bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S4 from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids
Authors: Suvilesh Kanve N. , Manjunath Yariswamy , Nussbaum Yulia I. , Gadelkarim Mohamed , Raju Murugesan , Srivastava Akhil , Li Guangfu , Warren Wesley C. , Shyu Chi-Ren , Gao Feng , Ciorba Matthew A. , Mitchem Jonathan B. , Rachagani Satyanarayana , Kaifi Jussuf T.
Published: September 2024

Supplementary Figure S4. Cellular heterogeneity comparison between matched patient-derived tumor organoids (PDTOs) and patient primary tumors (PT).
Supplementary Figure S2 from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids
Authors: Suvilesh Kanve N. , Manjunath Yariswamy , Nussbaum Yulia I. , Gadelkarim Mohamed , Raju Murugesan , Srivastava Akhil , Li Guangfu , Warren Wesley C. , Shyu Chi-Ren , Gao Feng , Ciorba Matthew A. , Mitchem Jonathan B. , Rachagani Satyanarayana , Kaifi Jussuf T.
Published: September 2024

Supplementary Figure S2. Genomic characterization of patient-matched primary tumors and PDTOs to identify genomic fidelity of organoid models.
Supplementary Figure S14 from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids
Authors: Suvilesh Kanve N. , Manjunath Yariswamy , Nussbaum Yulia I. , Gadelkarim Mohamed , Raju Murugesan , Srivastava Akhil , Li Guangfu , Warren Wesley C. , Shyu Chi-Ren , Gao Feng , Ciorba Matthew A. , Mitchem Jonathan B. , Rachagani Satyanarayana , Kaifi Jussuf T.
Published: September 2024

Supplementary Figure S14. Dose titration of commonly used cytotoxic agents against AKR1B10 knocked down and scramble shRNA treated A549 cells.
Supplementary Figure S12 from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids
Authors: Suvilesh Kanve N. , Manjunath Yariswamy , Nussbaum Yulia I. , Gadelkarim Mohamed , Raju Murugesan , Srivastava Akhil , Li Guangfu , Warren Wesley C. , Shyu Chi-Ren , Gao Feng , Ciorba Matthew A. , Mitchem Jonathan B. , Rachagani Satyanarayana , Kaifi Jussuf T.
Published: September 2024

Supplementary Figure S12. Validation of AKR1B10 expression in an internal cohort of sensitive (n = 7) and resistance (n = 7) patient tumors to platinum-based doublet therapy.
Data from Streamlined Intraoperative Brain Tumor Classification and Molecular Subtyping in Stereotactic Biopsies Using Stimulated Raman Histology and Deep Learning
Authors: Reinecke David , Ruess Daniel , Meissner Anna-Katharina , Fürtjes Gina , von Spreckelsen Niklas , Ion-Margineanu Adrian , Khalid Florian , Blau Tobias , Stehle Thomas , Al-Shugri Abdulkader , Büttner Reinhard , Goldbrunner Roland , Ruge Maximilian I. , Neuschmelting Volker
Published: September 2024

AbstractPurpose:
Recent artificial intelligence algorithms aided intraoperative decision-making via stimulated Raman histology (SRH) during craniotomy. This study assesses deep learning algorithms for rapid intraoperative diagnosis from SRH images in small stereotactic-guided brain biopsies. It defines a minimum tissue sample size threshold to ensure diagnostic accuracy.
Experimental Design:
A prospective single-center study examined 121 SRH images from 84 patients with unclear intracranial lesions undergoing stereotactic brain biopsy. Unprocessed, label-free samples were imaged using a portable fiber laser Raman scattering microscope. Three deep learning models were tested to (i) identify tumorous/nontumorous tissue as qualitative biopsy control; (ii) subclassify into high-grade glioma (central nervous system World Health Organization grade 4), diffuse low-grade glioma (central nervous system World Health Organization grades 2–3), metastases, lymphoma, or gliosis; and (iii) molecularly subtype IDH and 1p/19q statuses of adult-type diffuse gliomas. Model predictions were evaluated against frozen section analysis and final neuropathologic diagnoses.
Results:
The first model identified tumorous/nontumorous tissue with 91.7% accuracy. Sample size on slides impacted accuracy in brain tumor subclassification (81.6%, κ = 0.72 frozen section; 73.9%, κ = 0.61 second model), with SRH images being smaller than hematoxylin and eosin images (4.1 ± 2.5 mm2 vs. 16.7 ± 8.2 mm2, P < 0.001). SRH images with more than 140 high-quality patches and a mean squeezed sample of 5.26 mm2 yielded 89.5% accuracy in subclassification and 93.9% in molecular subtyping of adult-type diffuse gliomas.
Conclusions:
Artificial intelligence–based SRH image analysis is non-inferior to frozen section analysis in detecting and subclassifying brain tumors during small stereotactic-guided biopsies once a critical squeezed sample size is reached. Beyond frozen section analysis, it enables valid molecular glioma subtyping, allowing faster treatment decisions in the future; however, refinement is needed for long-term application.
Data from Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair–Deficient Uterine Leiomyosarcoma
Authors: Lee Horace H.Y. , Chow Kin Long , Wong Ho Shing , Chong Tsz Yan , Wong Alice S.T. , Cheng Grace H.W. , Ko Jasmine M.K. , Siu Hoi Cheong , Yeung Maximus C.F. , Huen Michael S.Y. , Tse Ka Yu , Bray Mark R. , Mak Tak Wah , Leung Suet Yi , Ip Philip P.C.
Published: September 2024

