Is the IROC H&N credentialing phantom an effective surrogate for different anatomical sites?: Using IROC's H&N phantom for various sites.

PURPOSE: The IROC head and neck phantom is used to credential institutions for IMRT delivery for all anatomical sites where delivery of modulated therapy is a primary challenge. This study evaluated how appropriate the use of this phantom is for varied clinical anatomy by evaluating how closely the IROC head and neck phantom described clinical dose errors from beam modeling compared to various anatomical sites. METHODS: The MLC offset, transmission, PDD and seven additional beam modeling parameters for a Varian accelerator were modified in RayStation to match community data at the 2.5, 25, 50, 75 and 97.5 percentile levels. Modifications were evaluated on 25 H&N phantom cases and 25 clinical cases (H&N, prostate, lung, mesothelioma, and brain), generating 2,000 plan perturbations. Differences in mean dose delivered to clinical target volumes (CTV) and organs at risk (OAR) were compared between phantom and clinical plans to assess the relationship between dose deviations in phantom versus clinical CTVs, and as a function of 18 different complexity metrics. RESULTS: Perturbations to MLC offset and transmission parameters demonstrated the greatest impact on dose accuracy for phantom and clinical plans (for all anatomic sites). The phantom demonstrated equivalent or greater sensitivity to these parameter perturbations when compared to clinical sites, largely aligning with treatment complexity. The mean MLC Gap best described the impact of errors in TPS beam modeling parameters in phantoms plan and clinical plans from various anatomical sites. CONCLUSION: When compared across various anatomical sites, the IROC H&N credentialing phantom exhibited similar or greater sensitivity to errors in the treatment planning system. As such, it is a suitable surrogate device for assessing institutional performance across various anatomical sites. If an institution successfully irradiates the phantom, that result confers confidence that IMRT to a wide range of anatomical sites can be successfully delivered by the institution.

Overexpression of the Liriodendron tulipifera TPS32 gene in tobacco enhances terpenoid compounds synthesis.

Liriodendron, a relic genus from the Magnoliaceae family, comprises two species, L. tulipifera and L. chinense. L. tulipifera is distinguished by its extensive natural distribution in Eastern North America. Conversely, L. chinense is nearing endangerment due to its low regeneration rate. A pivotal aspect in the difference of these species involves terpenoids, which play crucial roles in plant growth and attracting pollinators. However, the complex molecular mechanisms underlying terpenoid roles in Liriodendron are not well understood. Terpene Synthases (TPS) genes are widely reported to play a role in terpenoid biosynthesis, hence, this study centers on TPS genes in Liriodendron spp. Employing multiple bioinformatics methods, a differential expression gene in L. tulipifera, LtuTPS32, was discerned for further functional analysis. Subcellular localization results reveal the involvement of LtuTPS32 in chloroplast-associated processes, hence participate in terpenoid biosynthesis within chloroplasts. Heterologous transformation of the LtuTPS32 gene into tobacco significantly elevates the levels of common terpenoid compounds, including chlorophyll, gibberellin, and carotenoids. Collectively, these findings not only underscore the role of the LtuTPS32 gene in the biosynthesis of terpenoids but also lay a foundation for future research on interspecific differences in Liriodendron.

Impact of interplay effects on spot scanning proton therapy with motion mitigation techniques for lung cancer: SFUD versus robustly optimized IMPT plans utilizing a four-dimensional dynamic dose simulation tool.

