CD74 is expressed in a subset of pediatric acute myeloid leukemia patients and is a promising target for therapy: a report from the Children's Oncology Group.

As curative therapies for pediatric AML remain elusive, identifying potential new treatment targets is vital. We assessed the cell surface expression of CD74, also known as the MHC-II invariant chain, by multidimensional flow cytometry in 973 patients enrolled in the Children's Oncology Group AAML1031 clinical trial. 38% of pediatric AML patients expressed CD74 at any level and a comparison to normal hematopoietic cells revealed a subset with increased expression relative to normal myeloid progenitor cells. Pediatric AML patients expressing high intensity CD74 typically had an immature immunophenotype and an increased frequency of lymphoid antigen expression. Increased CD74 expression was associated with older patients with lower WBC and peripheral blood blast counts, and was enriched for t(8;21), trisomy 8, and CEBPA mutations. Overall, high CD74 expression was associated with low-risk status, however 26% of patients were allocated to high-risk protocol status and 5-year event free survival was 53%, indicating that a significant number of high expressing patients had poor outcomes. In vitro pre-clinical studies indicate that anti-CD74 therapy demonstrates efficacy against AML cells but has little impact on normal CD34+ cells. Together, we demonstrate that CD74 is expressed on a subset of pediatric AMLs at increased levels compared to normal hematopoietic cells and is a promising target for therapy in expressing patients. Given that nearly half of patients expressing CD74 at high levels experience an adverse event within 5 years, and the availability of CD74 targeting drugs, this represents a promising line of therapy worthy of additional investigation.

Young Plasma Attenuated Chronic Kidney Disease Progression after Acute Kidney Injury by Inhibiting Inflammation in Mice.

In the aged patients suffering from acute kidney injury, the risk for progression to chronic kidney disease and mortality is high. Aging accompanied by glomerulosclerosis, interstitial inflammation, and fibrosis might be one of the underlying mechanisms for vulnerability. In addition to sustained activation of the renin-angiotensin system, persistent chronic inflammation with tertiary lymphoid tissue formation is more common and is associated with disease progression in the aged kidney after acute injury. Based on recent laboratory evidence that young blood can rejuvenate the brain, muscle, and heart, we were intrigued by the possible protective effect of young plasma on acute kidney injury in aged mice. Here, we demonstrated that young plasma from 2-month-old mice could attenuate chronic kidney disease progression in 15-month-old mice subjected to acute kidney injury induced by ischemia-reperfusion. In the aged mice after acute kidney injury, young plasma administration decreased tubulointerstitial injury, fibrosis, and tertiary lymphoid tissue formation in kidneys assessed on day 28 after acute injury despite no significant beneficial effect on injury severity and survival. Mechanistically, young plasma inhibited angiotensin II-activated chemokines in pericytes that were responsible for tertiary lymphoid tissue formation. In summary, our data provide evidence that young plasma attenuates the transition from acute kidney injury to chronic kidney disease in aged mice. The therapeutic potential of young plasma infusion or exchange in the aged patients suffering acute kidney injury needs to be addressed in clinical trials.

Antibodies from dengue patients with prior exposure to Japanese encephalitis virus are broadly neutralizing against Zika virus.

Exposure to multiple mosquito-borne flaviviruses within a lifetime is not uncommon; however, how sequential exposures to different flaviviruses shape the cross-reactive humoral response against an antigen from a different serocomplex has yet to be explored. Here, we report that dengue-infected individuals initially primed with the Japanese encephalitis virus (JEV) showed broad, highly neutralizing potencies against Zika virus (ZIKV). We also identified a rare class of ZIKV-cross-reactive human monoclonal antibodies with increased somatic hypermutation and broad neutralization against multiple flaviviruses. One huMAb, K8b, binds quaternary epitopes with heavy and light chains separately interacting with overlapping envelope protein dimer units spanning domains I, II, and III through cryo-electron microscopy and structure-based mutagenesis. JEV virus-like particle immunization in mice further confirmed that such cross-reactive antibodies, mainly IgG3 isotype, can be induced and proliferate through heterologous dengue virus (DENV) serotype 2 virus-like particle stimulation. Our findings highlight the role of prior immunity in JEV and DENV in shaping the breadth of humoral response and provide insights for future vaccination strategies in flavivirus-endemic countries.