AbstractPurpose:
Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment.
Experimental Design:
Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay.
Results:
Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired.
Conclusions:
Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.
Data from Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol
Authors: Geurts Birgit S. , Zeverijn Laurien J. , Leek Lindsay V.M. , van Berge Henegouwen Jade M. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , van de Haar Joris , van Ommen-Nijhof Annemiek , Kok Marleen , Roepman Paul , Jansen Anne M.L. , de Leng Wendy W.J. , de Jonge Maja J.A. , Hoeben Ann , van Herpen Carla M.L. , Westgeest Hans M. , Wessels Lodewyk F.A. , Verheul Henk M.W. , Gelderblom Hans , Voest Emile E.
Published: September 2024

AbstractPurpose:
To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing–based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).
Patients and Methods:
Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing.
Results:
Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.
Conclusions:
Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study’s primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.

See related commentary by Hsu and Yen, p. 3652
Data from Differences in the Prognostic Role of Age, Extent of Resection, and Tumor Grade between Astrocytoma IDHmt and Oligodendroglioma: A Single-Center Cohort Study
Authors: van der Vaart Thijs , Wijnenga Maarten M.J. , van Garderen Karin , Dubbink Hendrikus J. , French Pim J. , Smits Marion , Dirven Clemens M.F. , Kros Johan M. , Vincent Arnaud J.P.E. , van den Bent Martin J.
Published: September 2024

AbstractPurpose:
IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood.
Experimental Design:
Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semiautomatic 3D segmentation on all pre- and post-operative MRI scans. Overall survival was assessed with the Cox-proportional hazards model.
Results:
A total of 383 patients with newly diagnosed IDH-mutant glioma were followed up for a median of 7.2 years. Grades 3 and 4 patients had significantly lower Karnofsky performance, with tumors having more contrast enhancement. Patients also received more aggressive postsurgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR, per cm3 1.19; 95% CI, 1.03–1.39) in IDH-mutant glioma. A separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma but not in oligodendroglioma. Higher age and histologic tumor grade were associated with worse survival in patients with oligodendroglioma but not with astrocytoma.
Conclusions:
Our data support an initial strategy of extensive resection in patients with oligodendroglioma and astrocytoma. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.
Data from Computational Model Predicts Patient Outcomes in Luminal B Breast Cancer Treated with Endocrine Therapy and CDK4/6 Inhibition
Authors: Schmiester Leonard , Brasó-Maristany Fara , González-Farré Blanca , Pascual Tomás , Gavilá Joaquín , Tekpli Xavier , Geisler Jürgen , Kristensen Vessela N. , Frigessi Arnoldo , Prat Aleix , Köhn-Luque Alvaro
Published: September 2024

AbstractPurpose:
Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer.
Experimental Design:
A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS).
Results:
The model showed significant association with patient’s outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64–0.92), 0.81 (0.60–1.00) and 0.80 (0.65–0.93)] and high PAM50 ROR [AUC of 0.78 (0.64–0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08–7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043].
Conclusions:
A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer.
Data from Playing Russian Roulette: Parent and Adolescent Perspectives on Tumor Surveillance for Adolescents with Cancer Predisposition Syndromes
Authors: Elias Rachel , Blake Alise , Dean Lori , Flynn Jessica S. , Sachner Leila , Harrison Lynn , McGee Rose B. , Nichols Kim E. , Howard Sharp Katianne M.
Published: September 2024

