Search results for: Tumor Microenvironment

Authors: Jaewoo Choi, Ki-Tae Hwang, Eunyoung Ko

Abstract:

Backgrounds/Aims: Patients with breast cancer are currently classified according to TNM stage. Nevertheless, the actual volume would be mis-estimated, and it would bring on inappropriate diagnosis. Tridimensional volume-stage derived from the ellipsoid formula was presented as useful measure. Methods: The medical records of 480 consecutive breast cancer between January 2001 and March 2013 were retrospectively reviewed. All patients were divided into three groups according to tumor volume by receiver operating characteristic analysis, and the ranges of each volume-stage were that V1 was below 2.5 cc, V2 was exceeded 2.5 and below 10.9 cc, and V3 was exceeded 10.9 cc. We analyzed outcomes of volume-stage and compared disease-free survival (DFS) and overall survival (OS) between size-stage and volume-stage with variant intrinsic factor. Results: In the T2 stage, there were patients who had a smaller volume than 4.2 cc known as maximum value of T1. These findings presented that patients in T1c had poorer DFS than T2-lesser (mean of DFS 48.7 vs. 51.8, p = 0.011). Such is also the case in OS (mean of OS 51.1 vs. 55.3, p = 0.006). The cumulative survival curves for V1, V2 compared T1, T2 showed similarity in DFS (HR 1.9 vs. 1.9), and so did it for V3 compared T3 (HR 3.5 vs. 2.6) significantly. Conclusion: This study demonstrated that tumor volume had good feasibility on the prognosis of patients with breast cancer. We proposed that volume-stage should be considered for an additional stage indicator, particularly in early breast cancer.

Keywords: breast cancer, tridimensional volume of tumor, TNM stage, volume stage

Procedia PDF Downloads 403

Authors: Mahmoodreza Tahamtan

Abstract:

Malignant surface epithelial ovarian tumors(SEOT) account for approximately 90% of primary ovarian cancer. We evaluate the immunohistochemical expression of WT1 protein among different histologic subtypes of SEOT. Immunohistochemistry for WT1 was done on 35 serous cystadenocarcinomas, 9 borderline serous tumors. A tumor was considered negative if < 1% of tumor cells were stained.Positive reactions were graded as follows:1+,1%-24%; 2+,25%-49%; 3+,50%-74%; 4+,75%-100%. Of the 35 cases of ovarian serous cystadenocarcinoma 30(85.7%)were diffusely positive(3+,4+),4 showed reactivity of < 50% of the tumor cells(1+,2+) and one were negative. All 9 borderline serous tumors showed immunoreactivity with WT1. WT1 is a good marker to distinguish primary ovarian serous carcinomas from other surface epithelial tumors.

Keywords: WT1, ovary, malignant, epithelial tumors

Procedia PDF Downloads 102

Authors: D. O. Miranda, L. R. Azevedo, J. F. C. Cordeiro, A. H. Dos Santos, S. F. Lisboa, F. S. Guimarães, G. S. Bisson

Abstract:

Background: The Colorectal cancer (CRC) is one of the most common cancers and the fourth leading cause of cancer death in the world. The prevalence of psychiatric-disorders among CRC patients, mainly depression, is high, resulting in impaired quality of life and side effects of primary treatment. High levels of proinflammatory cytokines at tumor microenvironment is a feature of CRC and the literature suggests that those mediators could contribute to the development of psychiatric disorders. Nevertheless, the ability of tumor-associated biological processes to affect the central nervous system (CNS) has only recently been explored in the context of symptoms of depression and is still not well understood. Therefore, the aim of the present study was to test the hypothesis that depressive-like behavior in an experimental model of CCR induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was correlated to proinflammatory profile in the periphery and in the brain. Methods: Colorectal carcinogenesis was induced in adult C57BL/6 mice (n=12) by administration of MNNG (5mg/kg, 0.1ml/intrarectal instillation) 2 times a week, for 2 week. Control group (n=12) received saline (0.1ml/intrarectal instillation). Eight weeks after beginning of MNNG administration animals were submitted to the forced swim test (FST) and the sucrose preference test for evaluation, respectively, of depressive- and anhedonia-like behaviors. After behavioral evaluation, the colon was collected and brain regions dissected (cortex-C, striatum-ST and hippocampus-HIP) for posterior evaluation of cytokine levels (IL-1β, IL-10, IL-17, and CX3CL1) by ELISA. Results: MNNG induced depressive-like behavior, represented by increased immobility time in the FST (Student t test, p < 0.05) and lower sucrose preference (Student t test, p < 0.05). Moreover, there were increased levels of IL-1β, IL-17 and CX3CL1 in the colonic tissue (Student t test, p < 0.05) and in the brain (IL-1 β in the ST and HIP, Student t test, p < 0.05; IL-17 and CX3CL1 in the C and HIP, p < 0.05). IL-10 levels, in contrast, were decreased in both the colon (p < 0.05) and the brain (C and HIP, p < 0.05). Conclusions: The results obtained in the present work support the notion that tumor growth induces neuroinflammation in stress-related brain regions and depressive-like behavior, which could be related to the high incidence of depression in colorectal carcinogenesis. This work have important clinical and research implications, taken into account that cytokine levels may be a marker promissory for the developing depression in CRC patients. New therapeutic strategies to assist in alleviating mental suffering in cancer patients might result from a better understanding of the role of cytokines in the pathophysiology of depression in these subjects.

Keywords: cytokines, brain, depression, colorectal cancer

Procedia PDF Downloads 270

Authors: R. R. Ramsheeja, R. Sreeraj

Abstract:

For view the internal structures of the human body such as liver, brain, kidney etc have a wide range of different modalities for medical images are provided nowadays. Computer Tomography is one of the most significant medical image modalities. In this paper use CT liver images for study the use of automatic computer aided techniques to calculate the volume of the liver tumor. Segmentation method is used for the detection of tumor from the CT scan is proposed. Gaussian filter is used for denoising the liver image and Adaptive Thresholding algorithm is used for segmentation. Multiple Region Of Interest(ROI) based method that may help to characteristic the feature different. It provides a significant impact on classification performance. Due to the characteristic of liver tumor lesion, inherent difficulties appear selective. For a better performance, a novel proposed system is introduced. Multiple ROI based feature selection and classification are performed. In order to obtain of relevant features for Support Vector Machine(SVM) classifier is important for better generalization performance. The proposed system helps to improve the better classification performance, reason in which we can see a significant reduction of features is used. The diagnosis of liver cancer from the computer tomography images is very difficult in nature. Early detection of liver tumor is very helpful to save the human life.