Verification of surface-guided radiation therapy (SGRT) alignment for proton breast and chest wall patients by comparison to CT-on-rails and kV-2D alignment.

BACKGROUND: Surface-guided radiation therapy (SGRT) systems have been widely installed and utilized on linear accelerators. However, the use of SGRT with proton therapy is still a newly developing field, and published reports are currently very limited. PURPOSE: To assess the clinical application and alignment agreement of SGRT with CT-on-rails (CTOR) and kV-2D image-guided radiation therapy (IGRT) for breast treatment using proton therapy. METHODS: Four patients receiving breast or chest wall treatment with proton therapy were the subjects of this study. Patient #1's IGRT modalities were a combination of kV-2D and CTOR. CTOR was the only imaging modality for patients #2 and #3, and kV-2D was the only imaging modality for patient #4. The patients' respiratory motions were assessed using a 2-min surface position recorded by the SGRT system during treatment. SGRT offsets reported after IGRT shifts were recorded for each fraction of treatment. The agreement between SGRT and either kV-2D or CTOR was evaluated. RESULTS: The respiratory motion amplitude was <4 mm in translation and <2.0° in rotation for all patients. The mean and maximum amplitude of SGRT offsets after application of IGRT shifts were ≤(2.6 mm, 1.6° ) and (6.8 mm, 4.5° ) relative to kV-2D-based IGRT; ≤(3.0 mm, 2.6° ) and (5.0 mm, 4.7° ) relative to CTOR-based IGRT without breast tissue inflammation. For patient #3, breast inflammation was observed for the last three fractions of treatment, and the maximum SGRT offsets post CTOR shifts were up to (14.0 mm, 5.2° ). CONCLUSIONS: Due to the overall agreement between SGRT and IGRT within reasonable tolerance, SGRT has the potential to serve as a valuable auxiliary IGRT tool for proton breast treatment and may improve the efficiency of proton breast treatment.

Traces of EEG-fMRI coupling reveals neurovascular dynamics on sleep inertia.

Upon emergence from sleep, individuals experience temporary hypo-vigilance and grogginess known as sleep inertia. During the transient period of vigilance recovery from prior nocturnal sleep, the neurovascular coupling (NVC) may not be static and constant as assumed by previous neuroimaging studies. Stemming from this viewpoint of sleep inertia, this study aims to probe the NVC changes as awakening time prolongs using simultaneous EEG-fMRI. The time-lagged coupling between EEG features of vigilance and BOLD-fMRI signals, in selected regions of interest, was calculated with one pre-sleep and three consecutive post-awakening resting-state measures. We found marginal changes in EEG theta/beta ratio and spectral slope across post-awakening sessions, demonstrating alterations of vigilance during sleep inertia. Time-varying EEG-fMRI coupling as awakening prolonged was evidenced by the changing time lags of the peak correlation between EEG alpha-vigilance and fMRI-thalamus, as well as EEG spectral slope and fMRI-anterior cingulate cortex. This study provides the first evidence of potential dynamicity of NVC occurred in sleep inertia and opens new avenues for non-invasive neuroimaging investigations into the neurophysiological mechanisms underlying brain state transitions.

Targeted therapy in glomerular diseases.

Targeted therapy has emerged as a more precise approach to treat glomerular diseases, focusing on specific molecular or cellular processes that contribute to disease development or progression. This approach complements or replaces traditional immunosuppressive therapy, optimizes supportive care, and provides a more personalized treatment strategy. In this review, we summarize the evolving understanding of pathogenic mechanisms in immune-mediated glomerular diseases and the developing targeted therapies based on these mechanisms. We begin by discussing pan-B-cell depletion, anti-CD20 rituximab, and targeting B-cell survival signaling through the BAFF/APRIL pathway. We also exam specific plasma cell depletion with anti-CD38 antibody. We then shift our focus to complement activation in glomerular diseases, which is involved in antibody-mediated glomerular diseases, such as IgA nephropathy, membranous nephropathy, ANCA-associated vasculitis, and lupus nephritis. Non-antibody-mediated complement activation occurs in glomerular diseases, including C3 glomerulopathy, complement-mediated atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. We discuss specific inhibition of terminal, lectin, and alternative pathways in different glomerular diseases. Finally, we summarize current clinical trials targeting the final pathways of various glomerular diseases, including kidney fibrosis. We conclude that targeted therapy based on individualized pathogenesis should be the future of treating glomerular diseases.