BACKGROUND: The interaction between breathing motion and scanning beams causes interplay effects in spot-scanning proton therapy for lung cancer, resulting in compromised treatment quality. This study investigated the effects and clinical robustness of two types of spot-scanning proton therapy with motion-mitigation techniques for locally advanced non-small cell lung cancer (NSCLC) using a new simulation tool (4DCT-based dose reconstruction). METHODS: Three-field single-field uniform dose (SFUD) and robustly optimized intensity-modulated proton therapy (IMPT) plans combined with gating and re-scanning techniques were created using a VQA treatment planning system for 15 patients with locally advanced NSCLC (70 GyRBE/35 fractions). In addition, gating windows of three or five phases around the end-of-expiration phase and two internal gross tumor volumes (iGTVs) were created, and a re-scanning number of four was used. First, the static dose (SD) was calculated using the end-of-expiration computed tomography (CT) images. The four-dimensional dynamic dose (4DDD) was then calculated using the SD plans, 4D-CT images, and the deformable image registration technique on end-of-expiration CT. The target coverage (V98%, V100%), homogeneity index (HI), and conformation number (CN) for the iGTVs and organ-at-risk (OAR) doses were calculated for the SD and 4DDD groups and statistically compared between the SD, 4DDD, SFUD, and IMPT treatment plans using paired t-test. RESULTS: In the 3- and 5-phase SFUD, statistically significant differences between the SD and 4DDD groups were observed for V100%, HI, and CN. In addition, statistically significant differences were observed for V98%, V100%, and HI in phases 3 and 5 of IMPT. The mean V98% and V100% in both 3-phase plans were within clinical limits (> 95%) when interplay effects were considered; however, V100% decreased to 89.3% and 94.0% for the 5-phase SFUD and IMPT, respectively. Regarding the significant differences in the deterioration rates of the dose volume histogram (DVH) indices, the 3-phase SFUD plans had lower V98% and CN values and higher V100% values than the IMPT plans. In the 5-phase plans, SFUD had higher deterioration rates for V100% and HI than IMPT. CONCLUSIONS: Interplay effects minimally impacted target coverage and OAR doses in SFUD and robustly optimized IMPT with 3-phase gating and re-scanning for locally advanced NSCLC. However, target coverage significantly declined with an increased gating window. Robustly optimized IMPT showed superior resilience to interplay effects, ensuring better target coverage, prescription dose adherence, and homogeneity than SFUD. TRIAL REGISTRATION: None.

PagTPS1 and PagTPS10, the trehalose-6-phosphate synthase genes, increase trehalose content and enhance drought tolerance.

Trehalose-6-phosphate synthase (TPS) genes play an active role in the trehalose metabolism pathway that regulates the responses of plants to diverse stresses. However, the functional identification, comparison, and conservatism of TPS genes in the responses of woody plants, especially poplars, to drought stress remain unclear. Here, the trehalose content of 84K (Populus alba × P. glandulosa) poplars was down-regulated and PagTPS and PagTPP genes had diverse response patterns under drought stress. Physicochemical properties, expression patterns, and functions of PagTPS1 and PagTPS10, two class I members of TPS gene family, were identified and compared. Transgenic 84K poplars overexpressing PagTPS1 and PagTPS10 had significantly higher trehalose content with approximately 138% and 123%, respectively, and stronger drought tolerance compared to WT. PagTPS1 and PagTPS10 promoted the expression of TPPA genes and drought-responsive genes. Accordingly, poplars inhibiting PagTPS1 and PagTPS10 expression via RNA interference had lower trehalose content and drought tolerance. Simultaneously, overexpressing PagTPS1 and PagTPS10 improved the trehalose content and drought tolerance of Arabidopsis. Overall, we proposed a model of the effects of PagTPS1 and PagTPS10 as conservative regulators on the responses of plants to drought, which would provide new insights into the functional explorations of TPS genes in plants.

The implementation of low instantaneous dose rate total body irradiation with linear accelerator in small-size treatment rooms.

PURPOSE: This paper describes the implementation of an instantaneous low-dose-rate total body irradiation (TBI) technique using block-filtered 6 MV X-rays with a linear accelerator (LINAC) to reduce pulmonary toxicity. METHODS: In the absence of dedicated TBI-specific meter-set dose rates in LINAC and sufficient treatment room size, a 2-cm-thick transmission block was used together with a 200-cm source-to-surface distance (SSD) to reduce the instantaneous dose rates of 6 MV x-rays down to 10 cGy/min, thus alteration to the beam properties. A TBI-specific dose calculation model was built with data acquired at the treatment planning system (TPS)-permitted maximum 140-cm SSD and was validated in phantoms at a 180-cm SSD. As for planning strategies, we adopted large anterior-to-posterior/posterior-to-anterior (AP/PA) open fields with multi-leaf collimator shielding for lungs to achieve target coverage, lung protection, and efficient dose delivery. A custom-designed sliding couch (Patent No. ZL202123085880.1) was manufactured to support patients during treatment. Measures to control the quality and safety of TBI treatment include machine interlocks, pretreatment checklists, and in-vivo dose monitoring. RESULTS: The instantaneous dose rate of block-filtered 6MV X-ray was reduced to approximately 7.0 cGy/min at 12.5-7.5 cm depth with a 185-200 cm SSD. The dose calculated by TPS differs from the measurements by 0.15%-1.55% in the homogeneous phantom and 1.2%-4.85% in the CIRS thorax phantom. The open-field TBI technique achieved V90% (PTV) ≈ 96.8% and MLD = 6.6 Gy with 1-h planning and 50-min beam delivery in a single fraction. From February 2021 to July 2023, 30 patients received TBI treatments in our center, and in-vivo monitoring results differed from TPS calculations by -1.49%-2.10%. After 6-12 months of follow-ups, all the patients treated in our center showed no pulmonary toxicities of grade 2 or higher. CONCLUSION: A low instantaneous dose rate TBI technique can be implemented in the clinic.

