A Case Report of Inflammatory Myofibroblastic Tumor of the Sphenoidal Sinus

Inflammatory myofibroblastic tumor (IMT) is a tumor composed of differentiated myofibroblastic spindle-shaped cells. It occurs in the soft tissues of the abdomen and lungs, and is very rare in the sphenoid sinus. The diagnosis depends on histopathology and immunohistochemistry, and is easily misdiagnosed. Although metastasis is rare, the recurrence rate is high. Surgical resection is the treatment of choice, and where complete resection is difficult, radiation therapy, hormonal therapy, or molecular targeted drug therapy can be administered. We report a rare case of IMT with a primary origin in the sphenoid sinus, which was entirely resected by nasal endoscopy and confirmed by histological examination.

Trend in Prescription and Treatment Retention of Molecular-Targeted Drugs in 121,131 Japanese Patients With Rheumatoid Arthritis: A Population-Based Real-World Study

Objectives To describe the real-world prescription and treatment retention of molecular-targeted drugs for rheumatoid arthritis (RA) in Japan. Materials and Methods 204,416 patients with RA prescribed at least one of the eight molecular-targeted drugs in 7 years from the National Database of Health Insurance Claims and Specific Health Checkups of Japan covering 98.3% of the Japanese population. The retention rate of each drug as well as head-to head comparisons were estimated by Kaplan–Meier method. Results 121,131 RA patients were prescribed any molecular-targeted drug for the first time, while 36,633 uses of molecular-targeted drug switched from another (switch use). The overall retention rates of molecular-targeted drugs at 12, 36, and 60 months were 0.64, 0.42, and 0.32 for the naïve use and 0.59, 0.40, and 0.31 for the switch use, respectively. Non-tumor necrosis factor (TNF)-inhibitor molecular-targeted drugs, particularly tocilizumab and tofacitinib, had higher retention rates than TNF inhibitors for both naïve and switch uses regardless of the previous drug, and showed higher retention rates in head-to-head comparisons between eight molecular-targeted drugs. Conclusions Our data reveal that the real-world drug retention is overall lower than previously reported and higher with non-TNF inhibitors than with TNF inhibitors.

Marine-derived pipeline anticancer natural products: a review of their pharmacotherapeutic potential and molecular mechanisms

Background Cancer is a complex and most widespread disease and its prevalence is increasing worldwide, more in countries that are witnessing urbanization and rapid industrialization changes. Although tremendous progress has been made, the interest in targeting cancer has grown rapidly every year. This review underscores the importance of preventive and therapeutic strategies. Main text Natural products (NPs) from various sources including plants have always played a crucial role in cancer treatment. In this growing list, numerous unique secondary metabolites from marine sources have added and gaining attention and became potential players in drug discovery and development for various biomedical applications. Many NPs found in nature that normally contain both pharmacological and biological activity employed in pharmaceutical industry predominantly in anticancer pharmaceuticals because of their enormous range of structure entities with unique functional groups that attract and inspire for the creation of several new drug leads through synthetic chemistry. Although terrestrial medicinal plants have been the focus for the development of NPs, however, in the last three decades, marine origins that include invertebrates, plants, algae, and bacteria have unearthed numerous novel pharmaceutical compounds, generally referred as marine NPs and are evolving continuously as discipline in the molecular targeted drug discovery with the inclusion of advanced screening tools which revolutionized and became the component of antitumor modern research. Conclusions This comprehensive review summarizes some important and interesting pipeline marine NPs such as Salinosporamide A, Dolastatin derivatives, Aplidine/plitidepsin (Aplidin®) and Coibamide A, their anticancer properties and describes their mechanisms of action (MoA) with their efficacy and clinical potential as they have attracted interest for potential use in the treatment of various types of cancers.

Planned drug holiday in a cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

6070 Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]

Oncopharmacogenomics of Hepatocellular Carcinoma - A Therapy Related Review

Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the fifth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways driving hepatocarcinogenesis, new treatment strategies are urgently needed for this devastating disease. The multi kinase inhibitor Sorafenib was the first molecular targeted drug in HCC that led to significant survival benefit in patients with advanced tumors. It is the first drug to be considered standard of care for advanced HCC and supports the importance of molecular therapies in the treatment of this cancer. Analysis of genetic and epigenetic alterations as well as different molecular pathways involved in the development of HCC help to identify potential new druggable targets. A variety of novel compounds are already under preclinical or clinical investigation, and accumulating evidence suggests that combination therapy targeting different pathways will potentiate anti-tumoral effects and will become the future therapeutic approach. In addition, the establishment of a robust molecular classification will pave the way for a more personalized treatment scheme in HCC. In this article a review of the current knowledge of the molecular pathogenesis of HCC and an overview of molecular targeted therapies in the management of HCC are provided.

Identification of KIF23 as a prognostic signature for ovarian cancer based on large scale samples and clinical validation

Background: Ovarian cancer is one of the common malignant tumors in gynecology. Although the treatment strategy for ovarian cancer has been greatly improved in recent years, due to the metastasis, recurrence and drug resistance, the 5-year overall survival rate of patients is still less than 47%. However, at present, there is no specific markers for clinical application. The purpose of this study is to verify the expression and clinical significance of KIF23 in ovarian cancer and identify potential targets for the clinical treatment of ovarian cancer. Methods: The expression of KIF23 in ovarian cancer tissues and its relationship between survival prognosis and clinical pathological parameters were analyzed in Oncomine, GEO, and TCGA databases. KIF23 expression was analyzed by Kaplan-Meier plotter database and its relationship with chemo-resistance was studied. The molecular mechanism involved in KIF23 was analyzed from the perspective of gene mutation, copy number variation and other genomics. Finally, immunohistochemistry experiment was used to verify the expression of KIF2, and its relationship between the clinical pathological parameters and prognosis of ovarian cancer patients was analyzed by single factor and multivariate Cox regression models. Results: Bioinformatic and experimental results have demonstrated that KIF23 is highly expressed in ovarian cancer, and its high expression is positively correlated with poor prognosis. Overexpression of KIF23 can cause chemotherapy resistance in ovarian cancer and affect the overall survival of patients. Genomics analysis showed that KIF23 expression was associated with mutations such as FLG2 and TTN, and it was significantly enriched in tumor signaling pathways such as DNA replication and cell cycle. Conclusions: KIF23 can not only be used as a biomarker of poor prognosis in patients with various stages of ovarian cancer, but also be used as a molecular targeted drug and an independent prognostic biomarker for the treatment of ovarian cancer patients.

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1–PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1–GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.