Ajay Srinivasan's research while affiliated with Datar Genetics Limited and other places

Publications (77)

Article
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Background: The low specificity of serum PSA resulting in the inability to effectively differentiate prostate cancer from benign prostate conditions is a persistent clinical challenge. The low sensitivity of serum PSA results in false negatives and can miss high-grade prostate cancers. We describe a non-invasive test for detection of prostate canc...
Article
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Purpose The selection of safe and efficacious anticancer regimens for treatment of patients with broadly refractory metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling...
Preprint
Backround Diagnosis of primary glial malignancies (GLI-M) in individuals presenting with Intracranial Space Occupying Lesions (ICSOL) is based on histopathological evaluation (HPE) of tissue obtained by surgical resection or biopsy with attendant resource implications and risks. Approximately 70% of ICSOLs have non-malignant etiology and distinctio...
Article
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Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDF...
Article
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Biomarker directed selection of targeted anti-neoplastic agents such as immune checkpoint inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant b...
Preprint
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Background Evaluation of serum prostate specific antigen (PSA) is a part of standard prostate cancer diagnostic work-up in symptomatic males as well as for elective prostate cancer screening in asymptomatic males. The low specificity of serum PSA leading to an inability to effectively differentiate prostate cancer from benign prostate conditions is...
Preprint
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BACKGROUND Screening of asymptomatic women for early detection of Breast Cancer (BrC) is associated with improved survival. Presently, mammography is the standard of care (SoC) for BrC screening but has lower accuracy for invasive cancers as well as in women with higher breast tissue density. METHODS In this manuscript, we describe an accurate blo...
Preprint
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Real time monitoring of disease status is an essential part of cancer management. The low sensitivity and specificity of serum markers and the constraints and risks associated with radiological scans prompt the need for accurate non-invasive means to monitor minimal residual disease (MRD) in solid tumors. In this study we describe MRD evaluation vi...
Preprint
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Biomarker directed selection of targeted anti-neoplastic agents such as immune check-point inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant...
Preprint
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Abstarct Prior attempts at personalizing anticancer treatments based on univariate tumor profiling (‘single gene variant’) for selection of monotherapy with targeted agents (‘single drug’) have generally yielded poor response rates. We report findings from the LIQUID IMPACT pilot trial where Multi-analyte Liquid Biopsy (MLB) profiling of circulatin...
Article
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Angiogenesis inhibitors (AGI) are not presently used for the treatment of gastric cancers. This report demonstrates that angiogenesis inhibitor can be safely and effectively used in combination with cytotoxic anti-cancer agents for treatment of Gastric cancers.
Preprint
We report a case of an advanced refractory Gastric AD which responded favourably to a combination regimen of AGI and other chemotherapy agents which were selected on the basis of multi-analyte tumor profiling. The treatment was well tolerated with transient manageable adverse events and yielded radiological partial response.
Article
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Background: Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with A...
Article
3047 Background: Immunohistochemistry (IHC) profiling of tumor tissue is the present standard for evaluation of therapeutically relevant biomarkers such as ER, PR, HER2, AR, ARv7, PD-L1 and MMR for selection of targeted, endocrine and checkpoint inhibitor therapy selection. However, this critical analysis is dependent on availability of tumor tissu...
Article
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Introduction: Encyclopedic Tumor Analysis (ETA) is multi-analyte, molecular and functional interrogation to identify latent vulnerabilities in solid tumors which can then be targeted in organ-and label-agnostic combination treatment regimens. Case Presentation: We describe here a case of metastatic rectal cancer in a 61-year-old male who was progre...
Conference Paper
Background: trucheckTM is a non-invasive micro-biopsy-like approach for diagnostic triaging of symptomatic individuals suspected of Breast Cancer. trucheckTM is based on the detection of Circulating Ensembles of Tumor Associated Cells (C-ETACs: EpCAM⁺, Pan-CK⁺, CD45±) of Breast Cancer origin (GCDFP15⁺, GATA3⁺); such C-ETACs are ubiquitous in blood...
