Determination Of Tumor Volume Research Articles

Automatic Contouring Analysis of Lung Cancer for Radiotherapy Radiation Planning from Ct-Simulator Image

Accurate determination of tumor and radiotherapy target volume is crucial to prevent local and regional failure in lung cancer. Radiotherapy planning considers critical normal tissue structures or Organs at Risk (OAR). While manual contouring is the gold standard in radiotherapy planning, it is still susceptible to intra- and inter-observer variation. A digital image processing system capable of automatically and semi-automatically determining tumor targets and OARs through computer programming can assist in the contouring process. The study aims to create a digital contouring computer program to aid in planning radiotherapy irradiation for lung cancer cases, guided by CT-Simulator image guidance. The research involved contouring CT-Simulator images of lung cancer cases using automatic segmentation, semi-automatic segmentation, and a combination of automatic, semi-automatic, and manual segmentation. Contour accuracy was assessed by a radiation oncologist. Automatic segmentation showed high accuracy for lungs (>95%), moderate for tumor targets (72.22%) and the heart (73.33%), but low accuracy for the esophagus (34.44%) and spinal cord (36.67%). Semi-automatic segmentation achieved high accuracy for the esophagus (96.67%) and spinal cord (95.56%), and moderate accuracy for tumor targets (73.33%), heart (66.67%), right lung (66.25%), and left lung (72.94%). The combination of automatic, semi-automatic, and manual segmentation resulted in high accuracy for tumor targeting and OARs (>95%). Automatic or semi-automatic segmentation using location and gray level classification methods for lung cancer cases did not produce optimal results. However, a contouring program combining automatic, semi-automatic, and manual segmentation proved more effective, balancing human interaction and automation in the lung cancer contouring process. This digital contouring program offers valuable support for radiation oncologists, potentially leading to improved treatment outcomes for lung cancer patients

Albumin nanoparticles and their folate modified counterparts for delivery of a lupine derivative to hepatocellular carcinoma

In this study, folate polyethylene glycol CTr albumin nanoparticles (FA-PEG-CTr-NPs) targeting hepatocellular carcinoma (HCC) were prepared. The nanoparticle preparation method was optimized using single-factor and response surface analysis. The prepared nanoparticles were characterized for their particle size, zeta potential, and morphology. The particle size and zeta potential were also determined. Additionally, drug loading, encapsulation efficiency, and in vitro drug release of the nanoparticles were determined. Using the Cell Counting Kit-8 method, their cytotoxicity and their cell-targeted uptake were determined using confocal microscopy and flow cytometry. Finally, the in vivo antitumor impact and tumor-targeting ability of the nanoparticles were evaluated by determining tumor volume inhibition and drug biodistribution and performing hematoxylin-eosin (H&E) staining. It was found that CTr could be effectively encapsulated into albumin nanoparticles and functionalized. The drug loading of the two nanoparticles was 67.12 ± 2.4% and 69.33 ± 2.8%, respectively. Regarding drug release, FA-PEG-CTr-NPs (89.0%) exhibited a superior release rate to CTr-NPs (70.5%) in an acidic environment. The in vitro experiments confirmed that FA-PEG-CTr-NPs yielded better cytotoxicity and faster drug uptake results than CTr and CTr-NPs. In vivo experiments confirmed that FA-PEG-CTr-NPs exhibited markedly better tumor inhibitory activity (inhibition rate was 80.21%), drug safety, and targeting than CTr and CTr-NPs. In conclusion, functionalized nanoparticles (FA-PEG-CTr-NPs) can specifically inhibit the malignant proliferation of HCC cells and are thus a promising nanoagent for the treatment of HCC.

Tumor sensitization to PARP inhibitors by DNA damaging synthetically lethal acylfulvenes.