Evaluation of CTLA-4 and PD-L1 Expression in Thyroid Carcinoma and Its Prognostic Significance.

Introduction Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) have revolutionised treatment and improved outcomes in various malignancies. We aimed to evaluate CTLA-4 and PD-L1 immunoexpression in thyroid tumours and correlated them with clinicopathological parameters. Methods The study included 90 cases of thyroid malignancies comprising papillary thyroid carcinoma (PTC) (n = 64, 54.2%), follicular thyroid carcinoma (FTC) (n = 19, 16.1%), anaplastic thyroid carcinoma (ATC) (n = 3, 2.5%), and poorly differentiated carcinoma (n = 4, 3.4%), two cases (1.69%) of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) along with 26 cases (22%) of benign thyroid lesions. CTLA-4 (UMAB249) and PD-L1 (SP263) expression were assessed in all the cases of thyroid tumours. Results were compared with clinicopathologic parameters and overall survival. Results PD-L1 was positive in all three cases of anaplastic thyroid carcinoma (ATC), 33% (n = 21) cases of PTC, and 16% (n = 3) cases of FTC. PD-L1 positivity was significantly associated at tumour proportion score (TPS) ≥1% with lymphovascular invasion and age ≤40 years and at TPS ≥50% with tumour necrosis and N-stage. Immune proportion score (IPS) did not correlate with any clinicopathological parameters except for the N-stage. CTLA-4 was positive in six cases of PTC (1-5%); five showed lymph node involvement (p = 0.032). IPS was positive in 14 cases, and a significant association was seen with lymph node metastasis, lymphocytic infiltration, and lymphovascular invasion. Three cases of PTC showed co-expression for PD-L1 and CTLA-4 in tumour cells. No significant association was seen between PD-L1 expression and survival. Conclusion The current data suggest that PD-L1 is expressed in differentiated thyroid carcinoma, mainly PTC and ATC, indicating higher responsiveness to immunotherapy. A subset of PTC showed co-expression of PD-L1 and CTLA-4. These findings suggest the need for further investigation to utilise combinational immunotherapy, including anti-PD-L1 and anti-CTLA-4.

Personality interferences in the pathology of breast cancer: a cross-sectional single-center study.

Individual personality refers to the Ego and the interpersonal sector. The Ego corresponds to consciousness and self-esteem, including the capacities for emotional self-regulation, self-control, self-evaluation, and self-direction in relation to personal goals. When neoplastic and psychiatric diseases coexist, a patient's quality of life is significantly impacted. While there are somatic differences in disease progression, how the illness is perceived and mainly experienced depends on personality traits. In this study, we administered the DECAS Personality Inventory (a Romanian-validated instrument based on the Five-Factor model of personality) to a group of 121 patients diagnosed with breast cancer to explore the relationships among their personality traits. Descriptive statistics revealed that the mean T scores for openness, extroversion, and emotional stability were low, while the scores for conscientiousness and agreeableness were at an average level. Our findings suggest that, in the studied group, low levels of emotional stability, extroversion, and openness were unfavorable personality dimensions that should be a primary focus of therapeutic strategies, as they significantly affect the quality of life in patients with breast cancer.

Estimation of suspected estrogenic transformation products generated during preservative butylparaben chlorination using a simplified effect-based analysis approach.