Conference Paper
Background: Despite the development of Checkpoint Inhibitor Treatments (Immunotherapy) and Targeted anticancer agents, cytotoxic (chemotherapy) agents remain the mainstay of breast cancer treatments. However, treatment failure is often encountered in breast cancers owing to innate or acquired chemoresistance. Real time monitoring of inherent or inc...
Conference Paper
Background: Common modalities for breast cancer screening include self-breast examination (SBE) for detection of palpable lumps as well as Mammography scans for detection of suspicious nodules or masses. While both approaches have low specificity, SBE has lower sensitivity for early stage cancers while mammography is associated with radiation expos...
Article
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Background: Diagnosis of lung cancer in suspected individuals is based on histopathological examination (HPE) of tumor tissue obtained by an invasive biopsy. However, lung biopsies are associated with various procedural risks and may often not be possible owing to anatomical considerations as well as patient co-morbidities. It is also estimated tha...
Article
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We present data on analytical validation of the multigene variant profiling assay (CellDx) to provide actionable indications for selection of targeted and immune checkpoint inhibitor (ICI) therapy in solid tumors. CellDx includes Next Generation Sequencing (NGS) profiling of gene variants in a targeted 452-gene panel as well as status of total Tumo...
Article
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Ovarian cancer is common gynaecological malignancy and a leading cause of death among women. Despite the advances in treatment strategies, majority of patients present with recurrence after first- or second-line treatment. Targeted therapy that has proven to be effective in other advanced or metastatic solid tumors have also demonstrated its effica...
Article
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Periampullary adenocarcinomas are rare neoplasm that originates from the pancreatic head, the ampulla of vater, the distal bile duct or the duodenum. Surgical resection followed by adjuvant therapy is considered as the standard of care treatment for these carcinomas. Despite several advances in diagnostics and therapeutics, only 5% of these patient...
Article
The diagnosis of Central Nervous System (CNS) malignancies such as Gliomas in individuals presenting with Intracranial Space Occupying Lesions (ICSOL) is based on histopathological examination (HPE) of tumor tissue obtained by an invasive brain biopsy. However, brain biopsies are resource intensive and are associated with procedural risks such as h...
Conference Paper
The success of treatment in solid organ cancers is ascertained by radiologic imaging as per standard-of-care protocol, with PET-CT being the modality of choice. However, even in cases where complete resolution of the disease is noted radiologically, recurrence or emergence of new metastases is not uncommon. To explore the underlying cause of such r...
Conference Paper
p>Differential diagnosis of prostatic adenocarcinomas is based on histopathologic analysis of tumor tissue obtained by transrectal ultrasound (TRUS)-guided biopsies. However, such invasive biopsies are associated with pain, procedural expenses, sequelae, and risk of complications. Though immunocytochemistry (ICC) profiling of circulating tumor cell...
Conference Paper
p>Definitive diagnosis of solid organ cancers is based on histopathologic analysis of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural expenses, sequelae, and risks. Though immunocytochemistry (ICC) profiling of circulating tumor cells (CTCs) has been previously attempted for diagnosis in some ca...
Conference Paper
Diagnosis of ovarian adenocarcinomas is based on histopathologic analysis of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural expenses, sequelae, and risk of complications. Though immunocytochemistry (ICC) profiling of circulating tumor cells (CTCs, defined as EpCAM+, panCK+, CD45-) has been prev...
Conference Paper
p>Diagnosis of suspected cases of gliomas such as intracranial space-occupying lesions (ICSOLs) is based on histopathologic analysis of tumor tissue obtained by invasive biopsies, which are, however, associated with risk of serious complication, high rates of mortality, procedural expenses, sequelae, and other risks. Liquid biopsy (LB)-based noninv...
Article
3525 Background: Despite the development of targeted therapy agents and immune checkpoint inhibitors (ICI), cytotoxic anticancer agents remain the mainstay of treatment in several solid organ cancers. However, instances of innate and acquired resistance towards these anticancer agents can lead to treatment failures, which remain undetectable until...
Article
3544 Background: There are presently no accepted non-invasive means for detection of cancers in asymptomatic individuals or suspected cases. Radiological and serological investigations, though non-invasive, are not confirmatory and necessitate an invasive biopsy to establish malignant status of suspected findings. Invasive biopsies, in turn, face c...
Article
e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (prec...
Article
e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies f...