Keywords: computed tomography (CT), multiple region of interest(ROI), feature values, segmentation, SVM classification

Procedia PDF Downloads 509

Authors: Mohamed Shafi Bin Mahboob Ali

Abstract:

Introduction: Synchronous tumor is defined as the presence of more than one primary malignant lesion in the same patient at the indexed diagnosis. It is a rare occurrence, especially in the spectrum of colorectal cancer, which accounts for less than 4%. The underlying pathology of a synchronous tumor is thought to be due to a genomic factor, which is microsatellite instability (MIS) with the involvement of BRAF, KRAS, and the GSRM1 gene. There are no specific sites of occurrence for the synchronous colorectal tumor, but many studies have shown that a synchronous tumor has about 43% predominance in the ascending colon with rarity in the sigmoid colon. Case Report: We reported a case of a young lady in the middle of her 30's with no family history of colorectal cancer that was diagnosed with a synchronous adenocarcinoma at the descending colon and rectosigmoid region. The lady's presentation was quite perplexing as she presented to the district hospital initially with simple, uncomplicated hemorrhoids and constipation. She was then referred to our center for further management as she developed a 'football' sized right gluteal swelling with a complete intestinal obstruction and bilateral lower-limb paralysis. We performed a CT scan and biopsy of the lesion, which found that the tumor engulfed the sacrococcygeal region with more than one primary lesion in the colon as well as secondaries in the liver. The patient was operated on after a multidisciplinary meeting was held. Pelvic exenteration with tumor debulking and anterior resection were performed. Postoperatively, she was referred to the oncology team for chemotherapy. She had a tremendous recovery in eight months' time with a partial regain of her lower limb power. The patient is still under our follow-up with an improved quality of life post-intervention. Discussion: Synchronous colon cancer is rare, with an incidence of 2.4% to 12.4%. It has male predominance and is pathologically more advanced compared to a single colon lesion. Down staging the disease by means of chemoradiotherapy has shown to be effective in managing this tumor. It is seen commonly on the right colon, but in our case, we found it on the left colon and the rectosigmoid. Conclusion: Managing a synchronous colon tumor could be challenging to surgeons, especially in deciding the extent of resection and postoperative functional outcomes of the bowel; thus, individual treatment strategies are needed to tackle this pathology.

Keywords: synchronous, colon, tumor, adenocarcinoma

Procedia PDF Downloads 108

Authors: Hakim Derradji, M’Hammedi Yousra, Sabrou Abdelmalek, Tabet Nacer

Abstract:

Introduction: This is a retrospective study carried out at the Central Hospital of Army from 2017 to 2022. Its objective is to demonstrate the best surgical method for the management of obstructive hydrocephalus secondary to a posterior fossa tumor in children, in pre, per, and post-operative. Patients and Methods: During this period, 24 children (over 1 year old) were admitted for treatment of the posterior fossa tumor with obstructive secondary hydrocephalus and the majority of whom benefited from VCS followed by surgery and excision, the rest, received after evacuation from other hospital structures, were managed there beforehand with ventriculoperitoneal diversion or external drainage. We found that the way hydrocephalus is managed has implications for subsequent management, hence the need for this study to determine the effectiveness of different surgical procedures used in the treatment of hydrocephalus in these patients. The evaluation is made on the basis of revision rate, complications, survival, and radiological evaluation. Results: 6 patients (25%) received a ventriculoperitoneal shunt (VPD), 15 patients (62%) underwent a ventriculocysternostomy (VCS), and 3 patients (12.5%) received temporary ventricular drainage before or during tumor excision. The post-operative results were almost similar. Nevertheless, a high failure rate (25%) was observed. No deaths are recorded. In total, 75% of children who had a DVP were reoperated. The revision by VCS was performed, in addition to the 4 patients benefiting from a DVP, with one patient having received external drainage, and only one revision of a VCS was recorded. In the two patients who received external drainage, restoration of CSF outflow was observed following tumor resection. Conclusion: VCS is indicated in the first intention in the treatment of hydrocephalus secondary to a posterior fossa tumor, in view of the satisfactory results obtained and the high failure rate in DVP, especially with the presence of metastatic cells in the peritoneum, but can be considered as a second-line treatment.

Keywords: posterior fossa tumor, obstructive hydrocephalus, DVP, VCS

Procedia PDF Downloads 117

Authors: Seyhan Karaçavuş, Bülent Yılmaz, Ömer Kayaaltı, Semra İçer, Arzu Taşdemir, Oğuzhan Ayyıldız, Kübra Eset, Eser Kaya

Abstract:

In this study, our goal was to perform tumor staging and subtype determination automatically using different texture analysis approaches for a very common cancer type, i.e., non-small cell lung carcinoma (NSCLC). Especially, we introduced a texture analysis approach, called Law’s texture filter, to be used in this context for the first time. The 18F-FDG PET images of 42 patients with NSCLC were evaluated. The number of patients for each tumor stage, i.e., I-II, III or IV, was 14. The patients had ~45% adenocarcinoma (ADC) and ~55% squamous cell carcinoma (SqCCs). MATLAB technical computing language was employed in the extraction of 51 features by using first order statistics (FOS), gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), and Laws’ texture filters. The feature selection method employed was the sequential forward selection (SFS). Selected textural features were used in the automatic classification by k-nearest neighbors (k-NN) and support vector machines (SVM). In the automatic classification of tumor stage, the accuracy was approximately 59.5% with k-NN classifier (k=3) and 69% with SVM (with one versus one paradigm), using 5 features. In the automatic classification of tumor subtype, the accuracy was around 92.7% with SVM one vs. one. Texture analysis of FDG-PET images might be used, in addition to metabolic parameters as an objective tool to assess tumor histopathological characteristics and in automatic classification of tumor stage and subtype.

Keywords: cancer stage, cancer cell type, non-small cell lung carcinoma, PET, texture analysis

Procedia PDF Downloads 326

Authors: Mahesh Pal, Tripti Mishra, Chandana Rao, Dalip Upreti

Abstract:

Cancer has been considered to be a very dreadful disease. Holmskioldia sanguinea is a large climbing shrub found in the Himalayas at an altitude of 5,000 ft and preliminary investigation showed the excellent yield of andrographolide and subjected for the anticancer activity. Protective effect of Holmskioldia sanguinea leaf ethanolic extract has been investigated against Ehrlich ascites carcinoma (EAC) and Daltons ascites lymphoma (DAL) in Swiss albino mice to evaluate the possible mechanism of action. The enzymatic antioxidant status was studied on tumor bearing mice, which shows the potential of the compound to possess significant free radical scavenging property and revealed significant tumor regression and prolonged survival time. The isolated bioactive molecule andrographolide from Holmskioldia sanguinea yields (2.5%) in subject to HPTLC/HPLC analysis. The cellular defense system constituting the superoxide dismutase, catalyses was enhanced whereby the lipid peroxidation content was restricted to a larger extent. The Holmskioldia sanguinea is a new source of andrographolide and demonstrated the potency in treatment of cancer.