Estrogenic transformation products (TPs) generated after water chlorination can be considered as an environmental and health concern, since they can retain and even increase the estrogenicity of the parent compound, thus posing possible risks to drinking water safety. Identification of the estrogenic TPs generated from estrogenic precursor during water chlorination is important. Herein, butylparaben (BuP), which was widely used as preservative in food, pharmaceuticals and personal care products (PPCPs), was selected for research. A simplified effect-based analysis (EDA) approach was applied for the identification of estrogenic TPs generated during BuP chlorination. Despite the removal of BuP corresponds to the decrease of estrogenicity in chlorinated samples, an significant increase of estrogenicity was observed (at T = 30 min, presented an estrogenicity equivalent to 17ß-estradiol). Chemical analysis of the estrogenic chlorinated samples that have been previously subjected to biological analysis (in vitro assays), in combination with the principal component analysis (PCA) evaluation, followed by validating the estrogenic potency of most relevant estrogenic TPs through an in silico approach (molecular dynamics simulations), identified that the halogenated TP3 (3,5-Dichloro-butylparaben) increased by 62.5 % and 61.8 % of the estrogenic activity of the parent compound in samples chlorinated with 30 min and 1 h, respectively being classified as a potentially estrogenic activity driver after BuP chlorination. This study provides a scientific basis for the more comprehensive assessment of the environmental and health risk associated with BuP chlorination, highlighting the necessity of identifying the unknown estrogenic TPs generateded from estrogenic precursors chlorination.

Enhanced Cognition and Modulation of Brain Connectivity in Mild Neurocognitive Disorder: The Promise of Transcranial Pulse Stimulation.

Existing pharmacological treatments for mild neurocognitive disorder (NCD) offer limited effectiveness and adverse side effects. Transcranial pulse stimulation (TPS) utilizing ultrashort ultrasound pulses reaches deep brain regions and may circumvent conductivity issues associated with brain stimulation. This study addresses the gap in TPS research for mild NCD during a critical intervention period before irreversible cognitive degradation. Our objective was to explore the effectiveness and tolerability of TPS in older adults with mild NCD. In an open-label study, 17 older adults (including 10 females and 7 males) with mild NCD underwent TPS for two weeks with three sessions per week. Cognitive evaluations and fMRI scans were conducted pre- and post-intervention. The results indicated changes in functional connectivity in key brain regions, correlating with cognitive improvement at B = 0.087 (CI, 0.007-0.167; p = 0.038). However, cortical thickness measurements showed no significant differences. Here we show that TPS can enhance cognitive function within mild NCD. This proof-of-concept study suggests that TPS has potential as a non-invasive therapy used to attenuate cognitive decline, encouraging further investigation in larger randomized trials. The findings could influence clinical practice by introducing TPS as an adjunctive treatment option and potentially impact policy by promoting its inclusion in new treatment strategies for mild NCD.

Get unbent! R tools for the removal of arching and bending in fish specimens for geometric morphometric shape analysis.

Geometric morphometrics is a powerful tool for studying fish body shape; however, body posture can be a hindrance to these analyses. Here I introduce new R language tools for correcting multiple types of bending of 3D data based on the TPS suite (geometric morphometric software) "unbend specimens" methodology. In a sample dataset of darters, these R tools adequately accounted for posture artifacts otherwise evident across multiple principal component axes. I hope these new tools will facilitate the incorporation of 3D landmark data into the comparative analysis of fish body shape.

Urinary Tract Cytopathology: Current and Future Impact on Patient Care.

Urine cytology is a non-invasive, cost-efficient, and sensitive test to detect high-grade urothelial carcinoma. The Paris System (TPS) for Reporting Urinary Cytology is an evidence-based system that uses the risk of malignancy to guide patient management. Since its inception, TPS has standardized urine cytology reports, facilitating communication among pathologists and between pathologists and clinicians. It is imperative to correlate the urine cytology findings with the concurrent tissue sample to avoid false-negative and false-positive results when possible. Several ancillary tests and artificial intelligence algorithms are being developed to increase the accuracy of urine cytology interpretation.

Genome-Wide Identification and Evolution-Profiling Analysis of TPS Gene Family in Triticum Plants.

Terpenoids play a crucial role in plant growth and development, as well as in regulating resistance mechanisms. Terpene synthase (TPS) serves as the final step in the synthesis process of terpenoids. However, a comprehensive bioinformatics analysis of the TPS gene family in Triticum plants had not previously been systematically undertaken. In this study, a total of 531 TPS members were identified in Triticum plants. The evolutionary tree divided the TPS proteins into five subfamilies: Group1, Group2, Group3, Group4, and Group5. The results of the duplication events analysis showed that TD and WGD were major driving forces during the evolution of the TPS family. The cis-element analysis showed that the TPS genes were related to plant growth and development and environmental stress. Moreover, the GO annotation displayed that the biological function of TPS was relatively conserved in wheat plants. The RNA-seq data showed that the rice and wheat TPS genes responded to low-temperature stress and exhibited significantly different expression patterns. This research shed light on the functions of TPSs in responding to abiotic stress and demonstrated their modulatory potential during root development. These findings provide a foundation for further and deeper investigation of the TPSs' functions in Triticum plants.

