Limb salvage in antiphospholipid syndrome with repetitive arterial occlusions.

Outcomes of vascular surgery for patients with primary antiphospholipid syndrome (APS) presenting with acute limb ischaemia (ALI) are poor, with a high rate of postoperative arterial thrombosis and limb amputation. A primary antiphospholipid syndrome 42-year-old male patient presented with acute limb ischaemia. Timely endovascular thrombectomy successfully prevented irreversible tissue damage but failed to maintain this due to recurrent thrombosis. Intensive plasma exchange following repeated endovascular therapy (EVT) ameliorated this thrombotic event. Two weeks post-discharge, thrombotic arterial reocclusion led to readmission and repeated management. Following successful reperfusion, intensive immunosuppressive therapy and anticoagulant agents ensured that the patient was free from recurrent events during the next eight months. This case highlights the combination of endovascular thrombectomy and intensive plasma exchange for limb salvage in such cases.

Prognostic Value of the Metabolic and Volumetric Parameters of 11C-Methionine Positron-Emission Tomography for Gliomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have demonstrated that 11C-methionine positron-emission tomography provides information on prognosis. PURPOSE: We performed a systematic review and meta-analysis of the prognostic value of the metabolic and volumetric parameters of 11C-methionine-PET for gliomas. DATA SOURCES: A systematic search was performed using the following combination of keywords: "methionine," "PET," "glioma," and "prognosis." STUDY SELECTION: The inclusion criteria were the use of 11C-methionine-PET as an imaging tool, studies limited to gliomas, studies including metabolic parameters (tumor-to-normal ratio) and/or volumetric parameters (metabolic tumor volume), and studies reporting survival data. The electronic search first identified 181 records, and 14 studies were selected. DATA ANALYSIS: Event-free survival and overall survival were the outcome measures of interest. The effect of the tumor-to-normal ratio and metabolic tumor volume on survival was determined by the effect size of the hazard ratio. Hazard ratios were extracted directly from each study when provided or determined by analyzing the Kaplan-Meier curves. DATA SYNTHESIS: The combined hazard ratios of the tumor-to-normal ratio for event-free survival was 1.74 with no significance and that of the tumor-to-normal ratio for overall survival was 2.02 with significance. The combined hazard ratio of the metabolic tumor volume for event-free survival was 2.72 with significance and that of the metabolic tumor volume for overall survival was 3.50 with significance. LIMITATIONS: The studies selected were all retrospective, and there were only 4 studies involving the metabolic tumor volume. CONCLUSIONS: The present meta-analysis of 11C-methionine-PET suggests that the tumor-to-normal ratio for overall survival and the metabolic tumor volume for event-free survival and overall survival are significant prognostic factors for patients with gliomas.

Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Prognostic significance of volume-based 18F-FDG PET/CT parameter in patients with surgically resected non-small cell lung cancer. Comparison with immunohistochemical biomarkers.

AIM: We investigated the prognostic value of volume-based 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) parameters compared with other factors including several immunohistochemical biomarkers in patients with surgically resected non-small cell lung cancer (NSCLC). STUDY PARTICIPANTS: 290 patients with surgically resected and histopathologically confirmed NSCLC. The maxmum standardized uptake value (SUVmax) and metabolic tumour volume (MTV) of the primary tumour were obtained on 18F-FDG PET/ computed tomography (CT) for initial staging and Ki-67 labeling index (LI), p16, CD31 and cyclin E were evaluated in the primary tumours by immunohistochemical staining. Survival analyses for variables including PET parameters, immunohistochemical biomarker and other clinical factors were performed using the Kaplan-Meier method and Cox proportional hazards regression analysis. RESULTS: In univariate analyses, tumour stage, tumour size, and MTV were significant prognostic factors for decreased overall survival (OS) and disease-free survival (DFS). Multivariate analyses showed MTV and tumour stage were significant predictors of poor OS (MTV, hazard ratio (HR) = 1.135, p = 0.015; stage, HR = 0.644, p = 0.025) and DFS (MTV, HR = 1.128, p = 0.043; stage, HR = 0.541, p = 0.009). CONCLUSION: The MTV of primary tumours is a significant prognostic factor for survival along with tumour stage in patients with surgically resected NSCLC. The MTV can predict OS and DFS better than immunohistochemical biomarkers.

A novel antagonist to the inhibitors of apoptosis (IAPs) potentiates cell death in EGFR-overexpressing non-small-cell lung cancer cells.