Keywords: Holmskioldia sanguinea, tumor, mice, andrographolide

Procedia PDF Downloads 264

Authors: F. Kashanian, M. M. Masoudi, A. Akbari, A. Shamloo, M. R. Zand, S. S. Salehi

Abstract:

Nano-sized materials present new opportunities in biology and medicine and they are used as biomedical tools for investigation, separation of molecules and cells. To achieve more effective cancer therapy, it is essential to select cancer cells exactly. This research suggests that using the antibody-functionalized nontoxic Arginine-doped magnetic nanoparticles (A-MNPs), has been prosperous in detection, capture, and magnetic separation of circulating tumor cells (CTCs) in tumor tissue. In this study, A-MNPs were synthesized via a simple precipitation reaction and directly immobilized Ep-CAM EBA-1 antibodies over superparamagnetic A-MNPs for Mucin BCA-225 in breast cancer cell. The samples were characterized by vibrating sample magnetometer (VSM), FT-IR spectroscopy, Tunneling Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). These antibody-functionalized nontoxic A-MNPs were used to capture breast cancer cell. Through employing a strong permanent magnet, the magnetic separation was achieved within a few seconds. Antibody-Conjugated nontoxic Arginine-doped Fe₃O₄ nanoparticles have the potential for the future study to capture CTCs which are released from tumor tissue and for drug delivery, and these results demonstrate that the antibody-conjugated A-MNPs can be used in magnetic hyperthermia techniques for cancer treatment.

Keywords: tumor tissue, antibody, magnetic nanoparticle, CTCs capturing

Procedia PDF Downloads 361

Authors: Akram Boubakri, Fethi Choubani, Tan Hoa Vuong, Jacques David

Abstract:

Nowadays, microwave hyperthermia is considered as an effective treatment for the malignant tumors. This microwave treatment which comes to substitute the chemotherapy and the surgical intervention enables an in-depth tumor heating without causing any diseases to the sane tissue. This technique requires a high precision system, in order to effectively concentrate the heating just in the tumor, without heating any surrounding healthy tissue. In the hyperthermia treatment, the temperature in cancerous area is typically raised up to over 42◦C and maintained for one hour in order to destroy the tumor sufficiently, whilst in the surrounding healthy tissues, the temperature is maintained below 42◦C to avoid any damage. Metamaterial lenses are widely used in medical applications like microwave hyperthermia treatment. They enabled a subdiffraction resolution thanks to the amplification of the evanescent waves and they can focus electromagnetic waves from a point source to a point image. Metasurfaces have been used to built metamaterial lenses. The main mechanical advantages of those structures over three dimensional material structures are ease of fabrication and a smaller required volume. Here in this work, we proposed a metasurface based lens operating at the frequency of 6 GHz and designed for microwave hyperthermia. This lens was applied and showed good results in focusing and heating the tumor inside a breast tissue with an increased and maintained temperature above 42°C. The tumor was placed in the focal distance of the lens so that only the tumor tissue will be heated. Finally, in this work, it has been shown that the hyperthermia area within the tissue can be carefully adjusted by moving the antennas or by changing the thickness of the metamaterial lenses based on the tumor position. Even though the simulations performed in this work have taken into account an ideal case, some real characteristics can be considered to improve the obtained results in a realistic model.

Keywords: focusing, hyperthermia, metamaterial lenses, metasurface, microwave treatment

Procedia PDF Downloads 227

Authors: Kolja Them, Priyal Chikhaliwala, Sudeshna Chandra

Abstract:

Purpose: The purpose of this work is to examine possibilities for noninvasive imaging and identification of tumor markers for cancer diagnosis. The proposed method uses antibody conjugated iron oxide nanoparticles and multicolor Magnetic Particle Imaging (mMPI). The method has the potential for radiation exposure free real-time estimation of local tumor marker concentrations in vivo. In this study, the method is applied to human Alpha-1-Fetoprotein. Materials and Methods: As tracer material AFP antibody-conjugated Dendrimer-Fe3O4 nanoparticles were used. The nanoparticle bioconjugates were then incubated with bovine serum albumin (BSA) to block any possible nonspecific binding sites. Parts of the resulting solution were then incubated with AFP antigen. MPI measurements were done using the preclinical MPI scanner (Bruker Biospin MRI GmbH) and the multicolor method was used for image reconstruction. Results: In multicolor MPI images the nanoparticles incubated only with BSA were clearly distinguished from nanoparticles incubated with BSA and AFP antigens. Conclusion: Tomographic imaging of human tumor marker Alpha-1-Fetoprotein is possible using AFP antibody conjugated iron oxide nanoparticles in presence of BSA. This opens interesting perspectives for cancer diagnosis.

Keywords: noninvasive imaging, tumor antigens, antibody conjugated iron oxide nanoparticles, multicolor magnetic particle imaging, cancer diagnosis

Procedia PDF Downloads 303

Authors: Ren-Jy Ben, Jo-Chi Jao, Chiu-Ya Liao, Ya-Ru Tsai, Lain-Chyr Hwang, Po-Chou Chen

Abstract:

Cancer is still one of the serious diseases threatening the lives of human beings. How to have an early diagnosis and effective treatment for tumors is a very important issue. The animal carcinoma model can provide a simulation tool for the study of pathogenesis, biological characteristics and therapeutic effects. Recently, drug delivery systems have been rapidly developed to effectively improve the therapeutic effects. Liposome plays an increasingly important role in clinical diagnosis and therapy for delivering a pharmaceutic or contrast agent to the targeted sites. Liposome can be absorbed and excreted by the human body, and is well known that no harm to the human body. This study aimed to compare the therapeutic effects between encapsulated (doxorubicin liposomal, LipoDox) and un-encapsulated (doxorubicin, Dox) anti-tumor drugs using Magnetic Resonance Imaging (MRI). Twenty-four New Zealand rabbits implanted with VX2 carcinoma at left thigh were classified into three groups: control group (untreated), Dox-treated group and LipoDox-treated group, 8 rabbits for each group. MRI scans were performed three days after tumor implantation. A 1.5T GE Signa HDxt whole body MRI scanner with a high resolution knee coil was used in this study. After a 3-plane localizer scan was performed, Three-Dimensional (3D) Fast Spin Echo (FSE) T2-Weighted Images (T2WI) was used for tumor volumetric quantification. And Two-Dimensional (2D) spoiled gradient recalled echo (SPGR) dynamic Contrast-enhanced (DCE) MRI was used for tumor perfusion evaluation. DCE-MRI was designed to acquire four baseline images, followed by contrast agent Gd-DOTA injection through the ear vein of rabbits. Afterwards, a series of 32 images were acquired to observe the signals change over time in the tumor and muscle. The MRI scanning was scheduled on a weekly basis for a period of four weeks to observe the tumor progression longitudinally. The Dox and LipoDox treatments were prescribed 3 times in the first week immediately after VX2 tumor implantation. ImageJ was used to quantitate tumor volume and time course signal enhancement on DCE images. The changes of tumor size showed that the growth of VX2 tumors was effectively inhibited for both LipoDox-treated and Dox-treated groups. Furthermore, the tumor volume of LipoDox-treated group was significantly lower than that of Dox-treated group, which implies that LipoDox has better therapeutic effect than Dox. The signal intensity of LipoDox-treated group is significantly lower than that of the other two groups, which implies that targeted therapeutic drug remained in the tumor tissue. This study provides a radiation-free and non-invasive MRI method for therapeutic monitoring of targeted liposome on an animal tumor model.

Keywords: doxorubicin, dynamic contrast-enhanced MRI, lipodox, magnetic resonance imaging, VX2 tumor model

Procedia PDF Downloads 457

Authors: Han Xiao

Abstract:

The development of nanomedicines has recently achieved several breakthroughs in the field of cancer treatment; however, the biocompatibility and targeted burst release of these medications remain a limitation, which leads to serious side effects and significantly narrows the scope of their applications. The self-assembly of intermediate filament protein (IFP) peptides was triggered by a hydrophobic cation drug 7-amino actinomycin D (7-AAD) to synthesize pH-activatable nanoparticles (NPs) that could simultaneously locate tumors and produce antitumor effects. The designed IFP peptide included a target peptide (arginine–glycine–aspartate), a negatively charged region, and an α-helix sequence. It also possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method. 7-AAD molecules with excellent near-infrared fluorescence properties could be target delivered into tumor cells by NPs and released immediately in the acidic environments of tumors and endosome/lysosomes, ultimately inducing cytotoxicity by arresting the tumor cell cycle with inserted DNA. It is noteworthy that the IFP/7-AAD NPs tail vein injection approach demonstrated not only high tumor-targeted imaging potential, but also strong antitumor therapeutic effects in vivo. The proposed strategy may be used in the delivery of cationic antitumor drugs for precise imaging and cancer therapy.

Keywords: 7-amino actinomycin D, intermediate filament protein, nanoparticle, tumor image

Procedia PDF Downloads 138

Authors: Shouta Sora, Shizuki Kuriu, Radhika Mishra, Ariunbuyan Sukhbaatar, Maya Sakamoto, Shiro Mori, Tetsuya Kodama

Abstract:

Lymph node (LN) metastasis accounts for 20 - 30 % of all deaths in patients with head and neck cancer. Therefore, the control of metastatic lymph nodes (MLNs) is necessary to improve the life prognosis of patients with cancer. In a classical metastatic theory, tumor cells are thought to metastasize hematogenously through a bead-like network of lymph nodes. Recently, a lymph node-mediated hematogenous metastasis theory has been proposed, in which sentinel LNs are regarded as a source of distant metastasis. Therefore, the treatment of MLNs at the early stage is essential to prevent distant metastasis. Radiation therapy is one of the primary therapeutic modalities in cancer treatment. In addition, total body irradiation (TBI) has been reported to act as activation of natural killer cells and increase of infiltration of CD4+ T-cells to tumor tissues. However, the treatment effect of TBI for MLNs remains unclear. This study evaluated the possibilities of low-dose total body irradiation (L-TBI) and middle-dose total body irradiation (M-TBI) for the treatment of MLNs. Mouse breast cancer FM3A-Luc cells were injected into subiliac lymph node (SiLN) of MXH10/Mo/LPR mice to induce the metastasis to the proper axillary lymph node (PALN) and lung. Mice were irradiated for the whole body on 4 days after tumor injection. The L-TBI and M-TBI were defined as irradiations to the whole body at 0.2 Gy and 1.0 Gy, respectively. Tumor growth was evaluated by in vivo bioluminescence imaging system. In the non-irradiated group, tumor activities on SiLN and PALN significantly increased over time, and the metastasis to the lung from LNs was confirmed 28 days after tumor injection. The L-TBI led to a tumor growth delay in PALN but did not control tumor growth in SiLN and metastasis to the lung. In contrast, it was found that the M-TBI significantly delayed the tumor growth of both SiLN and PALN and controlled the distant metastasis to the lung compared with non-irradiated and L-TBI groups. These results suggest that the M-TBI is an effective treatment method for MLNs in the early stage and distant metastasis from lymph nodes via blood vessels connected with LNs.

Keywords: metastatic lymph node, lung metastasis, radiation therapy, total body irradiation, lymphatic system

Procedia PDF Downloads 181

Authors: Eashwar V. Somasundaram, Raoul R. Wadhwa, Jacob G. Scott

Abstract:

The use of radiomics in measuring geometric properties of tumor images such as size, surface area, and volume has been invaluable in assessing cancer diagnosis, treatment, and prognosis. In addition to analyzing geometric properties, radiomics would benefit from measuring topological properties using persistent homology. Intuitively, features uncovered by persistent homology may correlate to tumor structural features. One example is necrotic cavities (corresponding to 2D topological features), which are markers of very aggressive tumors. We develop a data pipeline in R that clusters tumors images based on persistent homology is used to identify meaningful clinical distinctions between tumors and possibly new relationships not captured by established clinical categorizations. A preliminary analysis was performed on 16 Magnetic Resonance Imaging (MRI) breast tissue segments downloaded from the 'Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis' (I-SPY TRIAL or ISPY1) collection in The Cancer Imaging Archive. Each segment represents a patient’s breast tumor prior to treatment. The ISPY1 dataset also provided the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status data. A persistent homology matrix up to 2-dimensional features was calculated for each of the MRI segmentation. Wasserstein distances were then calculated between all pairwise tumor image persistent homology matrices to create a distance matrix for each feature dimension. Since Wasserstein distances were calculated for 0, 1, and 2-dimensional features, three hierarchal clusters were constructed. The adjusted Rand Index was used to see how well the clusters corresponded to the ER/PR/HER2 status of the tumors. Triple-negative cancers (negative status for all three receptors) significantly clustered together in the 2-dimensional features dendrogram (Adjusted Rand Index of .35, p = .031). It is known that having a triple-negative breast tumor is associated with aggressive tumor growth and poor prognosis when compared to non-triple negative breast tumors. The aggressive tumor growth associated with triple-negative tumors may have a unique structure in an MRI segmentation, which persistent homology is able to identify. This preliminary analysis shows promising results in the use of persistent homology on tumor imaging to assess the severity of breast tumors. The next step is to apply this pipeline to other tumor segment images from The Cancer Imaging Archive at different sites such as the lung, kidney, and brain. In addition, whether other clinical parameters, such as overall survival, tumor stage, and tumor genotype data are captured well in persistent homology clusters will be assessed. If analyzing tumor MRI segments using persistent homology consistently identifies clinical relationships, this could enable clinicians to use persistent homology data as a noninvasive way to inform clinical decision making in oncology.

Keywords: cancer biology, oncology, persistent homology, radiomics, topological data analysis, tumor imaging

Procedia PDF Downloads 135

Authors: V. R. Ahire, A. Kumar, B. N. Pandey, K. P. Mishra, G. R. Kulkarni

Abstract:

Radiation therapy is an effective vital strategy used globally in the treatment of cervical cancer. However, radiation efficacy principally depends on the radiosensitivity of the tumor, and not all patient exhibit significant response to irradiation. A radiosensitive tumor is easier to cure than a radioresistant tumor which later advances to local recurrence and metastasis. Herbal polyphenols are gaining attention for exhibiting radiosensitization through various signaling. Current work focuses to study the radiosensitization effect of ellagic acid (EA), on HeLa cells. EA intermediated radiosensitization of HeLa cells was due to the induction γ-H2AX foci formation, G1 phase cell cycle arrest, and loss of reproductive potential, growth inhibition, drop in the mitochondrial membrane potential and protein expression studies that eventually induced apoptosis. Irradiation of HeLa in presence of EA (10 μM) to doses of 2 and 4 Gy γ-radiation produced marked tumor cytotoxicity. EA also demonstrated radio-protective effect on normal cell, NIH3T3 and aided recovery from the radiation damage. Our results advocate EA to be an effective adjuvant for improving cancer radiotherapy as it displays striking tumor cytotoxicity and reduced normal cell damage instigated by irradiation.

Keywords: apoptotic radiosensitivity, ellagic acid, mitochondrial potential, cell-cycle arrest

Procedia PDF Downloads 354

Authors: Sajeeha Ansar, Asad Ali Safi, Sheikh Ziauddin, Ahmad R. Shahid, Faraz Ahsan

Abstract:

Gliomas are most challenging and aggressive type of tumors which appear in different sizes, locations, and scattered boundaries. CNN is most efficient deep learning approach with outstanding capability of solving image analysis problems. A fully automatic deep learning based 2D-CNN model for brain tumor segmentation is presented in this paper. We used small convolution filters (3 x 3) to make architecture deeper. We increased convolutional layers for efficient learning of complex features from large dataset. We achieved better results by pushing convolutional layers up to 16 layers for HGG model. We achieved reliable and accurate results through fine-tuning among dataset and hyper-parameters. Pre-processing of this model includes generation of brain pipeline, intensity normalization, bias correction and data augmentation. We used the BRATS-2015, and Dice Similarity Coefficient (DSC) is used as performance measure for the evaluation of the proposed method. Our method achieved DSC score of 0.81 for complete, 0.79 for core, 0.80 for enhanced tumor regions. However, these results are comparable with methods already implemented 2D CNN architecture.

Keywords: brain tumor segmentation, convolutional neural networks, deep learning, HGG

Procedia PDF Downloads 256

Authors: Abraham J. Rizkalla, Tristan D. Yan

Abstract:

Atrial myxoma is the most common primary cardiac tumor, and can result in cardiac failure secondary to obstruction, or systemic embolism due to fragmentation. Traditionally, excision of atrial an myxoma has been performed through median sternotomy, however the robotic approach offers several advantages including less pain, improved cosmesis, and faster recovery. Here, we highlight the less well recognized advantages and technical aspects to robotic myxoma resection. This video-presentation demonstrates the resection of a papillary subtype left atrial myxoma using the DaVinci© Xi surgical robot. The 10x magnification and 3D vision allows for the interface between the tumor and the interatrial septum to be accurately dissected, without the need to patch the interatrial septum. Several techniques to avoid tumor fragmentation and embolization are demonstrated throughout the procedure. The tumor was completely excised with clear margins. There was no atrial septal defect or mitral valve injury on post operative transesophageal echocardiography. The patient was discharged home on the fourth post-operative day. This video-presentation highlights the advantages of the robotic approach in atrial myxoma resection compared with sternotomy, as well as emphasizing several technical considerations to avoid potential complications.

Keywords: cardiac surgery, left atrial myxoma, cardiac tumour, robotic resection

Procedia PDF Downloads 72

Authors: Yelin Zhao, Xinxiu Li, Martin Smelik, Oleg Sysoev, Firoj Mahmud, Dina Mansour Aly, Mikael Benson

Abstract:

Background: Early diagnosis of pancreatic cancer is clinically challenging due to vague, or no symptoms, and lack of biomarkers. Polygenic risk score (PRS) scores may provide a valuable tool to assess increased or decreased risk of PC. This study aimed to develop such PRS by filtering genetic variants identified by GWAS using transcriptional programs identified by single-cell RNA sequencing (scRNA-seq). Methods: ScRNA-seq data from 24 pancreatic ductal adenocarcinoma (PDAC) tumor samples and 11 normal pancreases were analyzed to identify differentially expressed genes (DEGs) in in tumor and microenvironment cell types compared to healthy tissues. Pathway analysis showed that the DEGs were enriched for hundreds of significant pathways. These were clustered into 40 “programs” based on gene similarity, using the Jaccard index. Published genetic variants associated with PDAC were mapped to each program to generate program PRSs (pPRSs). These pPRSs, along with five previously published PRSs (PGS000083, PGS000725, PGS000663, PGS000159, and PGS002264), were evaluated in a European-origin population from the UK Biobank, consisting of 1,310 PDAC participants and 407,473 non-pancreatic cancer participants. Stepwise Cox regression analysis was performed to determine associations between pPRSs with the development of PC, with adjustments of sex and principal components of genetic ancestry. Results: The PDAC genetic variants were mapped to 23 programs and were used to generate pPRSs for these programs. Four distinct pPRSs (P1, P6, P11, and P16) and two published PRSs (PGS000663 and PGS002264) were significantly associated with an increased risk of developing PC. Among these, P6 exhibited the greatest hazard ratio (adjusted HR[95% CI] = 1.67[1.14-2.45], p = 0.008). In contrast, P10 and P4 were associated with lower risk of developing PC (adjusted HR[95% CI] = 0.58[0.42-0.81], p = 0.001, and adjusted HR[95% CI] = 0.75[0.59-0.96], p = 0.019). By comparison, two of the five published PRS exhibited an association with PDAC onset with HR (PGS000663: adjusted HR[95% CI] = 1.24[1.14-1.35], p < 0.001 and PGS002264: adjusted HR[95% CI] = 1.14[1.07-1.22], p < 0.001). Conclusion: Compared to published PRSs, scRNA-seq-based pPRSs may be used not only to assess increased but also decreased risk of PDAC.

Keywords: cox regression, pancreatic cancer, polygenic risk score, scRNA-seq, UK biobank

Procedia PDF Downloads 101

Authors: Babak Masoomian, Masoud Khorrami Nejad, Hamid Riazi Esfahani

Abstract:

Purpose: To report the result of strabismus surgery in eye-salvaged retinoblastoma (Rb) patients. Methods: A retrospective case series including 18 patients with Rb and strabismus who underwent strabismus surgery after completing tumor treatment by a single pediatric ophthalmologist. Results: A total of 18 patients (10 females and 8 males) were included with a mean age of 13.3 ± 3.0 (range, 2-39) months at the time tumor presentation and 6.0 ± 1.5 (range, 4-9) years at the time of strabismus surgery. Ten (56%) patients had unilateral, and 8(44%) had bilateral involvement, and the most common worse eye tumor’s group was D (n=11), C (n=4), B (n=2) and E (n=1). Macula was involved by the tumors in 12 (67%) patients. The tumors were managed by intravenous chemotherapy (n=8, 47%), intra-arterial chemotherapy (n=7, 41%) and both (n=3, 17%). After complete treatment, the average time to strabismus surgery was 29.9 ± 20.5 (range, 12-84) months. Except for one, visual acuity was equal or less than 1.0 logMAR (≤ 20/200) in the affected eye. Seven (39%) patients had exotropia, 11(61%) had esotropia (P=0.346) and vertical deviation was found in 8 (48%) cases. The angle of deviation was 42.0 ± 10.4 (range, 30-60) prism diopter (PD) for esotropic and 35.7± 7.9 (range, 25-50) PD for exotropic patients (P=0.32) that after surgery significantly decreased to 8.5 ± 5.3 PD in esotropic cases and 5.9±6.7 PD in exotropic cases (P<0.001). The mean follow-up after surgery was 15.2 ± 2.0 (range, 10-24) months, in which 3 (17%) patients needed a second surgery. Conclusion: Strabismus surgery in treated Rb is safe, and results of the surgeries are acceptable and close to the general population. There was not associated with tumor recurrence or metastasis.

Keywords: retinoblastoma, strabismus, chemotherapy, surgery

Procedia PDF Downloads 61

Authors: K. Mardaleishvili, G. Loladze, G. Shatirishivili, D. Chakhunashvili, A. Vishnevskaya, Z. Kakabadze

Abstract:

Benign osteoblastoma is a benign tumor of the bone, usually affecting the vertebrae and long tubular bones. It is a rarely seen tumor of the facial bones. The authors present a case of a 28-year-old male patient with a tumor in mandibular body. The lesion was radically resected and histological analysis of the specimen demonstrated features typical of a benign osteoblastoma. The defect of the jaw was reconstructed with titanium implants and decellularized and lyophilized cattle bone matrix with mesenchymal bone marrow stem cells transplantation. This presentation describes the procedures for rehabilitating a patient with decellularized bone scaffold in the region of the face, recovering the facial contours and esthetics of the patient.

Keywords: facial bones, osteoblastoma, stem cells, transplantation

Procedia PDF Downloads 422

Authors: Chao Wu

Abstract:

Thioredoxin reductase 2 is a mitochondrial enzyme that belongs to the cellular defense against oxidative stress. We deleted mitochondrial Txnrd2 in a KrasG12D-driven pancreatic tumor model. Despite an initial increase in precursor lesions, tumor incidence decreased significantly. We isolated cancer cell lines from these genetically engineered mice and observed an impaired proliferation and colony formation. Reactive Oxygen Species, as determined by DCF fluorescence, were increased. We detected a higher mitochondrial copy number in Txnrd2-deficient cells (KTP). However, measurement of mitochondrial bioenergetics showed no impairment of mitochondrial function and comparable O₂-consumption and extracellular acidification rates. In addition, the mitochondrial complex composition was affected in Txnrd2 deleted cell lines. To gain better insight into the role of Txnrd2, we deleted Txnrd2 in clones from parental KrasG12D cell lines using Crispr/Cas9 technology. The deletion was confirmed by western blot and activity assay. Interestingly, and in line with previous RNA expression analysis, we saw changes in EMT markers in Txnrd2 deleted cell lines and control cell lines. This might help us explain the reduced tumor incidence in KrasG12D; Txnrd2∆panc mice.