AbstractPurpose:
Cancer predisposition syndrome (CPS) surveillance allows for the early detection and treatment of neoplasms; however, the psychosocial impact of tumor surveillance is poorly understood for cancer-affected adolescents with CPS and their parents. To gain further insight, we qualitatively characterized the affective and cognitive experience of adolescents undergoing tumor surveillance.
Experimental Design:
Adolescents with a history of cancer and their parents independently completed semistructured interviews querying their experience with the adolescent’s tumor surveillance. Interviews were coded using emotion coding and content analysis before developing themes using thematic analysis.
Results:
Eight adolescents and 11 parents (seven mothers, four fathers) completed interviews. Parent themes included maternal anxiety, relief following surveillance, fathers’ positive expectations and emotions surrounding surveillance results, coping strategies, and perception of going through surveillance together with their child. Adolescent themes included normalization of surveillance, indifference about surveillance but excitement to return to the hospital, focus on physical and logistic aspects, relief focused on being done with scans, and belief that outcomes would be good. Past scans/surveillance experiences influencing surveillance feelings were a theme across both parents and adolescents.
Conclusions:
Our findings suggest that tumor surveillance is not causing marked emotional distress for cancer-affected adolescents with CPS. In contrast, mothers of cancer-affected adolescents undergoing surveillance may present with anxiety leading up to tumor surveillance and, for a subset, in between surveillance appointments. These observations highlight a need for ongoing psychosocial screening for families of children with CPS and a role for psychosocial providers in the multidisciplinary management of CPS.
Data from Identification of Therapy-Induced Clonal Evolution and Resistance Pathways in Minimal Residual Clones in Multiple Myeloma through Single-Cell Sequencing
Authors: Cui Jian , Li Xiaoyun , Deng Shuhui , Du Chenxing , Fan Huishou , Yan Wenqiang , Xu Jingyu , Li Xiaoqing , Yu Tengteng , Zhang Shuaishuai , Lv Rui , Sui Weiwei , Hao Mu , Du Xin , Xu Yan , Yi Shuhua , Zou Dehui , Cheng Tao , Qiu Lugui , Gao Xin , An Gang
Published: September 2024

AbstractPurpose:
In multiple myeloma (MM), therapy-induced clonal evolution is associated with treatment resistance and is one of the most important hindrances toward a cure for MM. To further understand the molecular mechanisms controlling the clonal evolution of MM, we applied single-cell RNA sequencing (scRNA-seq) to paired diagnostic and posttreatment bone marrow (BM) samples.
Experimental Design:
scRNA-seq was performed on 38 BM samples from patients with monoclonal gammopathy of undetermined significance (n = 1), MM patients at diagnosis (n = 19), MM posttreatment (n = 17), and one healthy donor (HD). The single-cell transcriptome data of malignant plasma cells (PC) and the surrounding immune microenvironment were analyzed.
Results:
Profiling by scRNA-seq data revealed three primary trajectories of transcriptional evolution after treatment: clonal elimination in patients with undetectable minimal residual disease (MRD−) and clonal stabilization and clonal selection in detectable MRD (MRD+) patients. We noted a metabolic shift toward fatty acid oxidation in cycling-resistant PCs, whereas selective PCs favored the NF-κB pathway. Intriguingly, when comparing the genetic and transcriptional dynamics, we found a significant correlation between genetic and nongenetic factors in driving the clonal evolution. Furthermore, we identified variations in cellular interactions between malignant PCs and the tumor microenvironment. Selective PCs showed the most robust cellular interactions with the tumor microenvironment.
Conclusions:
These data suggest that MM cells could rapidly adapt to induction treatment through transcriptional adaptation, metabolic adaptation, and specialized immune evasion. Targeting therapy-induced resistance mechanisms may help to avert refractory disease in MM.
Data from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids
Authors: Suvilesh Kanve N. , Manjunath Yariswamy , Nussbaum Yulia I. , Gadelkarim Mohamed , Raju Murugesan , Srivastava Akhil , Li Guangfu , Warren Wesley C. , Shyu Chi-Ren , Gao Feng , Ciorba Matthew A. , Mitchem Jonathan B. , Rachagani Satyanarayana , Kaifi Jussuf T.
Published: September 2024

