Edge restenosis: impact of low dose irradiation on cell proliferation and ICAM-1 expression

BACKGROUND: Low dose irradiation (LDI) of uninjured segments is the consequence of the suggestion of many authors to extend the irradiation area in vascular brachytherapy to minimize the edge effect. Atherosclerosis is a general disease and the uninjured segment close to the intervention area is often atherosclerotic as well, consisting of neointimal smooth muscle cells (SMC) and quiescent monocytes (MC). The current study imitates this complex situation in vitro and investigates the effect of LDI on proliferation of SMC and expression of intercellular adhesion molecule-1 (ICAM-1) in MC. METHODS: Plaque tissue from advanced primary stenosing lesions of human coronary arteries (9 patients, age: 61 ± 7 years) was extracted by local or extensive thrombendarterectomy. SMC were isolated and identified by positive reaction with smooth muscle α-actin. MC were isolated from buffy coat leukocytes using the MACS cell isolation kit. For identification of MC flow-cytometry analysis of FITC-conjugated CD68 and CD14 (FACScan) was applied. SMC and MC were irradiated using megavoltage photon irradiation (CLINAC2300 C/D, VARIAN, USA) of 6 mV at a focus-surface distance of 100 cm and a dose rate of 6 Gy min(-1 )with single doses of 1 Gy, 4 Gy, and 10 Gy. The effect on proliferation of SMC was analysed at day 10, 15, and 20. Secondly, total RNA of MC was isolated 1 h, 2 h, 3 h, and 4 h after irradiation and 5 μg of RNA was used in standard Northern blot analysis with ICAM-1 cDNA-probes. RESULTS: Both inhibitory and stimulatory effects were detected after irradiation of SMC with a dose of 1 Gy. At day 10 and 15 a significant antiproliferative effect was found; at day 20 after irradiation cell proliferation was significantly stimulated. Irradiation with 4 Gy and 10 Gy caused dose dependent inhibitory effects at day 10, 15, and 20. Expression of ICAM-1 in human MC was neihter inhibited nor stimulated by LDI. CONCLUSION: Thus, the stimulatory effect of LDI on SMC proliferation at day 20 days after irradiation may be the in vitro equivalent of a beginning edge effect. Extending the irradiation area in vascular brachytherapy in vivo may therefore merely postpone and not inhibit the edge effect. The data do not indicate that expression of ICAM-1 in quiescent MC is involved in the process

Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience

Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics

Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma

BackgroundLocal recurrence following definitive treatment for pancreatic adenocarcinoma is common and can be associated with significant morbidity and mortality. Retreatment options for these patients are limited. Proton beam reirradiation (PRT) may limit dose and toxicity to previously irradiated normal tissues in patients without evidence of metastatic disease.MethodsBetween 8/2010-2/2015, 15 patients with isolated, locally-recurrent pancreatic cancer were treated with PRT. Acute toxicity was graded using CTC v 4.0 and defined as occurring within 90 days. Kaplan-Meier survival analysis was performed from the start of PRT. A log-rank test was used to compare survival with or without concurrent chemotherapy.ResultsMedian follow-up was 15.7 months [2-48] from the start of PRT. The median clinical target volume (CTV) was 71 cc [15-200]. Ten (67%) patients received concurrent chemotherapy. Median PRT dose was 59.4 Gy (37.5-59.4 Gy). The median time interval from the prior treatment course was 26.7 months (7-461.3). There was a rate of 13% acute ≥ grade 3 toxicities attributed to PRT. The median overall survival (OS) was 16.7 months (95% CI, 4.7-36) and OS at 1 year was 67%. The "in-field" failure free survival at one year was 87%. The locoregional progression free survival (LPFS) and distant metastasis free survival (DMFS) at 1 year was 72% and 64% respectively. Concurrent chemotherapy was associated with a higher median survival.ConclusionsPRT was well tolerated, resulted in prolonged clinical outcomes compared to historical controls, and should be considered as a treatment option with concurrent chemotherapy in selected patients with locally-recurrent pancreatic cancer