Keywords: PDAC, TXNRD2, epithelial-to-mesenchymal-transition, ROS

Procedia PDF Downloads 122

Authors: Luciano Tarantino, Emanuele Balzano, Aurelio Nasto

Abstract:

S.R. 53 years. January 2009: HCV-related cirrhosis, Child-Pugh A5 class, EGDS no aesophageal Varices. No important comorbidities. Treated with PEG-IFN+Ribavirin (march-november 2009) with subsequent sustained virologic response. HCVRNA absent overtime. October 2016 :CT detected small HCC nodule in the VIII segment (diam.=12 mm). Treated with US guided RF-ablation. November 2016 CT: complete necrosis. Unfortunately, the patient dropped out US and CT follow-up controls.September 2018: asthenia and weight loss. CT showed a large tumor infiltrating V-VII-VI segments and complete PVTT of right portal vein and its branches . Surgical Consultation excluded indication to Liver resection and OLT . 23 october 2018: ECT of a large peri-hilar area of the tumor including the PVTT. 1 and 3 months post-treatment CT showed complete necrosis and retraction of the thrombus and residual viable tumor in the peripheral portion of the right lobe . Therefor, the patient was reevaluated for OLT and considered eligible in waiting list . March 2019: CT showed no perihilar or portal vein recurrence and distant progression in the right lobe . March 2019 : Trans-arterial-Radio-therapy (TARE) of the right lobe. Post-treatment CT demonstrated no perihilar or portal vein recurrence and extensive necrosis of the residual tumor . December 2019: CT demonstrated several recurrences of HCC infiltrating the VI and VII segment . Howewer no recurrence was observed at hepatic hilum and in portal vessels . Therefore, on February 2020 the patient received OLT. At 44 months follow-up, no complication or recurrence or liver disfunction have been observed.

Keywords: hepatocellular carcinoma, portal vein tumor thrombosis, interventional ultrasound, liver tumor ablation, liver transplantation

Procedia PDF Downloads 67

Authors: Samineh Barmaki, Ville Jokinen, Esko Kankuri

Abstract:

We report a microfluidic chip that can be used to modify the gaseous microenvironment of a cell-culture in ambient atmospheric conditions. The aim of the study is to show the cellular response to nitric oxide (NO) under hypoxic (oxygen < 5%) condition. Simultaneously targeting to hypoxic and nitric oxide will provide an opportunity for NO‑based therapeutics. Studies on cellular responses to lowered oxygen concentration or to gaseous mediators are usually carried out under a specific macro environment, such as hypoxia chambers, or with specific NO donor molecules that may have additional toxic effects. In our study, the chip consists of a microfluidic layer and a cell culture well, separated by a thin gas permeable polydimethylsiloxane (PDMS) membrane. The main design goal is to separate the gas oxygen scavenger and NO donor solutions, which are often toxic, from the cell media. Two different types of gas exchangers, titled 'pool' and 'meander' were tested. We find that the pool design allows us to reach a higher level of oxygen depletion than meander (24.32 ± 19.82 %vs -3.21 ± 8.81). Our microchip design can make the cells culture more simple and makes it easy to adapt existing cell culture protocols. Our first application is utilizing the chip to create hypoxic conditions on targeted areas of cell culture. In this study, oxygen scavenger sodium sulfite generates hypoxia and its effect on human embryonic kidney cells (HEK-293). The PDMS membrane was coated with fibronectin before initiating cell cultures, and the cells were grown for 48h on the chips before initiating the gas control experiments. The hypoxia experiments were performed by pumping of O₂-depleted H₂O into the microfluidic channel with a flow-rate of 0.5 ml/h. Image-iT® reagent as an oxygen level responser was mixed with HEK-293 cells. The fluorescent signal appears on cells stained with Image-iT® hypoxia reagent (after 6h of pumping oxygen-depleted H₂O through the microfluidic channel in pool area). The exposure to different levels of O₂ can be controlled by varying the thickness of the PDMS membrane. Recently, we improved the design of the microfluidic chip, which can control the microenvironment of two different gases at the same time. The hypoxic response was also improved from the new design of microchip. The cells were grown on the thin PDMS membrane for 30 hours, and with a flowrate of 0.1 ml/h; the oxygen scavenger was pumped into the microfluidic channel. We also show that by pumping sodium nitroprusside (SNP) as a nitric oxide donor activated under light and can generate nitric oxide on top of PDMS membrane. We are aiming to show cellular microenvironment response of HEK-293 cells to both nitric oxide (by pumping SNP) and hypoxia (by pumping oxygen scavenger solution) in separated channels in one microfluidic chip.

Keywords: hypoxia, nitric oxide, microenvironment, microfluidic chip, sodium nitroprusside, SNP

Procedia PDF Downloads 134

Authors: Nicole Ramlachan, Samuel Mark West

Abstract:

Lung cancer is the leading cause of cancer-associated deaths in North America, with the vast majority being non-small cell lung cancer (NSCLC), with a five-year survival rate of only 24%. Non-invasive discovery of biomarkers associated with early-diagnosis of NSCLC can enable precision oncology efforts using liquid biopsy-based multiomics profiling of plasma. Although tissue biopsies are currently the gold standard for tumor profiling, this method presents many limitations since these are invasive, risky, and sometimes hard to obtain as well as only giving a limited tumor profile. Blood-based tests provides a less-invasive, more robust approach to interrogate both tumor- and non-tumor-derived signals. We intend to examine 30 stage III-IV NSCLC patients pre-surgery and collect plasma samples.Cell-free DNA (cfDNA) will be extracted from plasma, and next-generation sequencing (NGS) performed. Through the analysis of tumor-specific alterations, including single nucleotide variants (SNVs), insertions, deletions, copy number variations (CNVs), and methylation alterations, we intend to identify tumor-derived DNA—ctDNA among the total pool of cfDNA. This would generate data to be used as an accurate form of cancer genotyping for diagnostic purposes. Using liquid biopsies offer opportunities to improve the surveillance of cancer patients during treatment and would supplement current diagnosis and tumor profiling strategies previously not readily available in Trinidad and Tobago. It would be useful and advantageous to use this in diagnosis and tumour profiling as well as to monitor cancer patients, providing early information regarding disease evolution and treatment efficacy, and reorient treatment strategies in, timethereby improving clinical oncology outcomes.

Keywords: genomics, multiomics, clinical genetics, genotyping, oncology, diagnostics

Procedia PDF Downloads 161

Authors: Tanushree Jaitly, Shailendra Gupta, Leila Taher, Gerold Schuler, Julio Vera

Abstract:

Genomics-based personalized medicine is a promising approach to fight aggressive tumors based on patient's specific tumor mutation and expression profiles. A remarkable case is, dendritic cell-based immunotherapy, in which tumor epitopes targeting patient's specific mutations are used to design a vaccine that helps in stimulating cytotoxic T cell mediated anticancer immunity. Here we present a computational pipeline for epitope-based personalized cancer vaccines using patient-specific haplotype and cancer mutation profiles. In the workflow proposed, we analyze Whole Exome Sequencing and RNA Sequencing patient data to detect patient-specific mutations and their expression level. Epitopes including the tumor mutations are computationally predicted using patient's haplotype and filtered based on their expression level, binding affinity, and immunogenicity. We calculate binding energy for each filtered major histocompatibility complex (MHC)-peptide complex using docking studies, and use this feature to select good epitope candidates further.