e15123 Background: 20-30% of solid tumors (ovarian, breast, pancreatic, prostate cancers) harbor some level of deficiency in DNA Damage Repair (DDR) pathways. Such cancers become dependent on alternative DDR pathways to maintain genome integrity, making them selectively vulnerable to DNA damaging agents. The concept of synthetic lethality has been leveraged to treat subsets of such tumors. Clinically, PARP inhibitors (PARPi) have been successful in Homologous Recombination Deficiency (HRD) cancers. LP-100 and LP-184 are acylfulvene (AF) class small molecule prodrugs that are metabolized to active compounds by prostaglandin reductase 1 (PTGR1) that is often elevated in solid tumors. AF-induced DNA lesions are likely selectively processed by repair pathways including BRCA1/2 mediated Homologous Recombination (HR). Methods: Cell Titer Glo based 10 day cell viability assays were used to generate drug IC50 values in vitro. Bliss synergy scores were computed with scores ≥ 10 reflecting synergy. Drug-induced DNA double strand breaks (DSB) were detected and quantified with STRIDE (SensiTive Recognition of Individual DNA Ends) assay in cancer cells. A subcutaneous tumor xenograft model was used to determine tumor volumes in control and drug treated mice. Results: In a BRCA2 mutant ovarian cancer cell line OVCAR3, LP-184 and olaparib co-treatment in vitro showed synergistic effects (Bliss score 10). Similarly in a BRCA2 mutant prostate cancer cell line 22Rv1, LP-100 combination with rucaparib was synergistic (Bliss score 18). 400 nM LP-184 showed a time dependent increase in DNA DSB signals in vitro, 1.7X more so in BRCA2 mutant vs wild type (WT) DLD-1 isogenic colon cancer cell lines up to 24 hours. To validate the hypothesis that AF-induced DSBs remain unresolved if exposed to and further synergize with PARPi in vivo, we tested LP-100 plus olaparib in a DU145 (BRCA2 mutant) prostate cancer xenograft model. LP-100 + olaparib treatment resulted in sustained, durable tumor regression indicating in vivo synergy whereas either agent alone did not produce tumor shrinkage. Day 42 tumor growth inhibition was 66% for 2.5 mg/kg LP-100 alone, 34% for 40 mg/kg olaparib alone and 108% for the combination. Moreover, LP-184 treatment resulted in early onset and complete tumor regression in 7 PDX models of PARPi resistant triple negative breast cancers (TNBC) harboring BRCA1/2 loss whereas olaparib/ niraparib remained entirely ineffective in these. Conclusions: AF response is influenced by tumor DNA repair competence. LP-100 and LP-184 are synthetically lethal resulting from their abilities to cause unresolvable DNA damage where tumor cells express high PTGR1 and are deficient in the HR pathway. LP-184 single agent was superior to PARPi in TNBC and LP-100 combination made an olaparib resistant tumor highly sensitive, thereby facilitating a path to extend the opportunities for both AFs and PARPis and enhance the clinical utilization of PARPi.

Oral squamous cell carcinoma-derived EVs promote tumor progression by regulating inflammatory cytokines and the IL-17A-induced signaling pathway

Inflammatory cytokines in the tumor microenvironment (TME) contribute to tumor growth, proliferation, and invasion, and tumor-derived extracellular vesicles (EVs) act as critical "messengers" of communication in the tumor microenvironment. The effects of EVs derived from oral squamous cell carcinoma (OSCC) cells on tumor progression and the inflammatory microenvironment are still unclear. Our study aims to investigate the role of OSCC-derived EVs in tumor progression, the imbalanced TME, and immunosuppression and their effect on the IL-17A-induced signaling pathway. EVs were isolated from the supernatant of a mouse OSCC cell line, SCC7. The effects of SCC7-EVs and the EV release-specific inhibitor GW4869 on the proliferation and migration of SCC7 cells were investigated in vitro by using CCK-8 and scratch wound healing assays. RT-qPCR and ELISA were performed to examine the alterations in cytokine levels. Then, a mouse xenograft model of OSCC was established by submucosal injection of SCC7 cells with or without SCC7-EV and GW4869 treatment. The effects of GW4869 and SCC7-EVs on xenograft tumor proliferation and invasion were investigated by tumor volume determination and histopathological examination. ELISA was used to investigate the changes in serum cytokine levels. Immunohistochemistry was adopted to analyze the alterations in the levels of inflammatory cytokines, immune factors, and crucial molecules in the IL-17A signaling pathway. SCC7-derived EVs increased the supernatant and serum levels of IL-17A, IL-10, IL-1β, and PD-L1, while GW4869 decreased those of TNF-α and IFN-γ. SCC7-EV treatment significantly increased xenograft tumor growth and invasion in mice but resulted in little liquefactive necrosis in tumors. However, GW4869 treatment significantly inhibited xenograft tumor growth but resulted in more liquefactive necrosis. SCC7-derived EVs decreased the expression level of PTPN2, suppressing the immune responses of CD8+T cells in vivo. Moreover, SCC7-EV treatment significantly enhanced the tumor expression levels of crucial molecules in the IL-17A pathway, including IL-17A, TRAF6 and c-FOS, whereas GW4869 treatment significantly reduced those levels in tumor tissues. Our results indicated that OSCC-derived EVs can promote tumor progression by altering the TME, causing an inflammatory cytokine imbalance, inducing immunosuppression, and contributing to overactivation of the IL-17A-induced signaling pathway. Our study might provide novel insights into the role of OSCC-derived EVs in tumor biological behavior and immune dysregulation.