In the effort to develop an efficient chemotherapy drug for the treatment of non-small-cell lung cancer (NSCLC), we analyzed the anti-tumorigenic effects of a novel small molecule targeting the inhibitor of apoptosis (IAPs), HM90822B, on NSCLC cells. HM90822B efficiently decreased IAP expression, especially that of XIAP and survivin, in several NSCLC cells. Interestingly, cells overexpressing epidermal growth factor receptor (EGFR) due to the mutations were more sensitive to HM90822B, undergoing cell cycle arrest and apoptosis when treated. In xenograft experiments, inoculated EGFR-overexpressing NSCLC cells showed tumor regression when treated with the inhibitor, demonstrating the chemotherapeutic potential of this agent. Mechanistically, decreased levels of EGFR, Akt and phospho-MAPKs were observed in inhibitor-treated PC-9 cells on phosphorylation array and western blotting analysis, indicating that the reagent inhibited cell growth by preventing critical cell survival signaling pathways. In addition, gene-specific knockdown studies against XIAP and/or EGFR further uncovered the involvement of Akt and MAPK pathways in HM90822B-mediated downregulation of NSCLC cell growth. Together, these results support that HM90822B is a promising candidate to be developed as lung tumor chemotherapeutics by targeting oncogenic activities of IAP together with inhibiting cell survival signaling pathways.

Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia.

BACKGROUND: Although the prognosis of interstitial pneumonia in connective tissue disorders is better than that of idiopathic pulmonary fibrosis (IPF), the prognosis of rheumatoid arthritis (RA) related usual interstitial pneumonia (UIP) is controversial. OBJECTIVES: To determine prognosis, clinical course and prognostic factors of the patients with RA-UIP and compare them to IPF. DESIGN: Retrospective review of 84 patients with RA-UIP (biopsy-proven: 30) from two tertiary referral centers. RESULTS: The median follow-up period was 33 months. One half of the patients were stable, one third progressed, 17% had acute exacerbation and 6% improved. TLC % predicted was the only significant predictor for the stable group. Among non-AEx patients, 41% was treated due to poor initial lung function or progression of the disease and one half of them improved or had stable lung function. Despite of worse initial lung function, the survival of treated group was similar to untreated group. Age, FVC and change in DLco during 6 months were significant predictors for mortality. The prognosis of RA-UIP was significantly better than that of IPF matched with age, sex, smoking and baseline lung function (median survival, 53 vs. 41 months respectively, p = 0.015). CONCLUSIONS: In spite of variable clinical course of RA-UIP, overall prognosis of RA-UIP was significantly better compared to IPF. Our data supported the treatment of the patients with significant functional impairments or progression.

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201).

BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89-1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.

Proteins involved in DNA damage response pathways and survival of stage I non-small-cell lung cancer patients.

BACKGROUND: Biological complexity leads to significant variation in the survival of patients with stage I non-small-cell lung cancer (NSCLC). DNA damage response (DDR) pathways play a critical role in maintaining genomic stability and in the progression of NSCLC. Therefore, the development of a prognostic biomarker focusing on DDR pathways is an intriguing issue. PATIENTS AND METHODS: Expression of several proteins (ATM, ATMpS1981, γH2AX, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, and ERCC1) and overall survival were investigated in 889 pathological stage I NSCLC patients. RESULTS: Low expression of BRCA1pS1423 or ERCC1 was significantly associated with worse survival in the whole cohort of patients. Analysis performed based on histology revealed that low expression of γH2AX, Chk2pT68, or ERCC1 was a poor prognostic factor in squamous cell carcinoma patients [adjusted hazard ratio (aHR), Cox P: 1.544, 0.012 for γH2AX; 1.624, 0.010 for Chk2pT68; 1.569, 0.011 for ERCC1]. The analysis of the interaction between two proteins showed that this effect was more pronounced in squamous cell carcinoma patients. However, these effects were not detected in adenocarcinoma patients. CONCLUSIONS: The proteins involved in DDR pathways exhibited differential expression between squamous cell carcinoma and adenocarcinoma and were important determinants of survival in stage I squamous cell carcinoma patients.

Clinical characteristics and risk of melanoma development from giant congenital melanocytic naevi in Korea: a nationwide retrospective study.

BACKGROUND: Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated. OBJECTIVES: To evaluate the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥5% body surface area in children or measuring ≥20cm in adults. METHODS: In total, 131 patients with GCMN were enrolled, with a mean age of 10·3years (range: birth-70years). RESULTS: The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients <4years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6-year-old girl, a 14-year-old girl and a 70-year-old man), and the incidence rate was 990 per 100000 person-years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma. CONCLUSIONS: We should be aware of melanoma development from GCMN, and lifelong follow-up is required due to the risk of melanoma arising in GCMN.

Pancreatic ductal adenocarcinoma with intratumoral cystic lesions on MRI: correlation with histopathological findings.

