Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-N-nitrosourea was evaluated by using a transgenic lacI reporter system. Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2^−/− animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both MSH2^+/+ and MSH2^−/− N-methyl-N-nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary non-polyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.     

Impact of a Low-Glucose Peritoneal Dialysis Regimen on Fibrosis and Inflammation Biomarkers

♦ Background: The impact of a low-glucose peritoneal dialysis (PD) regimen on biomarkers of peritoneal inflammation, fibrosis and membrane integrity remains to be investigated.♦ Methods: In a randomized, prospective study, 80 incident PD patients received either a low-glucose regimen comprising Physioneal (P), Extraneal (E) and Nutrineal (N) (Baxter Healthcare Corporation, Deerfield, IL, USA) (PEN group), or Dianeal (control group) for 12 months, after which both groups continued with Dianeal dialysis for 6 months. Serum and dialysate levels of vascular endothelial growth factor (VEGF), decorin, hepatocyte growth factor (HGF), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), hyaluronan (HA), adiponectin, soluble-intracellular adhesion molecule (s-ICAM), vascular cell adhesion molecule-1 (VCAM-1) and P-selectin, and dialysate cancer antigen 125 (CA125), were measured after 12 and 18 months. This paper focuses on results after 12 months, when patients in the PEN group changed to glucose-based PD fluid (PDF).♦ Results: At the end of 12 months, effluent dialysate levels of CA125, decorin, HGF, IL-6, adiponectin and adhesion molecules were significantly higher in the PEN group compared to controls, but all decreased after patients switched to glucose-based PDF. Macrophage migration inhibitory factor level was lower in the PEN group but increased after changing to glucose-based PDF and was similar to controls at 18 months. Serum adiponectin level was higher in the PEN group at 12 months, but was similar in the 2 groups at 18 months. Body weight, residual renal function, ultrafiltration volume and total Kt/V did not differ between both groups. Dialysate-to-plasma creatinine ratio at 4 h was higher in the PEN group at 12 months and remained so after switching to glucose-based PDF.♦ Conclusion: Changes in the biomarkers suggest that the PEN PD regimen may be associated with better preservation of peritoneal membrane integrity and reduced systemic vascular endothelial injury.     

The Olfactory Strip and Its Preservation in Endoscopic Pituitary Surgery Maintains Smell and Sinonasal Function

Background The return of olfaction and of sinonasal function are important end points after pituitary surgery. Opinions differ on the impact of surgery because techniques vary greatly. A modified preservation of the so-called olfactory strip is described that utilizes a small nasoseptal flap and wide exposure. Methods A cohort of patients undergoing pituitary surgery and endoscopic sinonasal tumor surgery were assessed. Patient-reported outcomes (Sino-Nasal Outcome Test [SNOT22] and Nasal Symptom Score [NSS]) were recorded. A global score of sinonasal function and the impact on smell and taste were obtained. Objective smell discrimination testing was performed in the pituitary group with the Smell Identification Test. Outcomes were assessed at baseline and at 6 months. Results Ninety-eight patients, n = 40 pituitary (50.95 ± 15.31 years; 47.5% female) and n = 58 tumor (52.35 ± 18.51 years; 52.5% female) were assessed. For pituitary patients, NSSs were not significantly different pre- and postsurgery (2.75 ± 3.40 versus 3.05 ± 3.03; p = 0.53). SNOT22 scores improved postsurgery (1.02 ± 0.80 versus 0.83 ± 0.70; p = 0.046). Objective smell discrimination scores between baseline and 6 months were similar (31.63 ± 3.49 versus 31.35 ± 4.61; p = 0.68). No difference in change of olfaction was seen compared with controls (Kendall tau-b p = 0.46). Conclusions Preservation of the olfactory strip can provide a low morbidity approach without adversely affecting olfaction and maintaining reconstruction options.     

诱导化疗在局部晚期头颈癌中的作用

作为标准化的非手术治疗,诱导化疗(ICT)在治疗局部晚期头颈鳞癌已有几十年的历史,但是关于其作用尚存争议。同期放化疗(CRT)是目前标准化的非手术治疗,然而由于ICT能够使肿瘤体积缩小,提高放疗的可行性,改善患者对放疗的耐受力,增加放疗后器官功能保留的可能性及降低远处转移率。所以,对ICT的研究从未停止。该文对近期随机试验进行回顾分析,与手术或单独CRT比较,评估ICT中紫杉醇的价值。Meta分析比较ICT中紫杉醇和顺铂及5氟尿嘧啶的作用。之前的随机试验中,并没有ICT提高生存率的报道。但