Abstract P4-01-06: LP-184, an acylfulvene class small molecule therapeutic, is synthetically lethal in HR deficient and PARP inhibitor resistant triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer accounting for approximately 15% to 20% of all newly diagnosed breast cancer cases. TNBCs are defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2).Due to its special molecular phenotype, it is not sensitive to endocrine therapy or targeted therapy. Therefore, chemotherapy such as anthracyclines or taxanes is the main systemic treatment, but the efficacy of conventional postoperative adjuvant chemoradiotherapy is poor. ~35% of TNBC tumors show abnormalities in the HR pathway, making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and DNA-damaging agents. Although more than 40% BRCA1/2-deficient patients fail to respond to PARPi and a substantial proportion of patients acquire PARPi resistance over time. TNBCs heterogeneous nature, poor prognosis and limited treatment options presents the urgent need of development of novel agents targeting tumor specific alterations. Lantern Pharma is advancing LP-184, an acylfulvene-derived prodrug that is specifically activated in tumors that overexpress the oxidoreductase enzyme Prostaglandin Reductase 1 (PTGR1), for the treatment of solid tumor indications including TNBC. LP-184 has multiple mechanisms of action (MOA). While It is synthetically lethal in tumors harboring DNA damage repair defects including Homologous Recombination (HR) deficiencies, it can also interrupt transcription. LP-184 efficacy was tested in a panel of breast cancer cell lines and patient derived TNBC xenografts models, both sensitive as well as resistant to PARP inhibitors and anthracyclines. LP-184 demonstrated nanomolar potency in six NCI-60 breast cancer cell lines (median IC50 = 327 nM). Subcutaneous patient-derived TNBC xenograft mouse models were used to determine tumor volume responses to LP-184 treatment in vivo. Xenograft tumors were derived from 10 treatment-naive HR deficient (HRD score > 50) primary TNBC patients with known BRCA1/2 loss of heterozygosity (LOH), 7 of which subsequently progressed on PARP inhibitor Olaparib. LP-184 (4mg/kg i.v., (q2d x 5 then 7 days off)x2) led to complete and durable regression in all 10 TNBC HRD-PDX models tested as compared to control (p < 0.0001). A tumor growth inhibition range of 107-141% was achieved across all the 10 models. For LP-184, T/C at the control group end day was 0% in 10/10 models, whereas across the same models for Olaparib, T/C was 0% in 2/10 models and ranged from 15 - 90% in 8/10 models. Terminal body weight change was only a transient weight loss < 4% with LP-184 treatment across all models. LP-184 exhibited superior potency than olaparib in TNBC PDX models that carry HRD mutations including PARP resistant models and was well tolerated in mice. As acylfulvene-induced damage is primarily repaired by transcription-coupled nucleotide-excision repair (TC-NER) and HR pathways, response to LP-184 is influenced by tumor DNA damage repair pathway status. Recent data highlight an important role of super enhancer driven core transcription regulatory circuits in the pathogenesis of TNBCs. Our results support the superior efficacy of LP-184 in TNBCs, likely linked to the multiple MOAs, and establish LP-184 as a promising new agent for future clinical testing in TNBC patients. We finally propose that LP-184 may be broadly efficacious in solid tumors with HR and/or TC-NER pathway defects, such as pancreatic, prostate, ovarian and bladder cancers. Citation Format: Aditya Kulkarni, Neha Biyani, Laura Brullé-Soumaré, Stefano Cairo, Panna Sharma, Kishor Bhatia. LP-184, an acylfulvene class small molecule therapeutic, is synthetically lethal in HR deficient and PARP inhibitor resistant triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-06.

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients: a literature review, implementation and multi-threshold evaluation

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool.A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures.High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc.No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter.

Therapeutic Effect of Curcumol on Chronic Atrophic Gastritis (CAG) and Gastric Cancer Is Achieved by Downregulating SDF-1α/CXCR4/VEGF Expression.