AbstractPurpose:
Systemic treatments given to patients with non–small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.
Experimental Design:
PDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome sequencing, and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential gene expression analysis identified drug-repurposing targets. Validations were performed with internal/external data sets of patients with NSCLC. NSCLC cell lines were used for aldo-keto reductase 1B10 (AKR1B10) knockdown studies and xenograft models to determine the intratumoral bioavailability of epalrestat.
Results:
PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.
Conclusions:
PDTOs are efficient preclinical models recapitulating the tumor characteristics and are suitable for drug testing. AKR1B10 can be targeted by repurposing epalrestat to overcome chemoresistance in NSCLC. Epalrestat has the potential to advance to clinical trials in patients with drug-resistant NSCLC due to favorable toxicity, pharmacological profile, and bioavailability.
Supplementary Table S3 from Endoplasmic Reticulum Stress Potentiates the Immunosuppressive Microenvironment in Hepatocellular Carcinoma by Promoting the Release of SNHG6-Enriched Small Extracellular Vesicles
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Yu Jiaping , Li Wenwen , Zhang Wanli , Liao Yanxia , Wang Haijian , Liu Li
Published: September 2024

Supplementary Table S3
Supplementary Table S1 from Endoplasmic Reticulum Stress Potentiates the Immunosuppressive Microenvironment in Hepatocellular Carcinoma by Promoting the Release of SNHG6-Enriched Small Extracellular Vesicles
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Yu Jiaping , Li Wenwen , Zhang Wanli , Liao Yanxia , Wang Haijian , Liu Li
Published: September 2024

Supplementary Table S1
Figure S5 from Endoplasmic Reticulum Stress Potentiates the Immunosuppressive Microenvironment in Hepatocellular Carcinoma by Promoting the Release of SNHG6-Enriched Small Extracellular Vesicles
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Yu Jiaping , Li Wenwen , Zhang Wanli , Liao Yanxia , Wang Haijian , Liu Li
Published: September 2024

Supplementary Fig. S5. Targeting SNHG6 expression reverts the immunosuppressive TME.
Figure S4 from Endoplasmic Reticulum Stress Potentiates the Immunosuppressive Microenvironment in Hepatocellular Carcinoma by Promoting the Release of SNHG6-Enriched Small Extracellular Vesicles
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Yu Jiaping , Li Wenwen , Zhang Wanli , Liao Yanxia , Wang Haijian , Liu Li
Published: September 2024

Supplementary Fig. S4. ATF4 facilitates SNHG6-laden sEVs release through HnRNPA2B1.
Figure S1 from Endoplasmic Reticulum Stress Potentiates the Immunosuppressive Microenvironment in Hepatocellular Carcinoma by Promoting the Release of SNHG6-Enriched Small Extracellular Vesicles
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Yu Jiaping , Li Wenwen , Zhang Wanli , Liao Yanxia , Wang Haijian , Liu Li
Published: September 2024

Supplementary Fig. S1. ER stress induces macrophage polarization through ATF4.
Figure S9 from Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways
Authors: Skadborg Signe K. , Maarup Simone , Draghi Arianna , Borch Annie , Hendriksen Sille , Mundt Filip , Pedersen Vilde , Mann Matthias , Christensen Ib J. , Skjøth-Ramussen Jane , Yde Christina W. , Kristensen Bjarne W. , Poulsen Hans S. , Hasselbalch Benedikte , Svane Inge M. , Lassen Ulrik , Hadrup Sine R.
Published: September 2024

Supplementary Figure 9 Co-expression of Inhibitory molecules on intratumoral T cells.
Figure S8 from Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways
Authors: Skadborg Signe K. , Maarup Simone , Draghi Arianna , Borch Annie , Hendriksen Sille , Mundt Filip , Pedersen Vilde , Mann Matthias , Christensen Ib J. , Skjøth-Ramussen Jane , Yde Christina W. , Kristensen Bjarne W. , Poulsen Hans S. , Hasselbalch Benedikte , Svane Inge M. , Lassen Ulrik , Hadrup Sine R.
Published: September 2024

Supplementary Figure 8 Transcriptomic comparison of NIVO versus control patients.
Figure S4 from Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways
Authors: Skadborg Signe K. , Maarup Simone , Draghi Arianna , Borch Annie , Hendriksen Sille , Mundt Filip , Pedersen Vilde , Mann Matthias , Christensen Ib J. , Skjøth-Ramussen Jane , Yde Christina W. , Kristensen Bjarne W. , Poulsen Hans S. , Hasselbalch Benedikte , Svane Inge M. , Lassen Ulrik , Hadrup Sine R.
Published: September 2024

Supplementary Figure 4
Supplementary Figure 1 from Identification of Core Techniques That Enhance Genome Editing of Human T Cells Expressing Synthetic Antigen Receptors
Authors: Chang Ju-Fang , Wellhausen Nils , Engel Nils W. , Landmann Jack H. , Hopkins Caitlin R. , Salas-McKee January , Bear Adham S. , Selli Mehmet E. , Agarwal Sangya , Jadlowsky Julie K. , Linette Gerald P. , Gill Saar , June Carl H. , Fraietta Joseph A. , Singh Nathan
Published: September 2024