Initial clinical evaluation of a novel combined biometric, radio-frequency identification, and surface imaging system.

PURPOSE: To evaluate and characterize the overall clinical functionality and workflow of the newly released Varian Identify system (version 2.3). METHODS: Three technologies included in the Varian Identify system were evaluated: patient biometric authentication, treatment accessory device identification, and surface-guided radiation therapy (SGRT) function. Biometric authentication employs a palm vein reader. Treatment accessory device verification utilizes two technologies: device presence via Radio Frequency Identification (RFID) and position via optical markers. Surface-guidance was evaluated on both patient orthopedic setup at loading position and surface matching and tracking at treatment isocenter. A phantom evaluation of the consistency and accuracy for Identify SGRT function was performed, including a system consistency test, a translational shift and rotational accuracy test, a pitch and roll accuracy test, a continuous recording test, and an SGRT vs Cone-Beam CT (CBCT) agreement test. RESULTS: 201 patient authentications were verified successfully with palm reader. All patient treatment devices were successfully verified for their presences and positions (indexable devices). The patient real-time orthopedic pose was successfully adjusted to match the reference surface captured at simulation. SGRT-reported shift consistency against couch readout was within (0.1 mm, 0.030). The shift accuracy was within (0.3 mm, 0.10). In continuous recording mode, the maximum variation was 0.2 ± 0.12 mm, 0.030 ± 0.020. The difference between Identify SGRT offset and CBCT was within (1 mm, 10). CONCLUSIONS: This clinical evaluation confirms that Identify accurately functions for patient palm identification and patient treatment device presence and position verification. Overall SGRT consistency and accuracy was within (1 mm, 10), within the 2 mm criteria of AAPM TG302.

[Enhancing Understanding Among Intensive Care Unit Nurses of Lower Back Musculoskeletal Disorders and Associated Risks].

BACKGROUND & PROBLEMS: Work-related musculoskeletal disorders (WMSDs) have received the most attention worldwide of the various diseases addressed by the field of occupational medicine. In intensive care units (ICUs), patients with critical illness typically rely heavily on assistance provided by nurses to engage in daily life and rehabilitation activities. This dependence increases the risk of nurses experiencing WMSDs. An injury screening revealed that 56.4% of the nurses working in the ICU of the case hospital faced a mild risk of lower back musculoskeletal disorders and that the main contributor to this risk was lack of understanding among these nurses of lower-back-related WMSDs. PURPOSE: This project was designed to enhance understanding of lower back WMSDs among the ICU nurses and to reduce the percentage of nurses facing a mild risk of contracting WMSDs. RESOLUTIONS: 1. Organize integrated courses to introduce human-induced hazards and enhance nurses' understanding and prevention of WMSDs. 2. Design slogans, posters, and teaching videos to promote awareness of patient turning tips and procedures to prevent nurses from experiencing WMSDs due to incorrect force application. 3. Design illustrations highlighting risky postures commonly performed by nurses in ICUs that may cause lower back WMSDs to prevent the occurrence of human-induced injuries. RESULTS: The rate of correct understanding of lower back WMSDs in the target nurse population improved from 73.8% to 96.2%. In addition, the percentage of those assessed with a mild risk of contracting lower back musculoskeletal injuries decreased from 56.4% to 25.5%. CONCLUSIONS: This project promoted multifaceted improvement measures based on the WMSD screening and risk classification and management processes stipulated by Taiwan's Ministry of Labor to increase understanding of lower back WMSDs among ICU nurses and reduce the percentage of those facing a mild risk of contracting WMSDs.

Technical note: Clinical evaluation of a newly released surface-guided radiation therapy system on DIBH for left breast radiation therapy.

