Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II—Report from the German/Swiss SIOP-LGG 2004 cohort

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.     

Prognostic value of lipoproteins and their relation to inflammatory markers among patients with coronary artery disease

BACKGROUND: Lipoproteins and their subfractions are associated with the incidence of atherosclerotic diseases. In patients with coronary artery disease (CAD), low serum concentrations of high density lipoprotein (HDL) and high low-density lipoproteins (LDL) are correlated to myocardial infarction and cardiovascular death. There is growing evidence indicating that those lipoprotein factors are related to the inflammatory process in atherogenesis. METHODS: We investigated in a median follow up of 3.9 years the association of HDL, apolipoprotein A-I (apoA-I), LDL, apolipoprotein B (apoB), and triglycerides with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and their relation to markers of inflammation in 1298 patients with angiographically documented CAD. RESULTS: In univariate analysis, serum concentrations of apoA-I were significantly and inversely related to the combined endpoint, whereas serum concentrations of LDL, apoB, and triglycerides were not. HDL was not significantly related to the endpoint in univariate analyses (p=0.057). Multivariate analyses showed that only apoA-I is an independent predictor. ApoA-I (and HDL) was significantly related to markers of inflammation. CONCLUSION: Serum apoA-I levels were an independent predictor for fatal and non-fatal cardiovascular events in patients with CAD. This may be related to its anti-inflammatory effect.     

Subcoronary implantation of a stentless valve in patients with aortic aneurysms

Experience with a new operation for patients with aortic valve disease and aneurysm or dissection of the ascending aorta is described. Twenty-four patients aged 66-87 years were operated on using a subcoronary implantation technique with a stentless aortic valve bioprosthesis and an extension using a vascular tube prosthesis. No major adverse cardiac events were observed in the postoperative period. This operation offers a safe alternative to the technically more demanding procedures of composite bioprosthetic ascending aortic replacement or full root replacement.     

劈离式肝移植中供肝分离的手术经验

目的探讨劈离式肝移植中供肝分离的手术经验。方法自2004年3月1日至9月1日，共计施行了10例体外供肝的劈离，将其分为左肝外侧叶（Ⅱ、Ⅲ段）和扩大右半肝（Ⅰ、Ⅳ～Ⅷ段）两部分，并为19位病人施行了劈离式肝移植。供体的平均年龄为32．7岁（15～51岁），平均体重64．5kg（45-75kg），ICU平均救治时间为2．4d（1～8d）。结果劈离前整体供肝和劈离后左肝外侧叶的平均重量分别为1322．6g（956～1665g）和281．8g（198～373g），后者与前者的平均比值为0．215（0．178～0．274）。左肝外侧叶部分的移植物与受体重量比（GRWR）的平均值为2．44％（1．22％～5．41％），而扩大右半肝部分GRWR的平均值为1．73％（1．31％～2．30％）。供肝劈离平均花费的时间为105min（85-135min）。共出现5例解剖变异，包括左肝静脉变异2例、肝动脉变异2例、胆管变异1例。结论劈离式肝移植已经成为扩大供肝来源的一种成熟的外科技术，且效果满意。在供肝劈离中需要正确应对各种可能的解剖变异，尤其是左肝静脉、左肝动脉和胆管的变异。     

Transjugular intrahepatic portosystemic shunt vs. small-diameter prosthetic H-graft portacaval shunt: Extended follow-up of an expanded randomized prospective trial

We report herein the results of extended follow-up of an expanded randomized clinical trial comparing transjugular intrahepatic portosystemic shunt (TIPS) to 8 mm prosthetic H-graft portacaval shunt as definitive treatment for variceal bleeding due to portal hypertension. Beginning in 1993, through this trial, both shunts were undertaken as definitive therapy, never as a “bridge to transplantation.” All patients had bleeding esophageal/gastric varices and failed or could not undergo sclerotherapy/banding. Patients were excluded from randomization if the portal vein was occluded or if survival was hopeless. Failure of shunting was defined as inability to shunt, irreversible shunt occlusion, major variceal rehemorrhage, hepatic transplantation, or death. Median follow-up after each shunt was 4 years; minimum follow-up was 1 year. Patients undergoing placement of either shunt were very similar in terms of age, sex, cause of cirrhosis, Child’s class, and circumstances of shunting. Both shunts provided partial portal decompression, although the portal vein-inferior vena cava pressure gradient was lower after H-graft portacaval shunt (P<0.01). TIPS could not be placed in two patients. Shunt stenosis/occlusion was more frequent after TIPS. After TIPS, 42 patients failed (64%), whereas after H-graft portacaval shunt 23 failed (35%) (P <0.01). Major variceal rehemorrhage, hepatic transplantation, and late death were significantly more frequent after TIPS (P <0.01). Both TIPS and H-graft portacaval shunt achieve partial portal decompression. TIPS requires more interventions and leads to more major rehemorrhage, irreversible occlusion, transplantation, and death. Despite vigilance in monitoring shunt patency, TIPS provides less optimal outcomes than H-graft portacaval shunt for patients with portal hypertension and variceal bleeding. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

