scholarly journals Increasing the efficiency of hyperthermic intraperitoneal chemotherapy (HIPEC) by a combination with a photosensitive drug in pediatric rhabdomyosarcoma

2021 ◽  
Author(s):  
Benedikt Wagner ◽  
Anna Adamus ◽  
Laura Hempfling ◽  
Reza Vahdad ◽  
Antje Haap-Hoff ◽  
...  
Keyword(s):  
Animal Model ◽  
Photodynamic Therapy ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Ki 67 ◽  
Tissue Samples ◽  
Proliferation Capacity ◽  
Tumor Dissemination ◽  
Cell Layers

Background: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an option in advanced peritoneal sarcomatosis. Nevertheless, CRS and HIPEC are not successful in all patients. An enhancement of HIPEC using photodynamic therapy might be beneficial. Therefore, a combination of the photosensitizer Hypericin (HYP) with HIPEC was evaluated in an animal model. Procedure: An established HIPEC animal model for rhabdomyosarcoma (NOD/LtSz-scid IL2Rγnullmice, n=80) was used. All groups received HYP (100 µg/200 µl) intraperitoneally with and without cisplatin-based (30 or 60 mg/m2) HIPEC (37 or 42 °C, for 60 min) (five groups, each n=16). Tumor dissemination was documented visually and by using HYP-based fluorescence guidance. HYP-based photodynamic therapy (PDT) of the tumor was performed. Finally, tissue samples were evaluated regarding proliferation (Ki-67) and apoptosis (TUNEL). Results: HYP uptake even in smallest tumor nodes (< 1 mm) was found. HYP-based fluorescence guidance allowed a better tumor detection in comparison to visual inspection. Immunohistochemistry revealed HYP penetration across the tumor surface. HYP-based PDT without HIPEC induced marginal apoptotic effects at the tumor surface. Combining HYP with HIPEC revealed cisplatin concentration dependent decrease in proliferation capacity and induction of apoptosis across determined cell layers of the tumor surfaces. Conclusion: HYP as fluorescent photosensitizer offers an intraoperative diagnostic advantage detecting intraperitoneal tumor dissemination. The combination of HYP and cisplatin-based HIPEC was feasible in vivo showing enhanced effects on tumor proliferation and apoptosis induction across the tumor surface. Further studies combining HYP and HIPEC will follow to establish a clinical application.

scholarly journals Establishment of a new valid animal model for the evaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric rhabdomyosarcoma

2021 ◽  
Author(s):  
Benedikt Wagner ◽  
Anna Adamus ◽  
Dörthe Sönnecken ◽  
Reza Vahdad ◽  
Paul Jank ◽  
...  
Keyword(s):  
Animal Model ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Caspase 3 ◽  
Tunel Assay ◽  
Evaluation Procedure ◽  
Temperature Dependent ◽  
Ki 67 ◽  
Optimal Drug ◽  
Apoptotic Effects

Background: Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy has been established as a novel treatment approach for peritoneal sarcomatosis. Despite promising clinical reports, there is still a lack of knowledge regarding optimal drug usage and local effects. Therefore, we intended to establish a murine animal model for further evaluation. Procedure: Alveolar rhabdomyosarcoma cells were xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice received a continuous intraperitoneal lavage with isotonic saline solution as control- or with cisplatin (30 or 60 mg/m2) as treatment group for 60 minutes at 37 or 42 °C (6 subgroups, each n=16). Tumor spread was documented by an adapted peritoneal cancer index and MRI (n=4). Tumor and tissue samples, harvested at the end of the perfusion, were evaluated regarding morphology, proliferation and apoptosis (H&E-, Ki-67-, Cleaved Caspase 3-staining, TUNEL-assay). Results: Extensive peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC was feasible without acute side effects. Ki-67 staining revealed concentration- or temperature-dependent effects of cisplatin-based HIPEC on the tumors. While Cleaved Caspase-3 showed only sporadic apoptotic effects. TUNEL-assay detected concentration- or temperature-dependent apoptotic effects at the outer tumor surface. MRI scans confirmed the observed tumor dissemination. Conclusion: This is the first animal model for evaluation of HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC had early effects on the proliferation whereas circumscribed apoptotic effects could be detected at the tumor surface. This model allows further insights on the possible efficiency of HIPEC in RMS. Further studies using other drug combinations and treatment will follow.