A, Representative ow cytometry plots of transduction efficiency of various synthetic receptors in control (unedited) and TRAC+TRBCKO T cells when editing is performed pre-stimulation. B, Stability of CRISPR editing over-time when performing post-stimulation editing.
Supplementary Table 1 from Intracellular Osteopontin Promotes the Release of TNFα by Mast Cells to Restrain Neuroendocrine Prostate Cancer
Authors: Sulsenti Roberta , Scialpi Giuseppina B. , Frossi Barbara , Botti Laura , Ferri Renata , Tripodi Irene , Piva Annamaria , Sangaletti Sabina , Pernici Davide , Cancila Valeria , Romeo Francesco , Chiodoni Claudia , Lecis Daniele , Bianchi Francesca , Fischetti Irene , Enriquez Claudia , Crivelli Filippo , Bregni Marco , Renne Giuseppe , Pece Salvatore , Tripodo Claudio , Pucillo Carlo E. , Colombo Mario P. , Jachetti Elena
Published: September 2024

Supplementary table 1 - list of antibodies used in the study
Supplementary Figure S8 from Intracellular Osteopontin Promotes the Release of TNFα by Mast Cells to Restrain Neuroendocrine Prostate Cancer
Authors: Sulsenti Roberta , Scialpi Giuseppina B. , Frossi Barbara , Botti Laura , Ferri Renata , Tripodi Irene , Piva Annamaria , Sangaletti Sabina , Pernici Davide , Cancila Valeria , Romeo Francesco , Chiodoni Claudia , Lecis Daniele , Bianchi Francesca , Fischetti Irene , Enriquez Claudia , Crivelli Filippo , Bregni Marco , Renne Giuseppe , Pece Salvatore , Tripodo Claudio , Pucillo Carlo E. , Colombo Mario P. , Jachetti Elena
Published: September 2024

Supplementary Figure S8. Hematoxylin and eosin staining in TRAMP mice. A. Hematoxylin and eosin staining in serial slides of tumors reported in Fig. 5A, showing an untreated TRAMP mouse with adenocarcinoma (ADENO) and a TRAMP mouse subjected to surgical castration showing a focal t-NEPC area.
Table S3 from Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor
Authors: Oberstein Paul E. , Dias Costa Andressa , Kawaler Emily A. , Cardot-Ruffino Victoire , Rahma Osama E. , Beri Nina , Singh Harshabad , Abrams Thomas A. , Biller Leah H. , Cleary James M. , Enzinger Peter , Huffman Brandon M. , McCleary Nadine J. , Perez Kimberly J. , Rubinson Douglas A. , Schlechter Benjamin L. , Surana Rishi , Yurgelun Matthew B. , Wang S. Jennifer , Remland Joshua , Brais Lauren K. , Bollenrucher Naima , Chang Eugena , Ali Lestat R. , Lenehan Patrick J. , Dolgalev Igor , Werba Gregor , Lima Cibelle , Keheler C. Elizabeth , Sullivan Keri M. , Dougan Michael , Hajdu Cristina , Dajee Maya , Pelletier Marc R. , Nazeer Saloney , Squires Matthew , Bar-Sagi Dafna , Wolpin Brian M. , Nowak Jonathan A. , Simeone Diane M. , Dougan Stephanie K.
Published: September 2024

Supplemental Table 3: Serum samples from baseline and on-treatment time points from patients in SR-1, the standard of care cohort, and healthy people who donated blood 28 days apart were analyzed by cytokine bead array. Significance was determined by Wilcoxon matched-pairs signed rank test.
Figure S6 from Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor
Authors: Oberstein Paul E. , Dias Costa Andressa , Kawaler Emily A. , Cardot-Ruffino Victoire , Rahma Osama E. , Beri Nina , Singh Harshabad , Abrams Thomas A. , Biller Leah H. , Cleary James M. , Enzinger Peter , Huffman Brandon M. , McCleary Nadine J. , Perez Kimberly J. , Rubinson Douglas A. , Schlechter Benjamin L. , Surana Rishi , Yurgelun Matthew B. , Wang S. Jennifer , Remland Joshua , Brais Lauren K. , Bollenrucher Naima , Chang Eugena , Ali Lestat R. , Lenehan Patrick J. , Dolgalev Igor , Werba Gregor , Lima Cibelle , Keheler C. Elizabeth , Sullivan Keri M. , Dougan Michael , Hajdu Cristina , Dajee Maya , Pelletier Marc R. , Nazeer Saloney , Squires Matthew , Bar-Sagi Dafna , Wolpin Brian M. , Nowak Jonathan A. , Simeone Diane M. , Dougan Stephanie K.
Published: September 2024