BACKGROUND: It has been shown that a significant reduction of mean heart dose and left anterior descending artery (LAD) dose can be achieved through the use of DIBH for left breast radiation therapy. Surface-guided DIBH has been widely adopted during the last decade, and there are mainly three commercially available SGRT systems. The reports of the performance of a newly released SGRT system for DIBH application are currently very limited. PURPOSE: To evaluate the clinical performance of a newly released SGRT system on DIBH for left breast radiation therapy. METHODS: Twenty-five left breast cancer patients treated with DIBH utilizing Varian's Identify system were included (total 493-fraction treatments). Four aspects of the clinical performance were evaluated: Identify offsets of free breathing post patient setup from tattoos, Identify offsets during DIBH, Identify agreement with radiographic ports during DIBH, and DIBH reference surface re-capture post patient shifts. The systematic and random errors of free breathing Identify offsets post patient setup were calculated for each patient, as well as for offsets during DIBH. Radiographic ports were taken when the patient's DIBH position was within the clinical tolerance of (± 0.3 cm, ± 30 ), and these were then compared with treatment field DRRs. If the ports showed that the patient alignment did not agree with the DRRs within 3 mm, a patient shift was performed. A new reference surface was captured and verification ports were taken. RESULTS: The all-patient average systematic and random errors of Identify offsets for free breathing were within (0.4 cm, 1.50 ) post tattoo setup. The maximum per-patient systematic and random errors were (1.1 cm, 6.20 ) and (0.9 cm, 20 ), and the maximum amplitude of Identify offsets were (2.59 cm, 90 ). All 493-fraction DIBH treatments were delivered and successfully guided by the Identify SGRT system. The systematic and random errors of Identify offsets for DIBH were within (0.2 cm, 2.30 ). Seven patients needed re-captured surface references due to surface variation or position shifts based on the ports. All patient DIBH verification ports guided by Identify were approved by attending physicians. CONCLUSION: This evaluation showed that the Identify system performed effectively for surface-guided patient setup and surface-guided DIBH imaging and treatment delivery. The feature of color-coded real-time patient surface matching feedback facilitated the evaluation of the patient alignment accuracy and the adjustment of the patient position to match the reference.

Measurements of fetal dose with Mevion S250i proton therapy system with HYPERSCAN.

PURPOSE: To characterize potential dose to the fetus for all modes of delivery (dynamic adaptive aperture, static adaptive aperture, and no adaptive aperture) for the Mevion S250i Proton Therapy System with HYPERSCAN and compare the findings with those of other available proton systems. MATERIALS AND METHODS: Fetal dose measurements were performed for all three modes of dose delivery on the Mevion S250i Proton therapy system with HYPERSCAN (static aperture, dynamic aperture and uncollimated). Standard treatment plans were created in RayStation for a left-sided brain lesion treated with a vertex field, a left lateral field, and a posterior field. Measurements were performed using WENDI and the RANDO with the detector placed at representative locations to mimic the growth and movement of the fetus at different gestational stages. RESULTS: The fetal dose measurements varied with fetus position and the largest measured dose was 64.7 µSv per 2 Gy (RBE) fraction using the dynamic aperture. The smallest estimated fetal dose was 45.0 µSv per 2 Gy (RBE) at the base of the RANDO abdomen (47 cm from isocenter to the outer width of WENDI and 58.5 cm from the center of the WENDI detector) for the static aperture delivery. The vertex fields at all depths had larger contributions to the total dose than the other two and the dynamic aperture plans resulted in the highest dose measured for all depths. CONCLUSION: The reported doses are lower than reported doses using a double-scattering system. This work suggests that avoiding vertex fields and using the static aperture will help minimize dose to the fetus.

The impact of Down syndrome-specific non-malignant hematopoietic regeneration in the bone marrow on the detection of leukemic measurable residual disease.