The purpose of this study was to evaluate intratumoral cystic lesions of pancreatic ductal adenocarcinoma (PDAC) depicted on MRI, and to correlate these cystic lesions with their histopathological findings. This study included 12 patients (7 males and 5 females; mean age, 59 years) with intratumoral cystic lesions of PDAC detected on a retrospective MRI review. We reviewed the histopathological findings of the cystic lesions within PDACs and analysed the MRI findings, focusing on the appearance of the intratumoral cystic lesions, i.e. the size, number, margin and intratumoral location, and on the ancillary findings of PDAC, i.e. peripancreatic infiltration, upstream pancreatic duct dilatation and distal parenchymal atrophy. Intratumoral cystic lesions were classified as neoplastic mucin cysts (n = 7, 58%) or cystic necrosis (n = 5, 42%) according to the histopathological findings; they ranged in greatest dimension from 0.5 cm to 3.4 cm (mean, 1.7 cm). Seven patients had only one cystic lesion each, while the remaining five had multiple cystic lesions. Most of the neoplastic mucin cysts had smooth margins (n = 6, 86%) and eccentric locations (n = 6), whereas most cystic necroses had irregular margins (n = 4, 80%) and centric locations (n = 4). The most common ancillary findings of PDAC were peripancreatic infiltration, distal pancreatic atrophy and upstream pancreatic duct dilatation (92%, 75% and 58%, respectively). The intratumoral cystic lesions of PDACs on MRI were classified as either neoplastic mucin cysts with smooth margins and eccentric locations or cystic necroses with irregular margins and centric locations.

Unchanging trend of esophagogastric junction adenocarcinoma in Korea: experience at a single institution based on Siewert's classification.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing in Western countries. It is unclear, however, whether similar changes are occurring in Asia. We therefore investigated the incidence of AEG in Korea, and assessed the clinical characteristics of three types of AEG based on Siewert's classification. We retrospectively reviewed the medical records of 16 811 patients diagnosed with esophageal squamous cell carcinoma (ESC, n= 1450) or gastric noncardiac adenocarcinoma (GNCA, n= 14 751) between 1992 and 2006. The patients were divided into three 5-year cohorts (cohort A [1992-1996], n= 2734, cohort B [1997-2001], n= 5727, and cohort C [2002-2006], n= 8350), and the ratios of AEG (n= 610) to non-AEG (ESC and GNCA) in each cohort were compared. Using Siewert's classification, the tumors were categorized into one of three types, and patient demographic features and 5-year survival rates were compared. The ratio of AEG to non-AEG cases did not change over time (0.037, 0.034, and 0.039 for cohorts A, B, and C, respectively; P= 0.40). Of the 610 patients with AEG, 23 (3.7%) had type 1 tumors, 47 (7.7%) had type 2, and 540 (88.5%) had type 3. The 5-year survival rate of patients with type 1 AEG was much lower (4.8 +/- 4.7%) than that of those with type 2 (47.9 +/- 7.8%) and type 3 (47.4 +/- 2.5%) tumors. Unlike in Western countries, the ratio of AEG to non-AEG cases has not increased over time in Korea. Type 1 AEG was rarer and associated with a more unfavorable prognosis in Korea than in Western countries.

Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions.

BACKGROUND: A relation between telomere attrition in early carcinogenesis and activation of DNA damage response (DDR) has been proposed. We explored telomere length and its link with DDR in colorectal multistep carcinogenesis. PATIENTS AND METHODS: We studied normal mucosa, low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and invasive carcinoma (IC) in matched human colon specimens by evaluating p-ataxia telangiectasia mutated (ATM), p-checkpoint kinase 2 (Chk2), c-H2AX, TRF1 and TRF2 expressions by immunohistochemistry. FISH was used to assess telomere length. RESULTS: Telomeres shortened significantly from normal (N) to LGD and HGD (P < 0.0001; P = 0.012), then increased in length in IC (P = 0.006). TRF1 and TRF2 expressions were diminished from N to LGD and HGD (P = 0.004, P < 0.0001, ns) and were reexpressed at the invasive stage (P = 0.053 and P = 0.046). Phosphorylated ATM, Chk2 and H2AX appeared already in LGD (respectively, P = 0.001, P = 0.002 and P = 0.02). Their expression decreased from HGD to IC (respectively, P = 0.03, P = 0.02 and P = 0.37). These activating phosphorylations were inversely correlated with telomere length and TRF1/2 expression. CONCLUSION: In a model of colon multistep carcinogenesis, our data indicate that telomeric length and protein expression levels are inversely correlated with the activation of the DDR pathway.

Prognostic significance of p53 gene mutations and protein overexpression in localized gastrointestinal stromal tumours.

