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Discover the most talked about and latest scientific content & concepts.

Journal: Expert review of anticancer therapy

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The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence. Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics. Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using “liquid biopsy”.

Concepts: Cancer, Mutation, Signal transduction, Therapy, Receptor tyrosine kinase, Protein kinase, Gastrointestinal stromal tumor, Growth factor receptor

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Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients' ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex. Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC. Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.

Concepts: Medicine, Cancer, Disease, Cure, Chemotherapy, Therapy, Classification of Pharmaco-Therapeutic Referrals, Ovarian cancer

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The adoption of liquid biopsies (LB) has modified the care of patients with late stage non-small-cell lung cancer (NSCLC). LB are used routinely in clinical practice in two situations for these patients, i) at the initial diagnosis when looking for activating mutations in EGFR in the absence of analyzable or available tissue DNA and, ii) during tumor progression on a tyrosine kinase inhibitor (TKI) treatment to look for the resistance mutation T790M in EGFR. Treatment with TKI may be adapted after detection of mutations using circulating cell-free DNA in plasma. However, despite promising research, LB are not presently recommended in daily practice for the diagnosis of NSCLC. Areas covered: This article reports the diagnosis of a NSCLC in a non-smoker patient with bilateral ocular metastases after detection of a deletion in exon 19 of EGFR when using plasma DNA. Detection of this mutation thereby resulted in treatment with TKI. Without histological analysis, the origin of the primary ocular metastasis was uncertain. In this context, a LB showing an activating mutation in EGFR and circulating tumor cells positive for TTF1 led to the diagnosis of NSCLC and targeted therapy. Expert commentary: When no tumor tissue sample is available a LB can be used to diagnose for metastatic NSCLC, when a mutation in EGFR is identified, and with subsequent delivery of targeted treatment for this mutation. While a tissue biopsy is still the gold standard approach for the diagnosis of a NSCLC and for identification of activating mutations that can be treated with targeted therapy, this case report shows that LB can exceptionally provide both a diagnosis of the primitive tumor and indicate appropriate therapies based on a molecular analysis.

Concepts: DNA, Cancer, Metastasis, Oncology, Lung cancer, Non-small cell lung carcinoma, Adenocarcinoma, Medical test

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Chimeric antigen receptor modified T cell (CAR-T) therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. Nevertheless, this success has not yet been extrapolated to solid tumors. This review focuses on new clinical regimens that could improve the therapeutic efficacy of CAR-T in solid tumors. Areas covered: Herein, the authors reviewed recent clinical trials using CAR-T therapies for the treatment of solid tumors. Specifically, this review covered the following areas: (1) the current status of CAR-T cells in the treatment of solid tumors; (2) the major factors constraining the efficacy of CAR-T cells in solid tumors; and (3) opinions regarding the future of CAR-T as a treatment for solid tumors. Expert commentary: While some recent studies have shown promising results, the ultimate success of CAR-T therapies in solid tumor patients will require the following improvements to clinical regimens: (1) local delivery of CAR-T cells; (2) combination of CAR-T cells with chemotherapeutic drugs to treat metastatic tumors; (3) combination of CAR-T with immune checkpoint inhibitors; (4) combination therapy using CAR-T cells targeting two different antigens; and (5) the use of CAR-T as a strategy to prevent tumor recurrence and metastasis after radical resection.

Concepts: Immune system, Protein, Cancer, Metastasis, Oncology, Benign tumor, Tumor, Neoplasm

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This study aimed to evaluate the prognostic value of the combination of serum levels of vascular endothelial growth factor (VEGF), C-reactive protein (CRP), and contrast-enhanced ultrasound (CEUS) in patients with primary liver cancer (PLC) after transcatheter arterial chemoembolization (TACE).

Concepts: Immune system, Cancer, Angiogenesis, Vascular endothelial growth factor, Hepatocellular carcinoma, Hepatology, C-reactive protein, Transcatheter arterial chemoembolization

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Colorectal cancer (CRC) is the third most common cancer in males and second in females, and the fourth most common cause of cancer death worldwide. Currently, about 60-70% of diagnosed cases in symptomatic patients are detected at an advanced stage of disease. Earlier stage detection through the use of screening strategies would allow for better outcomes in terms of reducing the disease burden. Areas covered: The aim of this paper is to review the current published evidence from literature which assesses the performance and effectiveness of different screening tests for the early detection of CRC. Expert commentary: Adequate screening strategies can reduce CRC incidence and mortality. In the last few decades, several tests have been proposed for CRC screening. To date, there is still insufficient evidence to identify which approach is definitively superior, and no screening strategy for CRC can therefore be defined as universally ideal. The best strategy would be the one that can be economically viable and to which the patient can adhere best to over time. The latest guidelines suggest colonoscopy every 10 years or annual fecal immuno-chemical test (FIT) for people with normal risk, while for individuals with high risk or hereditary syndromes specific recommendations are provided.