Article
Background: Post failure of 3 lines of systemic treatments in breast cancers, Standard of Care guidelines recommend palliative care or clinical trials for such patients. We retrospectively evaluated the efficacy of ultra-personalized treatment in a cohort of patients (n = 27) with advanced refractory breast cancers. These patients had availed of En...
Article
718 Background: Detection of genitourinary cancers is based on histopathological analysis of tumor tissue obtained by invasive biopsies following manifestation of clinical or radiological symptoms. There is presently no non-invasive blood-based test with high specificity and sensitivity for detection of genitourinary cancers. Considering that unpro...
Conference Paper
Background: Mammographic screening for breast cancer offers the possibility of reducing morbidity and mortality from the disease but has economic and safety implications. Thromboembolism is a well-recognized, potentially life-threatening complication of cancer. Detection and characterization of tumour emboli comprising Circulating Ensembles of Tumo...
Conference Paper
Background: Chemoresistance in cancer cells is the underlying reason for treatment failure. Real-time monitoring of chemoresistance and response (CRR) is a fundamental but unmet prerequisite of precision oncology. Repetitive invasive biopsies to obtain tumor tissue for in-vitro CRR profiling are neither feasible nor advisable. Circulating Tumor Ass...
Conference Paper
Oncological orthodoxy holds that (metastatic) breast cancer is an incurable disease. Response evaluation in metastatic breast cancer is determined by clinical, biochemical and radiological parameters, FDG PET CT being the imaging modality of choice for most types of breast cancer. However, even in cases where FDG PET CT and/or normalisation of seru...
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36 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Head and Neck cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been...
Article
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29 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Gastroesophageal cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have b...
Article
194 Background: Resistance to combination regimens of fluorouracil, oxaliplatin and irinotecan are commonly observed in Colorectal cancers (CRC). There are presently no viable approaches for ‘real-time’ monitoring of innate and acquired chemoresistance. We used a novel method for chemo-interrogation (CI) by harvesting from peripheral blood sufficie...
Article
808 Background: CEA and CA19-9 are non-specific markers for Gastrointestinal (GI) cancers. Molecular analysis of fecal blood is of limited utility in colorectal cancers. A non-invasive pan-GI-cancer blood-based test with high specificity and sensitivity is an unmet medical need. Considering that unprovoked thromboembolism is a significant risk in m...
Article
799 Background: Definitive diagnosis of gastrointestinal (GI) malignancies is reliant on histopathological examination of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural risks, complications and expenses. A non-invasive technique for diagnosis of GI cancers is presently unavailable. Here we pres...
Conference Paper
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Abstract Background Selection of Checkpoint Inhibitor therapies in several cancers are based on PD-L1 expression in tumor tissue determined by IHC. Invasive biopsy to obtain tumor tissue is associated with procedural risks, sequelae and expenses. Though PD-L1 profiling of Circulating Tumor Cells (CTCs) has been attempted previously, limitations ari...
Article
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Circulating Ensembles of Tumor Associated Cells (C-ETACs) which comprise tumor emboli, immune cells and fibroblasts pose well-recognized risks of thrombosis and aggressive metastasis. However, the detection, prevalence and characterization of C-ETACs has been impaired due to methodological difficulties. Our findings show extensive pan-cancer preval...
Article
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Brain metastasis in solid organ cancers is associated with adverse prognosis, which is further aggravated by limited systemic treatment options. Such patients are also often excluded from clinical trials since their poor prognosis is perceived to unfavorably impact trial outcomes and misrepresent efficacy data. We retrospectively evaluated the effi...
Article
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Survival of high-grade glioma patients remains dismal due to onset of resistance to even the limited systemic treatment option currently available. Except for indirect prediction of alkylating agent Temozolomide response through MGMT promotor methylation and NTRK fusions for larotrectinib, there are no biomarkers available for drug response predict...
Article
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Invasive procedures for diagnosis of CNS malignancies carry inherent risks of high morbidity and mortality. Although circulating biomarkers such as cell free DNA (cfDNA) and microvesicle (MV) borne nucleic acids have been proposed as potential diagnostic aids, their stand-alone utility has inherent limitations. However, Circulating Glial Cells (CGC...