BACKGROUND: Detection of measurable residual disease detection (MRD) by flow cytometry after the first course of chemotherapy is a standard measure of early response in patients with acute myeloid leukemia (AML). Myeloid leukemia associated with Down Syndrome (ML-DS) is a distinct form of AML. Differences in steady-state and regenerating hematopoiesis between patients with or without DS are not well understood. This understanding is essential to accurately determine the presence of residual leukemia in patients with ML-DS. METHODS: A standardized antibody panel defined quantitative antigen expression in 115 follow-up bone marrow (BM) aspirates from 45 patients following chemotherapy for ML-DS or DS precursor B-cell acute lymphoblastic leukemia (B-ALL-DS) with the "difference from normal (ΔN)" technique. When possible, FISH and SNP/CGH microarray studies were performed on sorted cell fractions. RESULTS: 93% of BM specimens submitted post chemotherapy had a clearly identifiable CD34+ CD56+ population present between 0.06% and 2.6% of total non-erythroid cells. An overlapping CD34+ HLA-DRheterogeneous population was observed among 92% of patients at a lower frequency (0.04%-0.8% of total non-erythroid cells). In B-ALL-DS patients, the same CD34+ CD56+ HLA-DRheterogeneous expression was observed. FACS-FISH/Array studies demonstrated no residual genetic clones in the DS-specific myeloid progenitor cells. CONCLUSIONS: Non-malignant myeloid progenitors in the regenerating BM of patients who have undergone chemotherapy for either ML-DS or B-ALL-DS express an immunophenotype that is different from normal BM of non-DS patients. Awareness of this DS-specific non-malignant myeloid progenitor is essential to the interpretation of MRD by flow cytometry in patients with ML-DS.

Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.

During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression.

An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.

A novel approach for Venezia ovoid commissioning with a comprehensive analysis of source positions in high-dose-rate brachytherapy.

PURPOSE: The lunar design of a Venezia ovoid makes commissioning of the applicator very challenging with traditional autoradiography. In this study, we propose a novel solution to ovoid commissioning and a quality assurance (QA) workflow to effectively assess the entire source path. METHODS AND MATERIALS: A two-step commissioning process, using electron radiation and radiochromic films, was developed to verify the most distal source position. The ovoid was first attached to a film and was irradiated with a 12 MeV linac beam. This process was repeated on a separate, unexposed film, followed by irradiating it with a HDR source at the most distal position. Two lengths, including the ovoid thickness and the distance between the irradiated spot and the ovoid's outer surface, were obtained from the films' intensity maps. The offset value was calculated from the subtraction of the two measured lengths. Besides acquiring the offset, a source positional simulator (SPS) and a series of planar x-rays from two orthogonal orientations were used to characterize source movement within the ovoid. RESULTS: Compared to x-ray-based autoradiography, the electron exposure significantly improved the ovoid's visibility on film. Our approach did not use surrogate, which further improved measurement outcomes by decreasing inherent uncertainties. The SPS results suggested the source movement was complex within the cervicovaginal area, but it was predictable with the proposed QA workflow. CONCLUSION: We introduced a novel, surrogate-free method to commission the Venezia ovoid, which facilitated a manual applicator reconstruction. Additionally, we recommended QA multiple source positions to safely use the ovoid in clinical settings.

A Fc-VEGF chimeric fusion enhances PD-L1 immunotherapy via inducing immune reprogramming and infiltration in the immunosuppressive tumor microenvironment.

BACKGROUND: Immunotherapy is an emerging cancer therapy with potential great success; however, immune checkpoint inhibitor (e.g., anti-PD-1) has response rates of only 10-30% in solid tumor because of the immunosuppressive tumor microenvironment (TME). This affliction can be solved by vascular normalization and TME reprogramming. METHODS: By using the single-cell RNA sequencing (scRNAseq) approach, we tried to find out the reprogramming mechanism that the Fc-VEGF chimeric antibody drug (Fc-VFD) enhances immune cell infiltration in the TME. RESULTS: In this work, we showed that Fc-VEGF121-VEGF165 (Fc-VEGF chimeric antibody drug, Fc-VFD) arrests excess angiogenesis and tumor growth through vascular normalization using in vitro and in vivo studies. The results confirmed that the treatment of Fc-VFD increases immune cell infiltration including cytotoxic T, NK, and M1-macrophages cells. Indeed, Fc-VFD inhibits Lon-induced M2 macrophages polarization that induces angiogenesis. Furthermore, Fc-VFD inhibits the secretion of VEGF-A, IL-6, TGF-ß, or IL-10 from endothelial, cancer cells, and M2 macrophage, which reprograms immunosuppressive TME. Importantly, Fc-VFD enhances the synergistic effect on the combination immunotherapy with anti-PD-L1 in vivo. CONCLUSIONS: In short, Fc-VFD fusion normalizes intratumor vasculature to reprogram the immunosuppressive TME and enhance cancer immunotherapy.