CAG is an essential procession of the transformation from gastritis into gastric cancer. A series of timely moves of diagnosis, treatment, and monitoring towards CAG to anticipate the potential population at risk of gastric cancer is an effective means to prevent gastric cancer occurrence. The main active monomer in Fuzheng Huowei Decoction is Curcumol, which is an indispensable ingredient in the treatment to CAG and gastric cancer. In this study, the CAG model, in vitro cultured gastric cancer cells, and participating nude mice were treated with Curcumol, and alterations in SDF-1α/CXCR4/VEGF expression were estimated using the assays of immunohistochemistry and Western blot. MTT, flow cytometry, transwell, HE staining, and tumor volume determination were applied for the verification of the regulatory effects of Curcumol on CAG and gastric cancer cells. The results showed that the expressions of VEGF, SDF-1α, CXCR4, and CD34 decreased in our CAG model with Curcumol treatment. Curcumol is in procession of an inhibitory effect toward the activity, migration, and invasion of gastric cancer cells, and it would also result in gastric cancer cells' apoptosis. We subsequently added SDF-1α overexpressing lentivirus to the Curcumol-treated group and found that the expressions of SDF-1α, CXCR4, and VEGF protein increased, and the inhibitory effect of Curcumol on gastric cancer cells was withdrawn. Our nude mouse experiment showed that Curcumol + SDF-1α group ended up with the largest tumor volume, while Fuzheng Huowei + NC group was with the smallest tumor volume. In conclusion, Curcumol is able to effectively protect the gastric tissue and suppress gastric cancer cells' viability. Curcumol functions as a therapeutic factor in chronic atrophic gastritis and gastric cancer by downregulating SDF-1α/CXCR4/VEGF expression.

The cell-line-derived subcutaneous tumor model in preclinical cancer research.

Tumor-bearing experimental animals are essential for preclinical cancer drug development. A broad range of tumor models is available, with the simplest and most widely used involving a tumor of mouse or human origin growing beneath the skin of a mouse: the subcutaneous tumor model. Here, we outline the different types of in vivo tumor model, including some of their advantages and disadvantages and how they fit into the drug-development process. We then describe in more detail the subcutaneous tumor model and key steps needed to establish it in the laboratory, namely: choosing the mouse strain and tumor cells; cell culture, preparation and injection of tumor cells; determining tumor volume; mouse welfare; and an appropriate experimental end point. The protocol leads to subcutaneous tumor growth usually within 1-3 weeks of cell injection and is suitable for those with experience in tissue culture and mouse experimentation.

Glioblastoma response to blood-brain-barrier permeable, MGMT-agnostic therapeutic LP-184 and sensitization by nucleotide-excision repair deficiency.

e14023 Background: Glioblastoma (GBM), a WHO Grade IV cancer, is the most common and most aggressive primary malignant brain tumor. Prognosis following best standard-of-care surgical resection, radiation and temozolomide (TMZ) chemotherapy is poor, with median overall survival 15-18 months. TMZ, which acts primarily by methylating DNA at O6-guanine, has marginal efficacy in ̃70% of patients due to tumor expression of O-6-methylguanine-DNA methyltransferase (MGMT) and there is no effective therapy at tumor recurrence. New treatment options are therefore desperately needed for GBM patients. LP-184 is an acylfulvene-derived prodrug that is activated by the oxidoreductase PTGR1 and primarily alkylates adenine at the N3-position. Bioinformatic analysis showed that PTGR1 is elevated in clinical GBM tumor samples compared to normal brain. LP-184 response is influenced by tumor DNA repair status, and acylfulvene-induced damage is mainly repaired by the transcription-coupled nucleotide-excision repair (TC-NER) pathway. Spironolactone, an FDA approved, blood-brain-barrier permeable diuretic, induces degradation of ERCC3 protein, a key TC-NER component. Response of NER-deficient GBM was tested through co-administration of LP-184 and spironolactone. Methods: Cell viability assays with exposure to LP-184, with and without spironolactone, were used to determine IC50 values in vitro. Subcutaneous or intracranial tumor xenograft models were used to determine tumor volume or survival differences between control and LP-184 treated mice. Results: Nanomolar concentrations of LP-184 inhibited in vitro viability of multiple GBM cell models including 4 NCI-60 GBM cell lines (mean IC50= 286 nM), the TMZ-resistant LN-18 cell line (IC50= 46 nM), M1123 GBM neurosphere line (IC50= 151 nM), and a low passage GBM neurosphere isolate (IC50= 306 nM). Co-treatment with spironolactone resulted in a 3-6 fold decrease in LP-184 IC50 values in M1123, Mayo39, and U87 cultures. Pharmacokinetic analyses in SCID mice following a single LP-184 infusion (4 mg/kg, i.v.) showed favorable CNS bioavailability with brain/plasma ratio 0.11 (Cmax= 839 nM) and brain tumor/plasma ratio 0.2 (Cmax= 2.53 µM). LP-184 (4mg/kg i.v., q.o.d X 4) induced complete regression of all pre-established s.c. U87 xenografts (N = 5) and 3 of 6 M1123 s.c. xenografts (mean tumor volumes: 1456 ± 349 mm 3 controls vs 84 ± 39 LP-184, p &lt; 0.001) and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 and M1123 xenografts (p &lt; 0.0001). Conclusions: These preclinical results establish LP-184 as a promising new agent for future clinical testing in patients with GBM and suggest that LP-184 may be particularly efficacious in patients with intrinsic or spironolactone-induced NER deficient tumors.