Article
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Background Hormone and Growth Factor Receptors (HR) such as ER, PR, HER2 and AR are involved in the pathogenesis of various cancers and are commonly targeted in treatment regimens. HR antagonists Standard of Care (SoC) are often administered as monotherapy or as combinations with selected cytotoxic or targeted agents. In the SHIVA trial, monotherap...
Article
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Background Though mTOR inhibition is considered an attractive strategy for cancer management, anti-mTOR monotherapies have not shown meaningful benefits. We hypothesized that an Encyclopedic Tumor Analysis (ETA) can identify vulnerabilities in the tumor in addition to mTOR activation. We further hypothesized that tandem synergistic targeting of the...
Article
Background Innate and acquired chemoresistance to anticancer therapies are a well-known phenomenon in Esophageal Squamous Cell Carcinomas (ESCC). There are presently no viable approaches for real-time monitoring of resistance in ESCC. We used a novel method for chemo-interrogation (CI) by harvesting sufficient number of Circulating-Tumor Associated...
Article
Background Refractory cancers pose formidable management challenges. We hypothesized that such malignancies have unexplored vulnerabilities that can be identified using Encyclopedic Tumor Analysis (ETA) and effectively targeted using conventional agents in a label- and organ-agnostic manner to yield treatment benefit. The pan-cancer RESILIENT trial...
Article
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Background Head and Neck Squamous Cell Carcinomas (HNSCC) account for 4.5% of global cancer incidences and mortality respectively. In India however, HNSCC accounts for 17% of cancer related incidences and 15% of cancer related mortality. Standard of Care (SoC) systemic treatment approaches for HNSCC are based on randomized clinical trials which do...
Article
115 Background: Androgen Receptor (AR) antagonists have been the mainstay of prostate cancer treatments. However, there is increasing interest in the use of anti-AR agents in treatment of other cancers such as Triple Negative Breast Cancer and Lung Cancer. AR antagonists are usually administered as single agents and rarely in combination with other...
Article
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Background Platins are used extensively to treat Solid Organ Cancers like Ovarian, Breast, Colorectal, Lung, Pancreatic and Bladder Cancer. Eventually however, most cancer patients develop resistance to these treatments. As presently, no assay is available to non-invasively determine the onset of resistance to platinum drugs, the lethal evolution i...
Article
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Background Anti-angiogenic agents are approved for treatment of various cancers like Colon, Ovary, Breast, Glioma, Lung, Kidney and Liver. Axitinib, a selective inhibitor of Vascular Endothelial Growth Factor Receptors (VEGFR 1 / 2 / 3) was initially approved as a single agent for treatment of advanced Renal Cell Carcinomas (RCC), following failure...
Article
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Copyright: Nagarkar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT RESILIENT (CTRI/2018/02/011808) was a single arm, open label,...

Citations

... The latter surgical approach removes the interface zone in its entirety. We believe this observation is related to the emerging understanding that breast cancer is a systemic disease, even in its early stages, as supported by the detection of circulating tumor cells [3]. These cells, when reactivated, can infiltrate the index breast quadrant and cause local recurrence near the interface zone. ...
... 58 The expression of PD-L1 on circulating tumor cells may also be a reliable predictive biomarker. 60 PD -L 1 expression in conventional immunohistochemistry assays lacks accuracy and reliability as the staining of cytoplasmic proteins interferes with cell membrane protein estimation. 61 ...
... Paired analysis of patient plasma from ctDNA using a targeted approach, like molecular tag-based sequencing, may reveal concordant mutations with the tumor tissue that could be used for disease monitoring during follow-up. In a recent study that monitored patient-specific ctDNA across a diverse set of tumors, the authors found that for patients (n=40) with three or more longitudinal time points the patient-specific ctDNA had a correlation with tumor burden in 16/19 (85%) patients with partial response and overall in 27/40 (68%) patients 162 . On the other hand, use of cancer antigens only correlated with tumor burden in 19/40 (47.5%) patients, suggesting a lower utility than patient-specific ctDNA. ...