Systems-level reconstruction of kinase phosphosignaling networks regulating endothelial barrier integrity using temporal data.

Phosphosignaling networks control cellular processes. We built kinase-mediated regulatory networks elicited by thrombin stimulation of brain endothelial cells using two computational strategies: Temporal Pathway Synthesizer (TPS), which uses phosphoproetiomics data as input, and Temporally REsolved KInase Network Generation (TREKING), which uses kinase inhibitor screens. TPS and TREKING predicted overlapping barrier-regulatory kinases connected with unique network topology. Each strategy effectively describes regulatory signaling networks and is broadly applicable across biological systems.

Commissioning and validation of a single photon beam model in RayStation for multiple matched Elekta Linacs.

PURPOSE: A single treatment planning system (TPS) model for matched linacs provides flexible clinical workflows from patient treatment to intensity-modulated radiation therapy (IMRT) quality assurance (QA) measurement. Since general guidelines for building a single TPS model and its validation for matched linacs are not well established, we present our RayStation photon TPS modeling strategy for matched Elekta VersaHD linacs. METHOD: The four linacs installed from 2013 to 2020 were matched in terms of Percent Depth Dose (PDD), profile, output factor and wedge factors for 6-MV, 10-MV, 15-MV, and 6-MV-FFF, and maintained following TG-142 recommendations until RayStation commissioning. The RayStation single model was built to represent all four linacs within the tolerance limits recommended by MPPG-5.a. The comprehensive validation tests were performed for one linac following MPPG-5.a and TG-119 guidelines, and spot checks for the other three. Our TPS modeling/validation method was evaluated by re-analyzing the previous 103 patient-specific IMRT/volumetric modulated arc therapy (VMAT) QA measurements with the calculated planar doses by the single model in comparison with the analysis results using four individual Pinnacle TPS models. RESULTS: For all energies, our single model PDDs were within 1% agreement of the four-linac commissioning measurements. The MPPG-5.a validation tests from 5.1 through 7.5 and all TG-119 measurements passed within the recommended tolerance limits. The IMRT QA results (mean ± standard deviation) for RayStation single model versus Pinnacle individual models were 98.9% ± 1.3% and 98.0% ± 1.4% for 6-MV, 99.9% ± 0.1% and 99.1% ± 1.9% for 10-MV, and 98.2% ± 1.3% and 97.9% ± 1.8% for 6-MV-FFF, respectively. CONCLUSION: We successfully built and validated a single photon beam model in RayStation for four Elekta Linacs. The proposed new validation methods were proven to be both efficient and effective.

Thermal Decomposition of Bio-Based Plastic Materials.

This research delves into a detailed exploration of the thermal decomposition behavior of bio-based polymers, specifically thermoplastic starch (TPS) and polylactic acid (PLA), under varying heating rates in a nitrogen atmosphere. This study employs thermogravimetry (TG) to investigate, providing comprehensive insights into the thermal stability of these eco-friendly polymers. In particular, the TPS kinetic model is examined, encompassing the decomposition of three distinct fractions. In contrast, PLA exhibits a simplified kinetic behavior requiring only a fraction described by a zero-order model. The kinetic study involves a systematic investigation into the individual contributions of key components within TPS, including starch, glycerin, and polyvinyl alcohol (PVA). This detailed analysis contributes to a comprehensive understanding of the thermal degradation process of TPS and PLA, enabling the optimization of processing conditions and the prediction of material behavior across varying thermal environments. Furthermore, the incorporation of different starch sources and calcium carbonate additives in TPS enhances our understanding of the polymer's thermal stability, offering insights into potential applications in diverse industries.

The chromosome-level genome assembly of Cananga odorata provides insights into its evolution and terpenoid biosynthesis.

Cananga odorata is known as a natural perfume tree of the Annonaceae family in Magnoliales. However, its phylogenetic position and the molecular mechanisms involved in the biosynthesis of the floral volatile organic compounds (VOCs) remain unclear. Here, by combining a variety of sequencing platforms, we present a telomere-to-telomere (T2T) genome of C. odorata with 735.83 Mb, which represents the highest integrity and assembly quality of genome in magnoliid plants reported to date. Phylogenetic analysis based on multiple datasets and approaches showed that C. odorata, as a member of magnoliids, is sister to eudicots, after their divergence from monocots. Metabolomic of VOCs in the essential oil and flowers scent showed that sesquiterpenes, especially ß-caryophyllene, were the major compounds. Two CoTPS21 homologues derived from tandem duplication events were highly expressed during flower development and were identified as the key sesquiterpene synthases for the production of ß-caryophyllene. In addition, CoSPL3 and CoSPL9 were considered as potential transcription factors for activating the expression of CoTPS21 homologues. Our results shed light on the molecular mechanisms underlying the biosynthesis of the unique floral fragrance in C. odorata and provide new insights into the phylogenetic position of magnoliids.