Auditory sensory memory and language abilities in former late talkers: A mismatch negativity study

The present study investigated whether (a) a reduced duration of auditory sensory memory is found in late talking children and (b) whether deficits of sensory memory are linked to persistent difficulties in language acquisition. Former late talkers and children without delayed language development were examined at the age of 4 years and 7 months using mismatch negativity (MMN) with interstimulus intervals (ISIs) of 500 ms and 2000 ms. Additionally, short‐term memory, language skills, and nonverbal intelligence were assessed. MMN mean amplitude was reduced for the ISI of 2000 ms in former late talking children both with and without persistent language deficits. In summary, our findings suggest that late talkers are characterized by a reduced duration of auditory sensory memory. However, deficits in auditory sensory memory are not sufficient for persistent language difficulties and may be compensated for by some children.     

Optical coherence tomography for presurgical margin assessment of non‐melanoma skin cancer – a practical approach

In the clinical setting, optical coherence tomography (OCT) is applicable for the non‐invasive diagnosis of skin cancer and may in particular be used for margin definition prior to excision. In this regard, OCT may improve the success rate of removing tumor lesions more effectively, preventing repetitive excision, which may subsequently result in smaller excisions. In this study, we have aimed to evaluate the applicability of OCT for in vivo presurgical margin assessment of non‐melanocytic skin tumors (NMSC) and to describe the feasibility of different scanning techniques. A total number of 18 patients planned for excision of lesions suspicious of NMSC were included in this study. Based on OCT, we defined the specific tumor margins on 19 lesions preoperatively using different scanning modalities. Sixty‐one margin points and five complete tumor margins were analysed on 18 patients with a total of 19 lesions including 63% basal cell carcinoma (BCC) (n = 12), 16% (n = 3) squamous cell carcinoma (SCC) and 21% of other types of skin tumors (n = 4) were classified. In 84% of the cases (n = 16), the OCT‐defined lateral margins correctly indicated complete removal of the tumor. The surgical margins chosen by the surgeon never fell below the OCT‐defined margin. Regarding the techniques of marginal definition, punctual tumor border scan in the perpendicular direction, with an extension of free‐run scans for unsure cases can hardly be recommended. This study shows that suspected NMSC can effectively be confirmed, and furthermore, resection margin can be minimized under OCT control without reducing the rate of complete removal.     

An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.

PURPOSE: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m(2) and increasing to 0.9 mg/m(2) based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m(2) than after 0.6 mg/m(2) (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). CONCLUSION: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.     

Infrared spectroscopic examination of aqueous humor.

OBJECTIVE: The aim of this study was to report on a new technique for examining aqueous humor. PARTICIPANTS: Aqueous humor samples obtained from 198 patients (cataract: n=66 eyes; age-related macular degeneration [AMD]: n=66; diabetic macular edema: n=66) were in vitro examined by mid infrared spectroscopy. After training and validating the technique, 66 samples were taken for the final independent prediction. RESULTS: In computerized analysis of the spectrometric data, 22 (100%) cataract eyes were diagnosed as the cataract group, 17 (77%) diabetic macular edema eyes were diagnosed as the diabetic macular edema group, and 14 (64%) eyes with AMD were diagnosed as the AMD group. Mid infrared spectrometry could statistically significantly (P=0.004) differentiate between the 3 study groups. CONCLUSIONS: Mid infrared spectroscopic examination of aqueous humor may be able to differentiate eyes with cataract, AMD, or diabetic macular edema.