Functional imaging for evaluation of cancers and biologically conformal radiotherapy: Past-history and present-day perspectives.

Over the past twenty years, nuclear medicine has enhanced the role of functional imaging in cancerology. A major milestone was achieved in the early 2000s with widespread availability of the positron emitter tracer 18F- deoxyglucose (FDG) and the introduction of hybrid imagers, i.e. positron imagers coupled with an X CT, providing anatomical landmarks and potently contributing to attenuation and scatter correction of the images. Other technical advances have progressively increased the quality of positron images. To date, the most widely used tracer remains FDG, which is highly beneficial in terms of sensitivity and specificity in detection of tumor sites, also providing biological information on tumors and early evaluation of treatment response for most cancers. Other highly specific tracers have been developed and are now routinely used for pheochromocytoma and paraganglioma, neuroendocrine tumors, and prostate cancer.Biological Radiotherapy has two aspects: Internal radiotherapy consisting in administration of a tumor-specific molecule radiolabeled with an isotope delivering an adequate radiation dose to the targeted tumor sites (on the model of thyroid cancer treated with radioiodine) and external radiotherapy designed to determine tumor volume, assess response and to dose radiation according to the tumor characteristics shown by functional imaging.

Tumor treating fields (TTFields) in combination with sorafenib inhibit hepatocellular carcinoma in vitro and in vivo.

464 Background: Hepatocellular carcinoma (HCC) is a highly malignant liver cancer and a leading cause of cancer related mortality. Sorafenib was the first approved systemic treatment for HCC, and remains one of few front-line treatments for this malignancy. Tumor treating fields (TTFields) are low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields that exert antimitotic effects on cancerous cells. Results of the phase 2 HEPANOVA study of TTFields (150 kHz) plus sorafenib for advanced HCC support investigation of TTFields in a randomized controlled phase 3 study. The current research aimed to describe the in vitro and in vivo efficacy of this combination and to elucidate details regarding the underlying mechanism of action. Methods: In vitro examinations were performed in HepG2 and Huh-7D12 human HCC cell lines, to which TTFields at a frequency of 150 kHz were applied using the inovitro system. Autophagy was examined by western blot and fluorescence detection of microtubule-associated protein light chain 3 (LC3) levels, an accepted autophagy marker. The effect of TTFields in combination with sorafenib was evaluated using cytotoxic, clonogenic, and apoptotic assays. In vivo, SD rats were inoculated orthotopically into the left hepatic lobe with N1S1 HCC cells. 7 days later, TTFields or sham (heat) were applied to the abdominal region of the rats, continuously for 6 days. Daily intraperitoneal injections of sorafenib (10 mg/kg/day) or vehicle were performed during this time. To determine tumor volume growth, MRI images were acquired before and after treatment. Levels of autophagy and apoptosis were examined in tumor sections by immunohistochemistry for LC3 and cleaved PARP, respectively. Results: Application of TTFields induced autophagy in HCC cells. TTFields delivery was cytotoxic to the cells, reduced their colony forming ability, and induced apoptosis while combination with sorafenib elevated these effects. In vivo, tumor volume increased 6-fold in control animals vs 1.6-fold in animals treated with TTFields plus sorafenib. This effect was accompanied by significantly elevated levels of cleaved PARP and LC3 within the tumors of treated relative to control rats. Conclusions: The results demonstrate induction of autophagy and apoptosis in HCC following treatment with TTFields. Concomitant application of TTFields with sorafenib enhanced efficacy via a mechanism that may involve overwhelming autophagy, in vitro and in vivo.

