RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms.

Ischemic preconditioning is an intrinsic process in which preconditioning ischemia (ischemia of shorter duration) protects the organs against the subsequent index ischemia (sustained ischemia). Remote ischemic preconditioning (RIPC) is an innovative treatment approach in which interspersed cycles of preconditioning ischemia followed by reperfusion to a remote organ (other than target organ) protect the target organ against index ischemia and reperfusion-induced injury. RIPC of various organs to provide multi-organ salvage became a successful approach in numerous species of animals. Consequently, the concept of RIPC evolved in clinical setups, and provided beneficial effects in alleviating ischemia-reperfusion-induced injury in various remote organs, including myocardium. Clinically, RIPC stimulus is generally delivered by inflating the blood pressure cuff tied on the upper arm 20 mm greater than the systolic blood pressure, rendering the forearm ischemic for 5 min, followed 5 min reperfusion by deflating the cuff. This cycle is repeated for 3-4 consecutive periods to precondition the tissue and improve the survival. The institution of RIPC is beneficial in mitigating myocardial injury in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, heart valve surgery, drug-eluting stent implantation, kidney transplantation, elective decompression surgery. The involvement of hypoxia inducible factor-1α (HIF-1α), ATP-sensitive potassium channels, signal transducer and activator of transcription (STAT), matrix metalloproteinases, O-linked ß-N-acetylglucosamine (O-GlcNAc) levels, autonomous nervous system in mediating RIPC-induced cardioprotective effects has been explored clinically. However, comprehensive studies are required to elucidate the other possible mechanisms responsible for producing multi-organ protection during RIPC.

Future directions from past experience: a century of prostate radiotherapy.

Prostate cancer is the most commonly diagnosed noncutaneous malignancy in men, yet 100 years ago it was considered a rare disease. Over the past century, radiation therapy has evolved from a radium source placed in the urethra to today's advanced proton therapy delivered by only a few specialized centers. As techniques in radiation have evolved, the treatment of localized prostate cancer has become one of the most debated topics in oncology. Today, patients with prostate cancer must often make a difficult decision between multiple treatment modalities, each with the risk of permanent sequelae, without robust randomized data to compare every treatment option. Meanwhile, opinions of urologists and radiation oncologists about the risks and benefits involved with each modality vary widely. Further complicating the issue is rapidly advancing technology which often outpaces clinical data. This article represents a complete description of the evolution of prostate cancer radiation therapy with the goal of illuminating the historical basis for current challenges facing oncologists and their patients.

A history of surgery for locally-advanced (T4) cancer of the thoracic esophagus in Japan and a personal perspective.

The history of esophageal surgery in Japan can be divided into three periods, an era of safety from 1930 to 1980, an era of radicality from 1980 to 2000, and the era of quality of life (QOL) from 2000 to the present. The treatment for T4 cancers of the thoracic esophagus has also changed over time from preoperative radiotherapy, combined resection of the neighboring organs with esophagectomy, and to definitive chemoradiotherapy (dCRT) with salvage surgery. At present, almost all patients with an unresectable T4 esophageal cancer receives dCRT. However, there are many patients with a residual or recurrent tumor after dCRT. Salvage surgery for such patients often results in incomplete resection of the tumor because the tumor involves the trachea and/or aorta. New techniques to enable the resection of such neighboring organs even during salvage surgery are needed. In the future, the mainstay of treatment for esophageal cancer will be CRT with the foreseeable progress in new drugs and new techniques of radiotherapy. Surgery will be indicated for a local failure after CRT, while combined resection of the neighboring organs will be necessary to treat a local failure after CRT for T4 cancers. New surgical techniques have to be developed through some application of new devices and equipment.

Treatment of multiple myeloma.

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.