Riles type 1A common carotid artery occlusion diagnosed by specific external carotid artery Doppler waveform pattern in carotid ultrasonography. Case report

A 67-year-old man was admitted for evaluation of left homonymous hemianopsia. Carotid ultrasonography showed that the right common carotid artery (CCA) was occluded up to just proximal to the carotid bifurcation, and the patent external carotid artery showed retrograde flow to the patent internal carotid artery via the carotid bifurcation. The Doppler waveform pattern of the external carotid artery showed high end-diastolic flow velocity and low pulsatility index. The diagnosis was Riles type 1A CCA occlusion. Digital subtraction angiography and iodine-123 N-isopropyl-p-iodoamphetamine single photon emission computed tomography were performed to confirm the collateral circulation and adequate intracranial hemodynamic sufficiency. Nonsurgical treatment with antiplatelet therapy was performed for the CCA occlusion. No stroke events have occurred within the 2-year follow-up period.     

<Emphasis Type="Italic">p53</Emphasis> Genotype Predicts Response to Chemotherapy in Patients with Squamous Cell Carcinoma of the Esophagus

Background  

Response to chemotherapy and anatomical spread are significant prognostic factors in patients with esophageal squamous cell carcinoma (ESCC) treated by chemotherapy then surgery. Predicting the response to chemotherapy would allow significant optimization of cancer treatment.     

Development of a method for effective amplification of human adenovirus 40

Human adenovirus 40 (Ad40) is an interesting candidate for vector construction because of its tropism for the gastrointestinal tract. Although effective preparation of the vector is necessary for its in vivo application, amplification of Ad40 has been very difficult. Ad40 E1 deletion mutants were detected by PCR in the viral DNA from Ad40 Dugan amplified by Ad5 E1-expressing human embryonic kidney (293) cells and in Ad40 Dugan plaques observed with Ad5 E1-expressing human retinoblastic cells. For the purpose of generating a single wild-type Ad40 clone, the entire Ad40 DNA was cloned into a plasmid by homologous recombination. A pure Ad40 was successfully generated by plasmid transfection and subsequently amplified with Ad5 E4orf6-inducible 293 (2V6.11) cells. 2V6.11 is an apposite cell line for effective Ad40 amplification and for future vector construction because Ad40 genetic integrity was maintained with this Ad5 E1 and E4orf6 trans-complementing cell line.     

A human case of subcutaneous dirofilariasis caused by Dirofilaria repens in Vietnam: histologic and molecular confirmation

Human dirofilariasis caused by infection with Dirofilaria worms has been frequently reported. The symptoms associated with infection by these filarial parasites, which are transmitted to humans by zooanthropophilic mosquitoes, are characterized by mainly pulmonary and subcutaneous nodules. Here, we report the first case in Vietnam of a subcutaneous dirofilariasis with a painful nodule in the right eyelid. An immature female worm was removed by excisional biopsy and identified as Dirofilaria repens by histology and DNA analysis.     

Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7 : Implications in the Pathogenesis of Gelatinous Drop-Like Corneal Dystrophy

Gelatinous drop-like dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterized by subepithelial amyloid depositions on the cornea. Previous clinical and laboratory observations have strongly suggested that epithelial barrier function is significantly decreased in GDLD. Despite the decade-old identification of the tumor-associated calcium signal transducer 2 (TACSTD2) gene as a causative gene for GDLD, the mechanism by which the loss of function of this causative gene leads to the pathological consequence of this disease remains unknown. In this study, we investigated the functional relationship between the TACSTD2 gene and epithelial barrier function. Through the use of immunoprecipitation and a proximity ligation assay, we obtained evidence that the TACSTD2 protein directly binds to claudin 1 and 7 proteins. In addition, the loss of function of the TACSTD2 gene leads to decreased expression and change in the subcellular localization of tight junction-related proteins, including claudin 1, 4, 7, and ZO1 and occludin, both in diseased cornea and cultured corneal epithelial cells. These results indicate that loss of function of the TACSTD2 gene impairs epithelial barrier function through decreased expression and altered subcellular localization of tight junction-related proteins in GDLD corneas.Gelatinous drop-like corneal dystrophy (GDLD) has been reported as an uncommon, autosomal recessive disease, characterized by bilateral corneal amyloidosis.¹ To date, this disease is still quite rare in many countries, whereas it is relatively common in Japan, with a prevalence rate of 1 in 31,546 estimated from the frequency of parental consanguinity.^2,3 During the first decade, GDLD patients develop subepithelial nodular amyloid depositions that result in severe photophobia, lacrimation, and an ocular foreign body sensation.^4,5 With age, the amyloid depositions typically enlarge, increase in number, coalesce with each other, and exhibit a mulberry-like appearance, thus leading to severe bilateral vision loss usually beginning within the third decade of their lives. The tumor-associated calcium signal transducer 2 (TACSTD2) has been identified as a causative gene for GDLD.^6,7We previously reported that the corneal epithelium of GDLD has significantly increased permeability for fluorescence⁸ and horseradish peroxidase⁹ and that the apical side of the corneal epithelium of GDLD exhibited loosened cell-to-cell junctions and an increased number of scarred cells compared with that of normal cornea.⁸ Furthermore, we have recently shown that the most apical side of the lateral membrane of the superficial cells did not express claudin (CLDN)1, ZO1 (tight junction protein 1 (TJP1)), and occludin (OCLN) proteins in GDLD corneas.¹⁰ These findings strongly suggest that the epithelial barrier function may be compromised in GDLD corneas, thereby allowing the formation of amyloid depositions through permeation of tear lactoferrin^11,12 or apolipoprotein.¹³ However, the exact molecular mechanisms by which the TACSTD2 protein affects the epithelial barrier function have yet to be elucidated.In this study, we sought to shed a light on the presumed role of the TACSTD2 gene in the epithelial barrier function. We found that the TACSTD2 protein directly binds to CLDN1 and 7 proteins and that the functional loss of the TACSTD2 gene leads to decreased expression and altered subcellular localization of the TJ-related proteins. From these findings we conclude that the loss of function of the TACSTD2 gene impairs epithelial barrier function through the functional change of the TJ-related proteins in GDLD corneas.     

Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer

Purpose

This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Methods

The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40?mg/m² twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle.

Results

In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90?mg/m² (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80?mg/m² of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8?% (90?% confidence interval (CI): 6.1–25.5?%), and the median progression-free and overall survival times were 4.5?months (95?% CI: 3.5–5.0) and 15.0?months (95?% CI: 9.5–20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9?% of the patients, thrombocytopenia in 5.1?% and nausea in 7.7?%.

Conclusion

Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.     

Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide

CD138 expression is a hallmark of plasma cells and multiple myeloma cells. However, decreased expression of CD138 is frequently observed in plasma cells of myeloma patients, although the clinical significance of this is unclear. To evaluate the significance of low expression of CD138 in MM, we examined the phenotypes of MM cells expressing low levels of CD138. Flow cytometric analysis of primary MM cells revealed a significant decrease in CD138 expression in patients with relapsed/progressive disease compared with untreated MM patients. Patients with low levels of CD138 had a worse overall survival compared with patients with high levels of CD138, in newly diagnosed patients and patients receiving high-dose chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines, KYMM-1 (CD138- low) and KYMM-2 (CD138- high), were established from a single MM patient with decreased CD138 expression. High expression of BCL6 and PAX5, and downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2 cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib was observed. KYMM-2 cells were further divided in CD138+ and CD138- fractions using anti-CD138-coated magnetic beads. CD138- cells sorted from the KYMM-2 cell line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide compared with CD138+ cells. Our observations suggest that low CD138 expression relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity to lenalidomide. The observed distinct characteristics of CD138 low MM cells, suggest this should be recognized as a new clinical entity. Establishment of a treatment strategy for MM cells expressing low levels of CD138 is needed to improve their poor outcome.     

Cancer specific promoter CpG Islands hypermethylation of homeodomain only protein X gene and its potential tumor suppressive role in pancreatic carcinogenesis

ABSTRACT: BACKGROUND: We have recently identified homeodomain only protein X (HOPX) as a tumor suppressor gene candidate, characterized by tumor-specific promoter DNA hypermethylation in human cancers, and it can remarkably inhibit tumors' aggressive phenotypes. In this current study, we for the first time examined methylation level of HOPX and tested the functional relevance in pancreatic cancer (PC). METHODS: Clinical features of HOPX promoter hypermethylation was investigated in 89 PC tissues, and immunohistochemistry was added. We also examined its functional relevance in phenotype assays such as soft agar, proliferation, invasion, and cell cycle analysis. RESULTS: PC tissues had HOPX gene hypermethylation as compared to the corresponding normal pancreas tissues, and its uniqueness was robust to discriminate tumor from normal tissues (AUC = 0.85, P < 0.0001). Unexpectedly, HOPX was increased in expression in tumor tissues, and immunohistochemistry revealed its predominant expression in the Langerhans islet cells, where HOPX is reduced in expression for PC cells with promoter hypermethylation. HOPX transfectants exhibited G1 arrest with subG1 accumulation, and inhibit tumor forming and invasive ability. CONCLUSION: Defective expression of HOPX which is consistent with promoter DNA hypermethylation may explain aggressive phenotype of pancreatic cancer, and intense expression of HOPX in the Langerhans cells may in turn uniquely contribute to pancreatic carcinogenesis.     

Epigenetic Silencing of HOPX Promotes Cancer Progression in Colorectal Cancer

Homeodomain-only protein X (HOPX)-β promoter methylation was recently shown to be frequent in human cancers and was suggested as tumor suppressor gene in esophageal and gastric cancer. The aim of this study was to investigate the mechanistic roles of HOPX-β promoter methylation and its clinical relevance in colorectal cancer (CRC). HOPX-β promoter methylation was assessed in human CRC cell lines and 294 CRC tissues. HOPX mRNA and protein levels were measured in relation to HOPX-β promoter methylation. The effects of forced HOPX expression on tumorigenesis were studied using in vitro and in vivo assays. The association between HOPX-β promoter methylation and clinical relevance of CRC patients was determined. HOPX-β promoter methylation is cancer-specific and frequently found in CRC cell lines and tissues, resulting in the down-regulation of HOPX mRNA and protein levels. In CRC cell lines, forced expression of HOPX suppressed proliferation, invasion, and anchorage-independent growth. DNA microarray analyses suggested critical downstream genes that are associated with cancer cell proliferation, invasion or angiogenesis. In a mouse xenograft model, HOPX inhibited tumorigenesis and angiogenesis. Finally, HOPX-β promoter methylation was associated with worse prognosis of stage III CRC patients (hazard ratio= 1.40, P = .035) and also with poor differentiation (P = .014). In conclusion, HOPX-β promoter methylation is a frequent and cancer-specific event in CRC progression. This epigenetic alteration may have clinical ramifications in the diagnosis and treatment of CRC patients.