Surface-Guided Patient Setup Versus Traditional Tattoo Markers for Radiation Therapy: Is Tattoo-Less Setup Feasible for Thorax, Abdomen and Pelvis Treatment?

PURPOSE: In this study, patient setup accuracy was compared between surface guidance and tattoo markers for radiation therapy treatment sites of the thorax, abdomen and pelvis. METHODS AND MATERIALS: A total of 608 setups performed on 59 patients using both surface-guided and tattoo-based patient setups were analyzed. During treatment setup, patients were aligned to room lasers using their tattoos, and then the six-degree-of-freedom (6DOF) surface-guided offsets were calculated and recorded using AlignRT system. While the patient remained in the same post-tattoo setup position, target localization imaging (radiographic or ultrasound) was performed and these image-guided shifts were recorded. Finally, surface-guided vs tattoo-based offsets were compared to the final treatment position (based on radiographic or ultrasound imaging) to evaluate the accuracy of the two setup methods. RESULTS: The overall average offsets of tattoo-based and surface-guidance-based patient setups were comparable within 3.2 mm in three principal directions, with offsets from tattoo-based setups being slightly less. The maximum offset for tattoo setups was 2.2 cm vs. 4.3 cm for surface-guidance setups. Larger offsets (ranging from 2.0 to 4.3 cm) were observed for surface-guided setups in 14/608 setups (2.3%). For these same cases, the maximum observed tattoo-based offset was 0.7 cm. Of the cases with larger surface-guided offsets, 13/14 were for abdominal/pelvic treatment sites. Additionally, larger rotations (>3°) were recorded in 18.6% of surface-guided setups. The majority of these larger rotations were observed for abdominal and pelvic sites (~84%). CONCLUSIONS: The small average differences observed between tattoo-based and surface-guidance-based patient setups confirm the general equivalence of the two potential methods, and the feasibility of tattoo-less patient setup. However, a significant number of larger surface-guided offsets (translational and rotational) were observed, especially in the abdominal and pelvic regions. These cases should be anticipated and contingency setup methods planned for.

Macrophage secretory IL-1ß promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling.

Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1ß was found to induce tumor expression of ICAM1. IL-1ß neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1ß activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1ß secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.

Incidence and extent of disease progression on MRI between surgery and initiation of radiotherapy in glioblastoma patients.

Background: A post-operative MRI (MRIpost-op) performed within 72 h is routinely used for radiation treatment planning in glioblastoma (GBM) patients, with radiotherapy starting about 4-6 weeks after surgery. Some patients undergo an additional pre-radiotherapy MRI (MRIpre-RT) about 2-6 weeks after surgery. We sought to analyze the incidence of rapid early progression (REP) between surgery and initiation of radiotherapy seen on MRIpre-RT and the impact on radiation target volumes. Methods: Patients with GBM diagnosed between 2018 and 2020 who had an MRIpost-op and MRIpre-RT were retrospectively identified. Criteria for REP was based on Modified RANO criteria. Radiation target volumes were created and compared using the MRIpost-op and MRIpre-RT. Results: Fifty patients met inclusion criteria. The median time between MRIpost-op and MRIpre-RT was 26 days. Indications for MRIpre-RT included clinical trial enrollment in 41/50 (82%), new symptoms in 5/50 (10%), and unspecified in 4/50 (8%). REP was identified in 35/50 (70%) of patients; 9/35 (26%) had disease progression outside of the MRIpost-op-based high dose treatment volumes. Treatment planning with MRIpost-op yielded a median undertreatment of 27.1% of enhancing disease and 11.2% of surrounding subclinical disease seen on MRIpre-RT. Patients without REP had a 38% median volume reduction of uninvolved brain if target volumes were planned with MRIpre-RT. Conclusion: Given the incidence of REP and its impact on treatment volumes, we recommend using MRIpre-RT for radiation treatment planning to improve coverage of gross and subclinical disease, allow for early identification of REP, and decrease radiation treatment volumes in patients without REP.