Concepts: Game theory, Epidemiology, Cancer, Patient, The Canon of Medicine, Colorectal cancer, Ulcerative colitis, Sigmoidoscopy

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The development of novel targeted treatment in soft tissue sarcomas (STS) is important since many sarcoma subtypes are resistant to conventional chemotherapy and effective therapeutic options are limited. Areas covered: This review discusses the molecular background and treatment in two STS types which became a model for targeted therapy - gastrointestinal stromal tumor (GIST) and dermatofibrosarcoma protuberans (DFSP). DFSP is characterized, in the majority of cases, by chromosomal translocation which results in the formation of COL1A1-PDGFB fusion gene causing platelet-derived growth factor receptor beta(PDGFRB) signaling activation in tumor cells. The majority of GIST malignancies are associated with activating, constitutive, mutually exclusive mutations of two genes: KIT and PDGFRA (PDGF receptor-alpha). Molecular diagnostics are an essential part of GIST and DFSP management. The first effective systemic therapy introduced into clinical practice in GIST and DFSP was imatinib - tyrosine kinase inhibitor acting on KIT and PDGFR alpha/beta. Use of the drug revolutionized treatment of inoperable and/or metastatic cases and demonstrated dramatic activity in locally advanced cases. This review summarizes the analogies of therapy and perspectives of GIST and DFSP management. Expert commentary: The next generation of kinase inhibitors are approved for use after the progression of GIST during imatinib treatment. However, little is still known about treatment beyond progression in DFSP.

Concepts: Cancer, Oncology, Soft tissue sarcoma, Chromosomal translocation, Imatinib, Gastrointestinal stromal tumor, Sarcoma, Dermatofibrosarcoma protuberans

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In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response. Areas Covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach. Expert Commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.

Concepts: Cancer, Oncology, Chernobyl disaster, Anatomical pathology, Benign tumor, Tumor, Neoplasm, Protein kinase

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With level 1 evidence now available on the diagnostic accuracy of multiparametric magnetic resonance imaging (MRI) we must now utilise this data in developing an MRI-stratified diagnostic pathway for the early detection of prostate cancer. Areas covered: A literature review was conducted and identified seven randomised control trials (RCT’s) assessing the diagnostic accuracy of such a pathway against the previously accepted systematic/random trans-rectal ultrasound guided (TRUS) biopsy pathway. The studies were heterogeneous in their design. Five studies assessed the addition of MRI-targeted biopsies to a standard care systematic TRUS biopsy pathway. Three of these studies showed either an increase in their diagnostic accuracy or the potential to remove systematic biopsies. Two studies looked specifically at a targeted biopsy only pathway and although the results were again mixed, there was no decrease in the diagnostic rate and overall significantly fewer biopsy cores were taken in the MRI group. Expert commentary: Results from these RCT’s together with multiple retrospective and prospective studies point towards either an improved diagnostic rate for clinically significant cancer and/or a reduction in the need for systematic biopsies with a MRI-stratified pathway. The challenge for the urological community will be to implement pre-biopsy MRI into a routine clinical pathway with likely independent monitoring of standards.

Concepts: Cancer, Oncology, Prostate cancer, Urology, Brain tumor, Nuclear magnetic resonance, Magnetic resonance imaging, Ultrasound

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Approximately 15-30% of men with localized prostate cancer will experience biochemical recurrence (BCR) after radical prostatectomy. Postoperative radiation therapy is used in men with adverse pathological features to reduce the risk of BCR or with curative intent in men with known BCR. In this study, we review the evidence for the adjuvant and salvage radiation therapy after radical prostatectomy. Areas covered: A literature review of the Medline and Embase databases was performed. The search strategy included the following terms: prostate cancer, adjuvant radiotherapy, salvage radiotherapy, radical prostatectomy, biochemical recurrence, and prostate cancer recurrence. Prospective randomized trials for the adjuvant radiotherapy and observational studies supporting salvage radiotherapy were included for discussion. Expert commentary: As postoperative radiotherapy is associated with non-trivial risks of acute and long-term toxicity and given the absence of compelling data supporting adjuvant over early salvage radiotherapy, the authors advocate, with rare exceptions, close observation and timely (early) salvage radiotherapy for patients with BCR and long life expectancy. Adjuvant radiotherapy may be considered in patients at high-risk for recurrence. Observation is appropriate in patients with limited life expectancy and/or absence of adverse features.

Concepts: Cancer, Ionizing radiation, Proton therapy, Prostate cancer, Urology, Radiation therapy, Benign prostatic hyperplasia, Hormonal therapy