Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.
Patients And Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO).
Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.
View Article and Find Full Text PDFBackground: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT.
View Article and Find Full Text PDFObjective: A novel motion-preserving technique to directly repair pars defects. Moreover, the indications for repair are expanded to include those with disc disease and associated spondylolisthesis.
Summary Of Background Data: The challenge in treating pars defects has been that there are few techniques available to stabilize them adequately.
Purpose: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT.
View Article and Find Full Text PDFOncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers.
View Article and Find Full Text PDFBackground: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).
Methods: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation.
Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells.
View Article and Find Full Text PDFIntroduction: Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported.
Methods: Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily.
Objective: To determine factors associated with the presence of residual disease in women who have undergone cervical conization for adenocarcinoma in situ (ACIS) of the cervix.
Study Design: We identified women who underwent a cervical conization for a diagnosis of ACIS followed by repeat conization or hysterectomy between Jan. 1, 1995, and April 30, 2010.
Purpose: B-Raf(V600E) may play a role in the progression from papillary thyroid cancer to anaplastic thyroid cancer (ATC). We tested the effects of a highly selective B-Raf(V600E) inhibitor, PLX4720, on proliferation, migration, and invasion both in human thyroid cancer cell lines (8505c(B-RafV600E) and TPC-1(RET/PTC-1 and wild-type B-Raf)) and in primary human normal thyroid (NT) follicular cells engineered with or without B-Raf(V600E).
Experimental Design: Large-scale genotyping analysis by mass spectrometry was performed in order to analyze >900 gene mutations.
B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity.
View Article and Find Full Text PDFUterine cancer is the most common gynecologic cancer in women in the United States with an estimated number of 40,100 women diagnosed in 2008, the great majority of which belongs to endometrial classification. The traditional approach to treatment of endometrial cancer has been primarily surgery via an open, laparotomy incision. Minimally invasive approaches with smaller incisions, i.
View Article and Find Full Text PDFJ Natl Compr Canc Netw
September 2008
Ovarian cancer is the fifth most common cause of cancer-related death among women in the United States, although the median survival of patients has been increasing over the past few decades. In patients with epithelial ovarian cancer, chemotherapy has increased survival. Platinum agents combined with taxanes have become standard treatment.
View Article and Find Full Text PDFCurr Treat Options Oncol
December 2007
In the United States, there are 11,150 cases and 3670 deaths projected due to invasive cervical cancer for 2007. Approximately 500,000 new cases and 274,000 deaths will occur in women throughout the world. Human papillomavirus (HPV) has been designated by the World Health Organization (WHO) as a "necessary cause" of cervical cancer.
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