Evaluation of Antioxidant and Antitumor Activities of Wrightia arborea

Wrightia arborea (Br.) (Family-Apocynaceae), locally known as Sathkurchi, is a small deciduous tree with small branches and densely velvety leaves. This study was designed to investigate the antioxidant and anti tumor activities of leaves of W. arborea.&#x0D; Antioxidant potential was evaluated in vitro by DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging- and reducing power- assay method which was concentration dependent that was 25-200 µg/ml. The extract showed scavenging activity with IC50 value of 15.23 ± 4.10 µg/ml for DPPH and also showed reducing activity in dose dependent manner. In addition, total phenol and flavonoid content were determined by Folin-Ciocalteu reagent and were found to be 112.54 ± 9.74 mg/g plant extract (in GAE) and 247.14 ± 15.45 mg/g plant extract (in quercetin equivalent), respectively. The antioxidant capacity was evaluated by phosphomolybdenum method and was found to be 117.27 ± 12.36 mg/g plant extract (in ascorbic acid equivalents). The anti tumor effect of the methanol extractwas determined with doses of 5, 10 and 20 mg/kg b.wt against Ehrlich ascites carcinoma (EAC) in mice with respect to the determination of tumor volume, tumor weight, % of cell growth inhibition, % increase in life span (%ILS), and hematological parameter (WBC, RBC and hemoglobin).&#x0D; The methanol extract of W. arborea decreased the tumor weight significantly compared to control group at all the mentioned doses and the highest was observed at the dose of 20 mg/kg b. wt. (1.28 ± 0.15 g). The % of cell growth inhibition increased in dose dependent manner like 36.43 ± 7.45, 58.76 ± 9.43 and 98.43 ± 12.45 at the doses of 5, 10, 20 mg/kg b.wt. respectively. The %ILS was also enhanced in all the doses where 20 mg/kg b.wt showed maximum effect (105.5 ± 3.57). Heamoglobin (Hb) content was significantly increased 8.12 ± 2.6, 10.23 ± 1.62 and 12.12 ± 2.09 g/dL at the doses of 5, 10 and 20 mg/kg b.wt. respectively, compared to EAC control mice (4.95 ± 1.80 g). There was a significant (p&lt; 0.05, p&lt; 0.01, p&lt;0.001) decrease in RBC count and increase in WBC counts in extract treated animals when compared to EAC control animals.&#x0D; This is the first report of biological activities of leaves of W. arborea and it showed significant antioxidant as well as antitumor activity.

Comparison of Quantification of Target-Specific Accumulation of [18F]F-siPSMA-14 in the HET-CAM Model and in Mice Using PET/MRI.

Simple SummaryAnimal studies are essential for the development of new radiopharmaceuticals to determine specific accumulation and biodistribution. Alternative models, such as the HET-CAM model, offer the possibility of reducing animal experiments in accordance with the 3Rs principles. Accurate quantification of tumor accumulation of a PSMA-specific ligand in the HET-CAM model and comparison with corresponding animal experiments was performed using the imaging modalities PET and MRI. It was demonstrated that the HET-CAM model leads to comparable results and is suitable as an alternative to animal experiments for the initial assessment of target-specific binding of novel radiopharmaceuticals. However, as evaluation of biodistribution in ovo is still limited, further animal experiments with promising compounds are mandatory.Assessment of biodistribution and specific tumor accumulation is essential for the development of new radiopharmaceuticals and requires animal experiments. The HET-CAM (hens-egg test—chorioallantoic membrane) model can be used in combination with the non-invasive imaging modalities PET and MRI for pre-selection during radiopharmaceutical development to reduce the number of animal experiments required. Critical to the acceptance of this model is the demonstration of the quantifiability and reproducibility of these data compared to the standard animal model. Tumor accumulation and biodistribution of the PSMA-specific radiotracer [18F]F-siPSMA-14 was analyzed in the chick embryo and in an immunodeficient mouse model. Evaluation was based on MRI and PET data in both models. γ-counter measurements and histopathological analyses complemented these data. PSMA-specific accumulation of [18F]F-siPSMA-14 was successfully demonstrated in the HET-CAM model, similar to the results obtained by mouse model studies. The combination of MR and PET imaging allowed precise quantification of peptide accumulation, initial assessment of biodistribution, and accurate determination of tumor volume. Thus, the use of the HET-CAM model is suitable for the pre-selection of new radiopharmaceuticals and potentially reduces animal testing in line with the 3Rs principles of animal welfare.

A head-to-head comparison of 68Ga-DOTA-FAPI-04 and 18F-FDG PET/MR in patients with nasopharyngeal carcinoma: a prospective study.