Keywords: cancer immunotherapy, epitope prediction, NGS data, personalized medicine

Procedia PDF Downloads 253

Authors: A. D. Zikiryahodjaev, L. V. Bolotina, A. S. Sukhotko

Abstract:

Purpose. To evaluate the expediency and timeliness of performance of surgical treatment as a component of multi-therapy treatment of patients with stage IV breast cancers. Materials and Methods. This investigation comparatively analyzed the results of complex treatment with or without surgery in patients with metastatic breast cancer. We analyzed retrospectively treatment experience of 196 patients with generalized breast cancer in the department of oncology and breast reconstructive surgery of P.A. Herzen Moscow Cancer Research Institute from 2000 to 2012. The average age was (58±1,1) years. Invasive ductul carcinoma was verified in128 patients (65,3%), invasive lobular carcinoma-33 (16,8%), complex form - 19 (9,7%). Complex palliative care involving drug and radiation therapies was performed in two patient groups. The first group includes 124 patients who underwent surgical intervention as complex treatment, the second group includes 72 patients with only medical therapy. Standard systemic therapy was given to all patients. Results. Overall, 3-and 5-year survival in fist group was 43,8 and 21%, in second - 15,1 and 9,3% respectively [p=0,00002 log-rank]. Median survival in patients with surgical treatment composed 32 months, in patients with only systemic therapy-21. The factors having influencing an influence on the prognosis and the quality of life outcomes for of patients with generalized breast cancer were are also studied: hormone-dependent tumor, Her2/neu hyper-expression, reproductive function status (age, menopause existence). Conclusion.Removing primary breast tumor in patients with generalized breast cancer improve long-term outcomes. Three- and five-year survival increased by 28,7 and 16,3% respectively, and median survival–for 11 months. These patients may benefit from resection of the breast tumor. One explanation for the effect of this resection is that reducing the tumor load influences metastatic growth.

Keywords: breast cancer, combination therapy, factors of prognosis, primary tumor

Procedia PDF Downloads 416

Authors: Kristina Jansen, Maximilian Lennartz, Patrick Lebok, Guido Sauter, Ronald Simon, David Dum, Stefan Steurer

Abstract:

DOG1 (Discovered on GIST1) is a voltage-gated calcium-activated chloride and bicarbonate channel that is highly expressed in interstitial cells of Cajal and in gastrointestinal stromal tumors (GIST) derived from Cajal cells. To systematically determine in what tumor entities and normal tissue types DOG1 may be further expressed, a tissue microarray (TMA) containing 15,965 samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. DOG1 immunostaining was found in 67 tumor types, including GIST (95.7%), esophageal squamous cell carcinoma (31.9%), pancreatic ductal adenocarcinoma (33.6%), adenocarcinoma of the Papilla Vateri (20%), squamous cell carcinoma of the vulva (15.8%) and the oral cavity (15.3%), mucinous ovarian cancer (15.3%), esophageal adenocarcinoma (12.5%), endometrioid endometrial cancer (12.1%), neuroendocrine carcinoma of the colon (11.1%) and diffuse gastric adenocarcinoma (11%). Low level-DOG1 immunostaining was seen in 17 additional tumor entities. DOG1 expression was unrelated to histopathological parameters of tumor aggressiveness and/or patient prognosis in cancers of the breast (n=1,002), urinary bladder (975), ovary (469), endometrium (173), stomach (233), and thyroid gland (512). High DOG1 expression was linked to estrogen receptor expression in breast cancer (p<0.0001) and the absence of HPV infection in squamous cell carcinomas (p=0.0008). In conclusion, our data identify several tumor entities that can show DOG1 expression levels at similar levels as in GIST. Although DOG1 is tightly linked to a diagnosis of GIST in spindle cell tumors, the differential diagnosis is much broader in DOG1 positive epithelioid neoplasms.

Keywords: biomarker, DOG1, immunohistochemistry, tissue microarray

Procedia PDF Downloads 216

Authors: Md Abdullah Al Mashud, M. Tariquzzaman, M. Jahangir Alam, Tapan Kumar Godder, M. Mahbubur Rahman

Abstract:

This paper presents a Monte Carlo (MC) method-based dose distributions on lung tumor for 6 MV photon beam to improve the dosimetric accuracy for cancer treatment. The polystyrene which is tissue equivalent material to the lung tumor density is used in this research. In the empirical calculations, TRS-398 formalism of IAEA has been used, and the setup was made according to the ICRU recommendations. The research outcomes were compared with the state-of-the-art experimental results. From the experimental results, it is observed that the proposed based approach provides more accurate results and improves the accuracy than the existing approaches. The average %variation between measured and TPS simulated values was obtained 1.337±0.531, which shows a substantial improvement comparing with the state-of-the-art technology.

Keywords: lung tumour, Monte Carlo, polystyrene, Elekta synergy, Monaco planning system

Procedia PDF Downloads 445

Authors: Zoe Goldberger, Priscilla S. Briquez, Jeffrey A. Hubbell

Abstract:

Tumor cells have mutations resulting from genetic instability that the immune system can actively recognize. Immune checkpoint immunotherapy (ICI) is commonly used in the clinic to re-activate immune reactions against mutated proteins, called neoantigens, resulting in tumor remission in cancer patients. However, only around 20% of patients show durable response to ICI. While tumor mutational burden (TMB) has been approved by the Food and Drug Administration (FDA) as a criterion for ICI therapy, the relevance of the subcellular localizations of the mutated proteins within the tumor cell has not been investigated. Here, we hypothesized that localization of mutations impacts the effect of immune responsiveness to ICI. We analyzed publicly available tumor mutation sequencing data of ICI treated patients from 3 independent datasets. We extracted the subcellular localization from the UniProtKB/Swiss-Prot database and quantified the proportion of membrane, cytoplasmic, nuclear, or secreted mutations per patient. We analyzed this information in relation to response to ICI treatment and overall survival of patients showing with 1722 ICI-treated patients that high mutational burden localized at the membrane (mTMB), correlate with ICI responsiveness, and improved overall survival in multiple cancer types. We anticipate that our results will ameliorate predictability of cancer patient response to ICI with potential implications in clinical guidelines to tailor ICI treatment. This would not only increase patient survival for those receiving ICI, but also patients’ quality of life by reducing the number of patients enduring non-effective ICI treatments.

Keywords: cancer, immunotherapy, membrane neoantigens, efficacy prediction, biomarkers

Procedia PDF Downloads 109