n=30) had any disease progression (5-year PFS: 28%; 95%CI: 17% - 48%). 5-year OS for the LRC group was 50% (95%CI: 37-68). There was no 30-day mortality. ConclusionLocal management of high risk colon cancer remains a challenge. Future studies in neoadjuvant chemoradiation and systemic therapy, and staging methodology in identifying the high risk group are urgently needed.

Degeneration of the nucleus pulposus affects the internal volumetric strains and failure location of adjacent human metastatic vertebral bodies.

Intervertebral disc (IVD) degeneration is suspected to affect the distribution of stress and strain near the vertebral endplates and in the underlying bone. This scenario is worsened by the presence of metastatic lesions on the vertebrae (primarily thoracic vertebrae (60-80%)) which increase the risk of fracture. As such, this study aimed to evaluate the effect of IVD degeneration on the internal volumetric strains and failure modes of human metastatic vertebral bodies. Five human thoracic spinal segments including one vertebra with lytic metastases and one radiologically healthy vertebra (control) were in-situ tested in pure compression within a mCT scanner (isotropic voxel size = 39 mm). Each specimen was tested in the elastic regime before and after inducing mock IVD degeneration (enzymatic degeneration with collagenase); and at failure after IVD degeneration. The volumetric strain field was measured using a global Digital Volume Correlation approach (BoneDVC). After IVD degeneration, larger maximum (+187%, P = 0.002, 95% CI= [-4447, -1209]) and minimum (+174%, P = 0.002, 95% CI= [1679, 4258]) principal strains were observed in both metastatic and control vertebrae, with peak differences in correspondence of the IVD anulus fibrosus. IVD degeneration caused a transversal fracture pattern in the vertebrae with failure location onset in the middle portion of the vertebral body and in the cortical shell. In conclusion, IVD degeneration was found to be a key factor in determining the failure mode, suggesting the clinical relevance of including IVD level of degeneration to assess patients' risk of spinal instability. STATEMENT OF SIGNIFICANCE: Vertebrae can be affected by pathologies, like bone metastases, while intervertebral discs tend to degenerate during life. Generally, these structures and pathologies are studied separately. In this study, we explored the effects of artificial intervertebral disc degeneration on the mineralised tissues of the vertebrae with metastases. We observed that the induced intervertebral disc degeneration changes the mechanical behaviour of the vertebral trabecular bone. We believe that the findings of this study may influence the scientific community to develop new clinical tools for the prediction of the risk of fracture in vertebrae with spinal metastases, including the degeneration of the intervertebral discs as a parameter.