To conduct a head-to-head comparison of the diagnostic ability of 68Ga-DOTA-FAPI-04 (68Ga-FAPI) and 18F-FDG PET/MR in nasopharyngeal carcinoma (NPC) patients. Patients diagnosed with NPC were prospectively enrolled. All patients underwent head-and-neck 68Ga-FAPI PET/MR and 18F-FDG PET/MR within 1 week. Primary tumor, lymph node numbers, and tracer uptake were compared by SUVmax and visual evaluation. The primary tumor volumes derived from 68Ga-FAPI, 18F-FDG PET, and MRI were also compared. Fifteen patients were enrolled from June to August 2020. Both 68Ga-FAPI and 18F-FDG PET had 100% detection rate of the primary tumor. The 68Ga-FAPI SUVmax of primary tumors (13.87 ± 5.13) was lower than that of 18F-FDG (17.73 ± 6.84), but the difference was not significant (p = 0.078). Compared with 18F-FDG, 68Ga-FAPI PET improved the delineation of skull-base invasion in eight out of eight patients and intracranial invasion in four out of four patients. When 25%SUVmax of 68Ga-FAPI or 20%SUVmax of 18F-FDG was utilized as a threshold for determining tumor volume, it was highly consistent with MRI. 18F-FDG PET detected much more positive lymph nodes than 68Ga-FAPI (100 vs 48). The SUVmax of 48 paired lymph nodes was significantly lower on 68Ga-FAPI than 18F-FDG (8.67 ± 3.88 vs 11.79 ± 6.17, p < 0.001). Additionally, 68Ga-FAPI further detected four highly suspected small, distant metastases in three patients. Compared with 18F-FDG, 68Ga-FAPI changed overall staging in six of fifteen patients, with three patients being up-staged, and three down-staged. 68Ga-FAPI outperforms 18F-FDG in delineating the primary tumor and detecting suspected distant metastases, particularly in the evaluation of skull-base and intracranial invasion, suggesting 68Ga-FAPI hybrid PET/MR has the potential to serve as a single-step staging modality for patients with NPC. However, its value regarding lymph node and distant metastases evaluation needs further study. NCT04554719. Registered September 8, 2020 - retrospectively registered, http://clinicaltrails.gov/show/NCT04554719.

Vestibular Schwannoma Measurements-Is Volumetric Analysis Clinically Necessary?

1) To compare vestibular schwannoma maximum linear dimensions and calculated volume with measured volume in accurately determining tumor volume and growth. 2) To determine natural growth history of vestibular schwannomas utilizing volumetric measurements in an observed patient population. Retrospective chart review. Tertiary academic referral. One hundred fifty two adults with a vestibular schwannoma who underwent observational management with sequential magnetic resonance imaging (MRI) scans (496 scans). MRI scans. Tumor volume calculated from linear dimensions compared with measured volume. The percentage change in tumor size (linear or volume) between consecutive MRI scans. The percentage change in tumor size between consecutive MRIs is significantly different between maximum linear dimension (MLD) and measured tumor volume (p = 0.03), but no difference exists in the percentage change between measured and calculated tumor volume (p = 0.882 for three linear measurements, p = 0.637 for two linear measurements). The overall number of growing tumors is 57.2% (n = 87) with an average growth rate of 62.6%. If a criterion for growth of 20% change is used, 32.2% of tumors monitored by linear volume would have demonstrated growth while 57.2% of tumors with measured volume demonstrated growth. Maximum linear dimensions are a significantly less sensitive measure of tumor growth compared with measured volumes. Calculated tumor volume utilizing three linear measurements is an accurate predictor of both measured tumor volume and tumor growth.

Importance of Pre-treatment Fractional Anisotropy Value in Predicting Volumetric Response in Patients with Meningioma Treated with Gamma Knife Radiosurgery.

BackgroundThe importance of pre-treatment Diffusion Tensor Imaging (DTI) parameters in determining the response to treatment after radiosurgery in patients with meningioma has not yet been clearly revealed.ObjectiveThis study was conducted to determine tumor volume changes in terms of radiological response in patients with meningioma treated with Gamma Knife Radiosurgery (GKR) and to analyze the relationship between Total Tumor Volume (TTV) and Diffusion Tensor Imaging (DTI) parameters. In addition, we investigated whether the response to treatment can be predicted by pre-radiosurgery DTI findings.MethodsFifty-four patients were assessed using MRI and DTI before and after GKR. Mean Diffusivity (MD), Fractional Anisotropy (FA), Radial Diffusivity (RD), and TTV of tumour were determined. Patients with 10% or more decrease in TTV after GKR were classified as group 1 and those with less than 10% decrease in volume or increase in volume were considered group 2. The relationships between MD, RD, and FA values and TTV were investigated.ResultsA decrease of 46.34% in TTV was detected in group 1 after GKR, while TTV increased by 42.91% in group 2. The lowest pre-treatment FA value was detected in group 1. In addition, after GKR, FA values showed a significant increase in group 1. MD and RD values increased in both groups after radiosurgery. There was a negative correlation between pre-treatment FA, RD, and MD values after radiosurgery.ConclusionDetection of low FA values due to the poor fiber content in meningioma before radiosurgery may be a guide in predicting the response to treatment. Further studies are required to have a better understanding of the relationship between pre- and post-treatment follow-up FA values and tumor volume in determining the efficacy of GKR in patients with meningioma.