Supplemental Figure 6. Cell populations identified by transcriptional profiling from tumor biopsies. (A) UMAP of all cells in the dataset, colored by cluster. (B-C) Relative expression of representative genes of the six major compartments across the full dataset. (D) Relative expression of IL1B, IL1R1, PDCD1, PDCDLG1, and PDCDLG2 across the full dataset. (E) The percent of each myeloid cluster that is found in each of the samples, separated into baseline and treated subgroups (Wilcoxon rank-sum test).
Figure S7 from MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming
Authors: Zewdie Eden Y. , Edwards George M. , Hunter Debra M. , Earp Henry Shelton , Holtzhausen Alisha
Published: September 2024

Supplemental Figure 7
Figure S6 from MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming
Authors: Zewdie Eden Y. , Edwards George M. , Hunter Debra M. , Earp Henry Shelton , Holtzhausen Alisha
Published: September 2024

Supplemental Figure 6
Figure S4 from MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming
Authors: Zewdie Eden Y. , Edwards George M. , Hunter Debra M. , Earp Henry Shelton , Holtzhausen Alisha
Published: September 2024

Supplemental Figure 4
Figure S2 from MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming
Authors: Zewdie Eden Y. , Edwards George M. , Hunter Debra M. , Earp Henry Shelton , Holtzhausen Alisha
Published: September 2024

Supplemental Figure 2
Supplementary Table 3 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Table 3
Supplementary Figure 6 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Figure 6: Stemness signature in pancreatic epithelial cells lacking IL-17RA.
Supplementary Figure 5 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Figure 5. IL-17/IL-17RA pancreatic epithelial signaling reshapes the tumor microenvironment.
Supplementary Figure 3 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Figure 3. IL-17RA deletion results in an increase in apoptosis, but not proliferation at 30 week time point.
Supplementary Figure 10 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Figure 10: IL-17 directly stabilizes B7-H4 mRNA
Supplementary Figure 1 from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Supplementary Figure 1. Representative (10X) images of quantified lesions.
Supplementary Table 1 from Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy
Authors: Porte Sarah , Audemard-Verger Alexandra , Wu Christian , Durand Aurélie , Level Théo , Giraud Léa , Lombès Amélie , Germain Mathieu , Pierre Rémi , Saintpierre Benjamin , Lambert Mireille , Auffray Cédric , Peyssonnaux Carole , Goldwasser François , Vaulont Sophie , Alves-Guerra Marie-Clotilde , Dentin Renaud , Lucas Bruno , Martin Bruno
Published: September 2024

List of used antibodies.
Supplementary Figure 9 from Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy
Authors: Porte Sarah , Audemard-Verger Alexandra , Wu Christian , Durand Aurélie , Level Théo , Giraud Léa , Lombès Amélie , Germain Mathieu , Pierre Rémi , Saintpierre Benjamin , Lambert Mireille , Auffray Cédric , Peyssonnaux Carole , Goldwasser François , Vaulont Sophie , Alves-Guerra Marie-Clotilde , Dentin Renaud , Lucas Bruno , Martin Bruno
Published: September 2024

Iron and anti-PD1 cancer immunotherapy combination increases serum concentrations of IFN-γ, TNF-α and IL-2 in LLC tumor transplanted mice.
Supplementary Figure 7 from Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy
Authors: Porte Sarah , Audemard-Verger Alexandra , Wu Christian , Durand Aurélie , Level Théo , Giraud Léa , Lombès Amélie , Germain Mathieu , Pierre Rémi , Saintpierre Benjamin , Lambert Mireille , Auffray Cédric , Peyssonnaux Carole , Goldwasser François , Vaulont Sophie , Alves-Guerra Marie-Clotilde , Dentin Renaud , Lucas Bruno , Martin Bruno
Published: September 2024

CRISPR/Cas9 generated MC38 IFN-γR1-KO tumor cell line.
Supplementary Figure 5 from Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy
Authors: Porte Sarah , Audemard-Verger Alexandra , Wu Christian , Durand Aurélie , Level Théo , Giraud Léa , Lombès Amélie , Germain Mathieu , Pierre Rémi , Saintpierre Benjamin , Lambert Mireille , Auffray Cédric , Peyssonnaux Carole , Goldwasser François , Vaulont Sophie , Alves-Guerra Marie-Clotilde , Dentin Renaud , Lucas Bruno , Martin Bruno
Published: September 2024