scholarly journals Therapeutic pathomorphosis in malignant glioma tissues after photodynamic therapy with сhlorin e6 (reports of two clinical cases)

2020 ◽  
Vol 9 (2) ◽  
pp. 45-54
Author(s):  
A. Yu. Rynda ◽  
D. M. Rostovtsev ◽  
V. E. Olyushin ◽  
Yu. M. Zabrodskaya
Keyword(s):  
Photodynamic Therapy ◽  
Malignant Glioma ◽  
Immunohistochemical Analysis ◽  
Malignant Neoplasms ◽  
Glial Tumor ◽  
Ki 67 ◽  
Tissue Samples ◽  
Malignant Glioma Cells ◽  
Cell Proliferation Marker

In recent years, photodynamic therapy (PDT) has been increasingly introduced into the surgical practice of treating malignant neoplasms. In this publication, the authors show the appearance of therapeutic pathomorphosis in vivo in human malignant glioma cells after intraoperative photodynamic therapy. Tissue samples obtained 10–14 days after PDT revealed nuclear and cytoplasmic signs indicating apoptosis, necrosis, and autophagy. A decrease in the proliferative activity of glial tumor cells and their higher death count were detected.. Immunohistochemical analysis shows decreases expression of Ki-67 cell proliferation marker and decreased amount of transcription factor protein p53.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

scholarly journals Niraparib Suppresses Cholangiocarcinoma Tumor Growth by Inducing Oxidative and Replication Stress

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4405
Author(s):  
Vladimir Bezrookove ◽  
John M. Patino ◽  
Mehdi Nosrati ◽  
Pierre-Yves Desprez ◽  
Sean McAllister ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Growth ◽  
The Cancer Genome Atlas ◽  
Genomic Alteration ◽  
M Cell ◽  
Ki 67 ◽  
Tissue Samples ◽  
Patient Derived Xenograft ◽  
Fork Stalling

Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes (ARID1A, BAP1 and ATM), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.

scholarly journals In vivo killing of Staphylococcus aureus by toluidine blue-mediated photosensitization in an animal model wounds

2009 ◽  
Vol 7 (4) ◽  
pp. 423-430 ◽  
Author(s):  
Paulo de Tarso Camillo De Carvalho ◽  
Filipe Abdalla dos Reis ◽  
Ana Carulina Guimarães Belchior ◽  
Baldomero Antônio Kato da Silva ◽  
Daniel Martins Pereira ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Animal Model ◽  
Photodynamic Therapy ◽  
Toluidine Blue ◽  
Therapy Group ◽  
Control Group ◽  
Group I ◽  
Significant Difference ◽  
Group Ii

The aims of this study were to determine whether S. aureus could be killed by toluidine blue-mediated photosensitization in vivo in an animal model. Twelve Wistar rats divided into three groups (n = 12): Group I: Control Group, the wounds were made and submitted to the application of the laser without the drug photosensitizing; Group II: The implementation of wounds received the toluidine blue, without application of laser; Group III: it was used toluidine blue, and application of laser-Indio phosphide Gallium-Aluminum (InGaAIP)  660nm power and density of 20 Joules/cm2. Statistical analysis of CFU by analysis of variance Kruskal-Wallis test shows significant intraoperative difference, photodynamic therapy group (p 0, 05), the Dunns post hoc test shows significant difference between Group I when compared to Group II treated with LLLT (p 0001). The results of this study show that photodynamic therapy with toluidine blue has reduced the number of Staphylococcus aureus in vivo.

scholarly journals Hyperthermic intraperitoneal chemotherapy with recombinant mutant human TNF-α and raltitrexed in mice with colorectal-peritoneal carcinomatosis

2020 ◽  
Vol 245 (6) ◽  
pp. 542-551
Author(s):  
Qianyi Gong ◽  
Changfeng Song ◽  
Xiaotong Wang ◽  
Renjie Wang ◽  
Guoxiang Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Experimental Data ◽  
Peritoneal Carcinomatosis ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Antitumor Effect ◽  
Tnf Α ◽  
Colorectal Cancer Cells

Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. In vitro, we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. In vivo, we established xenograft models of CRC-PC and assessed the antitumor effect by in vivo imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly in vitro, and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited in vivo. Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application. Impact statement Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both in vitro and vivo. The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.

scholarly journals A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3516
Author(s):  
Daan R. Löke ◽  
Roxan F. C. P. A. Helderman ◽  
Jan Sijbrands ◽  
Hans M. Rodermond ◽  
Pieter J. Tanis ◽  
...  
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Computer Aided Design ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
In Vivo Experiments ◽  
The One ◽  
Aided Design ◽  
The Impact ◽  
Phosphate Buffered Saline

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols.

scholarly journals Systematic Review of Variations in Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis from Colorectal Cancer

2018 ◽  
Vol 7 (12) ◽  
pp. 567 ◽  
Author(s):  
Can Yurttas ◽  
Giulia Hoffmann ◽  
Alexander Tolios ◽  
Sebastian P. Haen ◽  
Matthias Schwab ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Treatment Approach ◽  
Eligibility Criteria ◽  
Drug Concentrations ◽  
Recent Developments ◽  
Temperature Exposure ◽  
Minimal Information

Cytoreductive surgery (CRS), followed by hyperthermic intraperitoneal chemotherapy (HIPEC), combines radical surgery with abdominal heated chemotherapy, constituting a multimodal treatment approach. Since clear standards for HIPEC conduct in colorectal carcinoma (CRC) are lacking, we aimed to provide a comprehensive structured survey. Data sources and study eligibility criteria: A systematic literature search was performed in PubMed, with keywords “HIPEC” and “colorectal cancer”, according to established guidelines. Articles were systematically screened, selecting 87 publications complemented by 48 publications identified through extended search for subsequent synthesis and evaluation, extracting inter alia details on used drugs, dosage, temperature, exposure times, and carrier solutions. Results: Compiled publications contained 171 reports on HIPEC conduct foremost with mitomycin C and oxaliplatin, but also other drugs and drug combinations, comprising at least 60 different procedures. We hence provide an overview of interconnections between HIPEC protocols, used drugs and carrier solutions as well as their volumes. In addition, HIPEC temperatures and dosing benchmarks, as well as an estimate of in vivo resulting drug concentrations are demonstrated. Conclusions and implications: Owing to recent developments, HIPEC conduct and practices need to be reassessed. Unfortunately, imprecise and lacking reporting is frequent, which is why minimal information requirements should be established for HIPEC and the introduction of final drug concentrations for comparability reasons seems sensible.

scholarly journals Intraoperative photodynamic therapy and hyperthermic intraperitoneal chemotherapy in cytoreductive treatment of patients with disseminated mucinous carcinoma of appendix

2021 ◽  
Vol 9 (4) ◽  
pp. 23-30
Author(s):  
D. V. Sidorov ◽  
N. A. Grishin ◽  
M. V. Lozhkin ◽  
A. A. Troitsky ◽  
R. I. Moshurov ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Surgical Treatment ◽  
Postoperative Complications ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Mucinous Carcinoma ◽  
Peritoneal Carcinomatosis Index ◽  
Treat Ment ◽  
Cytoreductive Treatment

The article presents the experience of surgical treatment of 57 patients with peritoneal pseudomyxoma of appendicular genesis. In 32 (56.1%) patients, the operation was supplemented with intraoperative photodynamic therapy (IOPDT). In the other 25 (43.9%) patients, hyperthermic intraperitoneal chemotherapy (HIPEC) was performed. The analysis according to the value of the peritoneal carcinomatosis index, completeness of cytoreduction, the volume of operations performed, postoperative complications and hospital mortality, as well as long-term treat- ment results in two groups is presented. It was shown that with significantly worse results in terms of cytoreduction completeness obtained in the IOPDT group compared to the HIPEC group, the 5-year survival rate in the HIPEC group was 86.6%, with IOPDT - 65.2%. At the same time, in the IOPDT group, the rate of postoperative complications was significantly lower (11.1%), and there was no mortality; in the HIPEC group, these indicators were 23.8% and 12.0%, respectively. The results obtained indicate that the IOPDT method is an effective and promising direction in the surgical treatment of peritoneal pseudomyxoma.

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