Pan-cancer evaluation of tumor-infiltrating lymphocytes and programmed cell death protein ligand-1 in metastatic biopsies and matched primary tumors.

Tumor immunological characterization includes evaluation of tumor-infiltrating lymphocytes (TILs) and programmed cell death protein ligand-1 (PD-L1) expression. This study investigated TIL distribution, its prognostic value, and PD-L1 expression in metastatic and matched primary tumors (PTs). Specimens from 550 pan-cancer patients of the SHIVA01 trial (NCT01771458) with available metastatic biopsy and 111 matched PTs were evaluated for TILs and PD-L1. Combined positive score (CPS), tumor proportion score (TPS), and immune cell (IC) score were determined. TILs and PD-L1 were assessed according to PT organ of origin, histological subtype, and metastatic biopsy site. We found that TIL distribution in metastases did not vary according to PT organ of origin, histological subtype, or metastatic biopsy site, with a median of 10% (range: 0-70). TILs were decreased in metastases compared to PT (20% [5-60] versus 10% [0-40], p < 0.0001). CPS varied according to histological subtype (p = 0.02) and biopsy site (p < 0.02). TPS varied according to PT organ of origin (p = 0.003), histological subtype (p = 0.0004), and metastatic biopsy site (p = 0.00004). TPS was higher in metastases than in PT (p < 0.0001). TILs in metastases did not correlate with overall survival. In conclusion, metastases harbored fewer TILs than matched PT, regardless of PT organ of origin, histological subtype, and metastatic biopsy site. PD-L1 expression increased with disease progression. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PD-L1 Expression in Paired Samples of Rectal Cancer.

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

Standardized Digital Image Analysis of PD-L1 Expression in Head and Neck Squamous Cell Carcinoma Reveals Intra- and Inter-Sample Heterogeneity with Therapeutic Implications.

For practical reasons, in many studies PD-L1 expression is measured by combined positive score (CPS) from a single tumor sample. This does not reflect the heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma (HNSCC). We investigated the extent and relevance of PD-L1 expression heterogeneity in HNSCC analyzing primary tumors and recurrences (LRs), as well as metastases. Tumor tissue from 200 HNSCC patients was immunohistochemically stained for PD-L1 and analyzed using image-analysis software QuPath v3.4 with multiple specimens per patient. CPS was ≥20 in 25.6% of primary tumors. Intra-tumoral heterogeneity led to a therapeutically relevant underestimation of PD-L1 expression in 28.7% of patients, when only one specimen per patient was analyzed. Inter-tumoral differences in PD-L1 expression between primary tumors and lymph node metastasis (LNM) or LR occurred in 44.4% and 61.5% (CPS) and in 40.6% and 50% of cases (TPS). Overall survival was increased in patients with CPS ≥ 1 vs. CPS < 1 in primary tumors and LNM (hazard ratio: 0.46 and 0.35; p < 0.005); CPS in LR was not prognostic. Our analysis shows clinically relevant intra- and inter-sample heterogeneity of PD-L1 expression in HNSCC. To account for heterogeneity and improve patient selection for immunotherapy, multiple sample analyses should be performed, particularly in patients with CPS/TPS < 1.

Extraction of a 6-year-old leadless pacemaker (MICRA transcatheter pacing system) using commercially available removal tools: A case report.

INTRODUCTION: Leadless pacemakers are associated with a low risk of infection, so indications for their removal are rare. One can expect that the dwell time of the device correlates with a more difficult removal, but it has not been proved so far. METHODS AND RESULTS: We present a case of a patient in whom MICRA transcatheter pacing system was successfully removed with nondedicated commercially available tools, 70 months after implantation. CONCLUSION: A successful removal of the MICRA leadless pacemaker is possible, and may be safe even many years after the device implantation, despite a lack of dedicated tools. Due to the potential risk of complications, the benefits and risks of the procedure should be weighted before making a final decision.