Impact of iron supplementation on CD71 expression by T cells in vitro.
Supplementary Figure 4 from Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy
Authors: Porte Sarah , Audemard-Verger Alexandra , Wu Christian , Durand Aurélie , Level Théo , Giraud Léa , Lombès Amélie , Germain Mathieu , Pierre Rémi , Saintpierre Benjamin , Lambert Mireille , Auffray Cédric , Peyssonnaux Carole , Goldwasser François , Vaulont Sophie , Alves-Guerra Marie-Clotilde , Dentin Renaud , Lucas Bruno , Martin Bruno
Published: September 2024

Iron increases the proportion of Th1 cells in the LLC tumor microenvironment.
Supplemental Figure S7 from Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion
Authors: De Munter Stijn , Buhl Juliane L. , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Jansen Hanne , Billiet Lore , Pille Melissa , Van Duyse Julie , Bonte Sarah , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Leclercq Georges , Taghon Tom , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart
Published: September 2024

Differential gene expression reveals distinct differences between the clusters.
Supplemental Figure S5 from Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion
Authors: De Munter Stijn , Buhl Juliane L. , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Jansen Hanne , Billiet Lore , Pille Melissa , Van Duyse Julie , Bonte Sarah , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Leclercq Georges , Taghon Tom , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart
Published: September 2024

CD70KO improves the functionality of CD70-specific nanoCAR T-cells.
Supplemental Figure S4 from Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion
Authors: De Munter Stijn , Buhl Juliane L. , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Jansen Hanne , Billiet Lore , Pille Melissa , Van Duyse Julie , Bonte Sarah , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Leclercq Georges , Taghon Tom , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart
Published: September 2024

Surface expression of CD70-BFP and nanoCAR-eGFP fusion proteins.
Supplemental Figure S2 from Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion
Authors: De Munter Stijn , Buhl Juliane L. , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Jansen Hanne , Billiet Lore , Pille Melissa , Van Duyse Julie , Bonte Sarah , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Leclercq Georges , Taghon Tom , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart
Published: September 2024

CD70KO has no effect on CD20-specific nanoCAR T-cells.
Data from Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways
Authors: Skadborg Signe K. , Maarup Simone , Draghi Arianna , Borch Annie , Hendriksen Sille , Mundt Filip , Pedersen Vilde , Mann Matthias , Christensen Ib J. , Skjøth-Ramussen Jane , Yde Christina W. , Kristensen Bjarne W. , Poulsen Hans S. , Hasselbalch Benedikte , Svane Inge M. , Lassen Ulrik , Hadrup Sine R.
Published: September 2024

Abstract
Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD-1 immune checkpoint inhibitor nivolumab 1 week prior to surgery, compared with control patients receiving salvage resection without prior nivolumab treatment. We observed saturating levels of nivolumab bound to intratumorally and tissue-resident T cells in the brain, implicating saturating levels of nivolumab reaching brain tumors. Following nivolumab treatment, significant changes in T-cell activation and proliferation were observed in the tumor-resident T-cell population, and peripheral T cells upregulated chemokine receptors related to brain homing. A strong nivolumab-driven upregulation in compensatory checkpoint inhibition molecules, i.e., TIGIT, LAG-3, TIM-3, and CTLA-4, was observed, potentially counteracting the treatment effect. Finally, tumor-reactive tumor-infiltrating lymphocytes (TIL) were found in a subset of nivolumab-treated patients with prolonged survival, and neoantigen-reactive T cells were identified in both TILs and blood. This indicates a systemic response toward GBM in a subset of patients, which was further boosted by nivolumab, with T-cell responses toward tumor-derived neoantigens. Our study demonstrates that nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, various anti-inflammatory mechanisms mitigate the clinical efficacy of the anti-PD-1 treatment.
Data from Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis
Authors: Castro-Pando Susana , Howell Rian M. , Li Le , Mascaro Marilina , Faraoni Erika Y. , Le Roux Olivereen , Romanin David , Tahan Virginia , Riquelme Erick , Zhang Yu , Kolls Jay K. , Allison James P. , Lozano Guillermina , Moghaddam Seyed J. , McAllister Florencia
Published: September 2024