Diffusion-weighted MRI improves response assessment after definitive radiotherapy in patients with NSCLC

BackgroundComputed tomography (CT) is the standard procedure for follow-up of non-small-cell lung cancer (NSCLC) after radiochemotherapy. CT has difficulties differentiating between tumor, atelectasis and radiation induced lung toxicity (RILT). Diffusion-weighted imaging (DWI) may enable a more accurate detection of vital tumor tissue. The aim of this study was to determine the diagnostic value of MRI versus CT in the follow-up of NSCLC.MethodsTwelve patients with NSCLC stages I-III scheduled for radiochemotherapy were enrolled in this prospective study. CT with i.v. contrast agent and non enhanced MRI were performed before and 3, 6 and 12 months after treatment. Standardized ROIs were used to determine the apparent diffusion weighted coefficient (ADC) within the tumor. Tumor size was assessed by the longest longitudinal diameter (LD) and tumor volume on DWI and CT. RILT was assessed on a 4-point-score in breath-triggered T2-TSE and CT.ResultsThere was no significant difference regarding LD and tumor volume between MRI and CT (p ≥ 0.6221, respectively p ≥ 0.25). Evaluation of RILT showed a very high correlation between MRI and CT at 3 (r = 0.8750) and 12 months (r = 0.903). Assessment of the ADC values suggested that patients with a good tumor response have higher ADC values than non-responders.ConclusionsDWI is equivalent to CT for tumor volume determination in patients with NSCLC during follow up. The extent of RILT can be reliably determined by MRI. DWI could become a beneficial method to assess tumor response more accurately. ADC values may be useful as a prognostic marker.

Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo.

Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20–40%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-XL, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.

Validating impact of pretreatment tumor growth rate on outcome of early-stage lung cancer treated with stereotactic body radiation therapy.

BackgroundTo assess correlation of pretreatment specific growth rate (SGR) value of 0.43 × 10‐2 with overall and failure‐free survival of patients with early‐stage non‐small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT).MethodsA retrospective chart review of 160 patients with pathologically confirmed stage I NSCLC treated with SBRT between June 2010 and December 2012 in a large, tertiary cancer institute was undertaken. Both diagnostic and archived planning CT were uploaded to the treatment planning system to determine tumor volume at diagnosis (GTV1) and planning time (GTV2). The time (t) between both CTs was recorded. SGR was calculated using GTV1, GTV2, and t. The median SGR (0.43 × 10‐2) from our previous data was used to group patients into low and high SGR cohorts. Log‐rank test was used to compare overall (OS) and failure‐free survivals (FFS) of SGR groups.ResultsThe median time interval between diagnostic and planning CT scans was 87 days. The median OS was 38 and 66 months for high and low SGR cohorts, respectively (P = 0.03). The median FFS was 27 and 55 months for high and low SGR cohorts, respectively (P = 0.005). High SGR (P < 0.05), male gender (P = <0.01), and GTV2 (P = <0.05) were associated with poorer FFS.ConclusionsHigh SGR was associated with poorer outcome in patients with early‐stage NSCLC treated with SBRT. SGR can be used in conjunction with other well‐known predictive factors to formulate a practical predictive model to identify subgroups of the patient at higher risk of recurrence after SBRT.

Evaluation of Tumour Volume as a Prognostic Factor in Carcinoma Buccal Mucosa.

(1) To determine tumor volume by clinical measurement, imaging and histopathological examination in patients with squamouscarcinoma of buccal mucosa. (2) To correlate tumor volume with lymph-node metastasis and loco-regional control. Retrospective Observational Study. Rural tertiary care hospital. 75 Patients undergoing surgery for T2 (68%) and T3 (32%) Oral squamous carcinomas were included in this observational study. Tumor volume-a product of maximum length, breadth and thickness, was determined clinically and by imaging. Tumor volume on histopathology was documented and correlated with lymph-node metastasis. After 13months minimum follow-up, tumor volume was correlated with loco-regional control. Recurrences were analysed with regard to tumor volume, depth of invasion, lymph-node metastasis and resection margins. Average tumor volume was 7.1cm3among T2 and 14.4cm3among T3. 25% of T2 tumors had metastatic lymph-nodes compared to 33.3% in T3. There was positive correlation between tumor volume and lymph-node metastasis. Lymph-node metastasis was absent when tumor volume was < 8cm3. There were 4 local and 2 regional recurrences in this study. Average histopathological tumor volume among patients who had local recurrence was 12.95cm3. Regional recurrences occurred in tumors staged N2b and N3b on histopathology. Average depth of invasion in patients with recurrence was 10.33mm.. Tumor volume represents actual tumor load and correlates with lymph node metastasis and prognosis in oral cancers. Depth of invasion and tumor thicknessinfluence staging and prognosis. Large volume tumors have poor oncological outcome.