... However, parental VQ-D2 cells show little to no expression of FGFR1-4 at the mRNA level, comparable to control plasma cells ( Figure S6A) and do not harbor any mutations in FGFR1-4 either (our unpublished results). To determine if FGFR inhibition plays a role in Pon efficacy, we next tested the FGFR1 inhibitor sorafenib 17 , the FGFR1-3 inhibitor pazopanib 18 , and the pan-FGFR inhibitors dovitinib and lenvatinib 19,20 in our VQ MM cell lines. Similar as other TKIs tested in the AOD IX panel, none of the FGFR inhibitors displayed single agent efficacy at 100 nM and 1000 nM or in combination with Tra ( Figure S6B), suggesting that the efficacy of Pon in VQ MM cells is not primarily mediated through FGFR signaling. ...
... Inhibitors targeting PDGFR, VEGFR, or FGFR family receptors and Ret: Tumor angiogenesis is a hallmark of cancer. Several growth factors and their receptors, such as platelet-derived growth factor (PDGF)/PDGFR, vascular endothelial growth factor (VEGF)/VEGFR, fibroblast growth factor (FGF)/FGFR, stem cell factor (SCF)/c-Kit, glial cell line-derived neurotrophic factor (GDNF)-family ligands/ rearranged during transfection (RET), and angiopoietin/Tie 22,111 , regulate the growth, differentiation and migration of cancer cells and angiogenic activities of vascular endothelial cells 22,111 . PDGFs are members of the 'cysteine knot' growth factor superfamily, the members of which contain at least three disulfide bridges and forms homo-or heterodimers 112 . ...
... We used synthetic androgen, R1881 in our co-culture study to test the adhesion of fallopian tube cells to the ovary since the ovary expresses aromatase and could metabolize testosterone to estrogen. Bicalutamide, an anti-androgen, was not consistently successful in treating ovarian cancer in early clinical trials, although second generation enzalutamide is now being evaluated in phase II clinical trials [50,51]. The effects of bicalutamide on reducing ovarian cancer cell proliferation are less significant after treatment with chemotherapeutic due to reduced levels of AR [49]; therefore, the use of anti-androgen should be considered based on expression of AR and may be more impactful prior to other chemotherapy or as cancer prevention. ...
... Currently, common gene mutations associated with PACs include oncogenic mutations of KRAS, BRAF, and HER2 [62], among which KRAS is the most common oncogenic mutant in PACs with common mutation sites including G12D, G12V, G13D, G12C, G12N, G12S, G12A, and G12R [62]. Trastuzumab can be used as a targeted therapy for HER2 positive mutations, and various studies have demonstrated the presence of HER2 amplification or overexpression in 0-23.0% of PAC patients [64]. One study showed that insertion mutations in BRCA2 at c.156_157ins Alu are found in 12.5% of Portuguese patients with PACs, indicating that these patients may benefit from a treatment with the PARP inhibitor [62]. ...
... There is evidence showing that exosomes are closely related to lung carcinogenesis by playing a key role in the growth and progression of lung malignancies through tumor angiogenesis and EMT [93]. Several studies have demonstrated how the use of exosomes and exosomal RNA, combined with ctDNA and proteins, is giving rise to a multi-analyte approach that is very advantageous in terms of sensitivity to the detection of mutations [94][95][96][97][98]. This is demonstrated in Krug AK and colleagues' studies [96,97], in which they reported how it is possible to obtain up to 10 times more copies of the mutation by combining the data coming from both the exosomal RNA and the ctDNA compared to the single use of ctDNA, allowing detection of the disease in the early stages. ...
... Bcl-2 is an important antiapoptotic factor, functioning in the mitochondrial pathway to inhibit cell apoptosis. The process of tumor cell apoptosis is abnormal and provides an opportunity for the malignant transformation of cells (12). Nougarede et al. (13) found that Bcl-2 was highly expressed in esophageal cancer, which plays an important role in tumorigenesis and development. ...
... The appearance of CTCs is the premise and basis for distant metastasis [5,6]. Consequently, the detection of CTCs in peripheral blood of patients with tumor is of great clinical significance in early diagnosis, disease progression and prognosis judgment, and real-time monitoring of curative effects of breast cancer, colorectal cancer, lung cancer, gastric cancer, liver cancer, pancreatic cancer, etc. [7][8][9][10][11][12]. ...