Abstract
IL17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. However, the cellular compartment and downstream molecular mediators of IL17-mediated pancreatic tumorigenesis have not been fully identified. This study examined the cellular compartment required by generating transgenic animals with IL17 receptor A (IL17RA), which was genetically deleted from either the pancreatic epithelial compartment or the hematopoietic compartment via generation of IL17RA-deficient (IL17-RA−/−) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL17RA from the pancreatic epithelial compartment, but not from hematopoietic compartment, resulted in delayed initiation and progression of premalignant lesions and increased infiltration of CD8+ cytotoxic T cells to the tumor microenvironment. Absence of IL17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness, and immunological pathways. B7-H4, a known inhibitor of T-cell activation encoded by the gene Vtcn1, was the checkpoint molecule most upregulated via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed the development of pancreatic premalignant lesions and reduced immunosuppression. Thus, our data reveal that pancreatic epithelial IL17RA promotes pancreatic tumorigenesis by reprogramming the immune pancreatic landscape, which is partially orchestrated by regulation of B7-H4. Our findings provide the foundation of the mechanisms triggered by IL17 to mediate pancreatic tumorigenesis and reveal the avenues for early pancreatic cancer immune interception.

See related Spotlight by Lee and Pasca di Magliano, p. 1130
Table S3 from Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-Cell Lymphoma
Authors: Meriranta Leo , Sorri Selma , Huse Kanutte , Liu Xiaonan , Spasevska Ivana , Zafar Sadia , Chowdhury Iftekhar , Dufva Olli , Sahlberg Eerika , Tandarić Luka , Karjalainen-Lindsberg Marja-Liisa , Hyytiäinen Marko , Varjosalo Markku , Myklebust June H. , Leppä Sirpa
Published: September 2024

Table S3 shows data from interactome analysis of KLHL6 in B-cell lymphoma cell lines. Strep-tag affinity purification and mass-spec peptide identification (AP-MS).
Data from Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition
Authors: Sarchi Martina , Clough Courtnee A. , Crosse Edie I. , Kim Jason , Baquero Galvis Laura D. , Aydinyan Nelli , Wellington Rachel , Yang Feini , Gallì Anna , Creamer J. Philip , Stewart Sintra , Bradley Robert K. , Malcovati Luca , Doulatov Sergei
Published: September 2024

Abstract
Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition.

Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.
A MULTIDISCIPLINARY APPROACH TO PERFORMING ENDOVASCULAR OPERATIONS AND ECONOMICAL FOOT AMPUTAIONS AGAINST THE BACKGROUND OF CHRONIC THREATENING ISCHEMIA OF THE LOWER EXTREMITIES (CLTI)
Authors: GOSHCHYNSKY V. B. , MIGENKO B. O. , SVISTUN R. V.
Published: September 2024

The aim of the work: to determine the effectiveness of a multidisciplinary approach to the treatment of chronic threatening ischemia of the lower extremities associated with necrotic changes in the area of the foot.
Мaterials and Methods. The results of the use of endovascular operations in 39 patients with CLTI IV class were analyzed according to the Fontaine classification (category 6 according to the Rutherford classification), with open wounds after amputation of a part of the foot due to dry gangrene and PRP and PRF therapy using the PRGF®-ENDORET® technology, according to the examination and conclusions of the multidisciplinary team. The control group consisted of 41 patients with a similar pathology and stage of the necrotic process, in the treatment of which no relevant specialists were involved, and the treatment of open wounds after amputation of a part of the foot due to dry gangrene was carried out according to traditional methods. The average age of the patients was 56.7±9.3 years, all men. A multidisciplinary team consisting of vascular surgeons, ultrasound specialists and angioradiologists, an interventional physician, an orthopedic surgeon, and functional diagnosticians was created for the specific treatment tactics of the above-mentioned patients. In order to determine the indications for performing small amputations on the foot, we performed a comprehensive assessment of the limb's blood supply after endovascular operations and the use of platelet-rich plasma.
 Results and Discussion.The use of endovascular operations in combination with PRP and PRF has a positive effect on the blood supply in the ischemic limb. This is evidenced by: improvement of indicators of microcirculation, speed of blood flow, increase of local skin temperature on the foot, indicators of the Ankle Brachial Index. As our studies have shown, the activity of the tyrosine kinase system, as well as the peculiarities of the cytokine relationship, which is a reflection of the processes of alteration and proliferation in the wound, can be an objective criterion for skin autotransplantation on the wound surface. After consultation with an orthopedist, we performed amputation of the foot: according to Garangeau – in 10 patients, according to Chopar – in 51 cases, according to Lisfranc or Lisfranc-Haye in 19 patients. Due to the lack of skin flaps, the wounds were treated by an open method followed by autodermoplasty, except for 39 patients (after endovascular surgery and PRP therapy), who were stimulated on the 5-6th day after foot amputation with the help of a plasma membrane (PRGF supernatant) ®-Endoret®), enriched with a growth factor, which covered the entire area of the wound surface.