ABSTRACT
The role of immunotherapy in bladder urothelial cancers is rapidly expanding. Since the initial second-line therapy approval for patients who fail prior platinum-based chemotherapy, the use of immunotherapy with checkpoint inhibitors has been rapidly evolving. There are approved indications for first-line metastatic disease in the platinum-ineligible patients or the cisplatin-ineligible PD-L1 positive patients, and there is a label for high-risk non-muscle-invasive bladder cancer who are BCG-refractory. In addition, a trial on maintenance immunotherapy with avelumab showed positive findings with improvement in overall survival that has also changed standard of care for these patients. There are ongoing clinical trials evaluating its use in the neoadjuvant and adjuvant perioperative muscle-invasive bladder cancer setting. The pivotal trials that led to these FDA approvals and promising and ongoing trials are discussed herein.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/therapy , Immune Checkpoint Inhibitors/therapeutic use , Urinary Bladder Neoplasms/therapy , Administration, Intravesical , Antineoplastic Combined Chemotherapy Protocols/pharmacology , B7-H1 Antigen/analysis , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , BCG Vaccine/administration & dosage , Carcinoma, Transitional Cell/immunology , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/pathology , Chemotherapy, Adjuvant/methods , Cystectomy , Humans , Immune Checkpoint Inhibitors/pharmacology , Induction Chemotherapy/methods , Maintenance Chemotherapy/methods , Neoadjuvant Therapy/methods , Programmed Cell Death 1 Receptor/analysis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Progression-Free Survival , Randomized Controlled Trials as Topic , Urinary Bladder/immunology , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathologyABSTRACT
The phosphoinositide 3-kinase (PI3K) pathway integrates multifarious environmental cues to regulate cell survival, growth, and metabolism. Hyperactivation of the PI3K pathway increases biological fitness by offering a high degree of adaptability to and resilience against diverse perturbations, thus conferring survival benefits on premalignant and transformed cells. In prostate cancer, the PI3K pathway is aberrantly activated by various genetic and epigenetic alterations and its hyperactivation is closely associated with a poor clinical outcome. In this review, we discuss the challenges encountered with clinically effective therapies targeting the PI3K pathway in prostate cancer, highlighting the clinical importance of combination therapies. In particular, we address how prostate cancer cells utilize the PI3K pathway for the development of resistance to a broad range of anticancer treatments. In addition, we describe the molecular mechanisms by which prostate cancer cells become resistant to PI3K pathway inhibitors. This review will be helpful in translating biological knowledge into therapeutic strategies for the treatment of prostate cancer and provide insight into overcoming therapeutic challenges associated with prostate cancer.
Subject(s)
Drug Resistance, Neoplasm/physiology , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/enzymology , Animals , Humans , Male , Signal Transduction/drug effectsABSTRACT
Transhiatal esophagectomy with primary anastomosis to the stomach (gastric pull-up) is an attractive surgical alternative to colic interposition in patients with cancer of the esophagus and hypopharynx. However, the lack of intrinsic gastric peristalsis and complaints by patients ol postprandial regurgitation prompted us to measure the effect of body posture on the rates of gastric emptying in these patients. The rates of solid and liquid gastric emptying were measured in 14 patients who had undergone gastric interposition for esophageal and hypopharyngeal carcinoma. Rates of emptying were measured in both the supine and upright position using a dualisotope radiolabeling technique. In these patients, the rate of gastric emptying of both solids and liquids was significantly slower in the supine position than in the upright position. Emptying in supine patients was also prolonged when compared with supine normal volunteers. Conversely, the upright rate of solid and liquid emptying in the patients was accelerated when compared with published values for upright normal volunteers. We conclude that gastric emptying after gastric interposition is dependent on upright posture after meals.