AIMS: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumours (GISTs). The aim was to determine the prognostic significance of p53 alterations as an additional genetic change in GISTs. METHODS AND RESULTS: We reviewed 125 patients with localized GISTs subjected to complete resection between 1990 and 2002. Mutational analyses of c-kit exons 9, 11, 13 and 17, p53 exons 4-8 and immunohistochemistry for p53 protein were conducted using paraffin-embedded tissues. Alterations of p53 were observed in 50 patients (40.0%). Based on the National Institutes of Health's risk category, p53 alterations were noted more frequently in the higher risk categories (P = 0.041). With a median follow-up of 56.5 months (range: 2.3-126.8), 5-year relapse-free survival (RFS) rates were 61.7% without p53 alterations, compared with only 40.2% with p53 alterations (P = 0.009). Multivariate analysis indicated that p53 alterations comprised an independent, poor prognostic factor for RFS, in addition to c-kit mutations, large size, a high mitotic count and non-gastric primary sites. CONCLUSIONS: Alterations in p53 were more commonly observed in localized GISTs at higher risk of relapse. This suggests that they are significant as an independent, poor prognostic factor.

Low-grade fibromyxoid sarcoma of the colon.

Low-grade fibromyxoid sarcoma is a recently recognised soft tissue neoplasm. It is rare and has a tendency to arise from deep soft tissue of the lower extremities. An origin from the colon has not been reported in the medical literature. We report the low-grade fibromyxoid sarcoma originating from the colon in a 43-year-old male patient, treated by right hemicolectomy and nephrectomy.

Clinicopathological review of 61 patients with early bile duct cancer.

AIMS: The concept of early cancer is already established in the hollow viscus. However, there is no broadly accepted concept of early bile duct cancer. We aimed to assess whether early bile duct cancer patients have characteristic clinicopathological features and a better prognosis compared with patients with advanced bile duct cancer. MATERIALS AND METHODS: Between June 1996 and December 2004, 614 patients were histologically confirmed with primary bile duct cancers after resection. Extrahepatic early bile duct cancers are defined as carcinoma where invasion is confined within the fibromuscular layer of the extrahepatic bile duct. Intrahepatic early bile duct cancers arising from intrahepatic large bile ducts are also defined as carcinoma confined within the fibromuscular layer. We retrospectively reviewed medical records to obtain demographic, laboratory, radiological and pathological data. RESULTS: Sixty-one (10%) patients were categorised with early bile duct cancers. They were frequently detected at asymptomatic (39%) or non-icteric (84%) stages. The most common gross type was the intraductal-growing type (58%). Not otherwise specified adenocarcinoma was only 67%, whereas papillary carcinoma was 31% of cancers. No lymph node metastasis and no lymphovascular/perineural invasions were noted in 89% of patients. The 5-year survival rate for early bile duct cancer was excellent (80%). CONCLUSIONS: Although early bile duct cancer is not a common disease, it is not a very rare entity either. The clinicopathological features of early bile duct cancer patients differ from those of advanced bile duct cancer patients, with asymptomatic clinical presentation, different macroscopic and microscopic findings, and excellent prognosis.

Primary sclerosing lipogranuloma of the rectum: CT findings.

Sclerosing lipogranuloma is a rare, benign disease which is a peculiar granulomatous reaction of fatty tissue. This disease affects multiple organs and the majority of cases are secondary to exogenous foreign bodies. The authors report a case of primary sclerosing lipogranuloma of the rectum mimicking a submucosal rectal tumour.

The difference between the constitutive and facultative skin color does not reflect skin phototype in Asian skin.

BACKGROUND/PURPOSE: The assessment of the sensitivity of human skin to ultraviolet (UV) radiation is important in the area of phototherapy, photodermatoses, photo-aging, photo-carcinogenesis, and photo-protection. Some reports have shown that quantitatively measured skin color is a good indicator for predicting UV sensitivity to human skin in Caucasians. In this study, our aim was to define the correlation between skin color and the skin phototype assessed by the Fitzpatrick method in Asian brown skin. METHODS: A total of 180 medical students with similar life styles were included in this study. Their skin phototype was classified according to the system introduced by Fitzpatrick. Then, using a Minolta Spectrophotometer CM-2002, their skin color was determined on the buttocks and forehead. The buttock color was taken as the constitutive skin color, and the forehead color as the facultative skin color. Using these measured values, we compared the skin color with the skin phototype to find their correlation. Also, we investigated whether the difference between the constitutive and facultative skin colors of each individual had a relationship with his or her skin phototype. RESULTS: The constitutive skin color became darker with increasing skin phototype, and this change was statistically significant. As for the facultative skin color, it also became darker with increasing skin phototype, but was less well correlated with the skin phototype than the constitutive skin color. However, the difference between the constitutive and facultative skin colors did not show consistent results in predicting the skin phototype. CONCLUSION: In this study, we found that the constitutive skin color can be a good indicator of the skin phototype. However, the difference between the constitutive and facultative skin colors of each individual does not give any meaningful information for the assessment of his or her skin phototype in Asian skin.