Akiko Sumi

Identification of non-small-cell lung cancer with activating EGFR mutations in malignant effusion and cerebrospinal fluid: Rapid and sensitive detection of exon 19 deletion E746-A750 and exon 21 L858R mutation by immunocytochemistry

BACKGROUND Recently, we have reported that EGFR mutation-specific antibodies performed well in immunohistochemical analysis, with good sensitivity. We investigated whether this method could detect non-small-cell lung cancer (NSCLC) carrying EGFR mutations in malignant effusions and cerebrospinal fluid (CSF), comparable to the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp assay. Furthermore, we compared activating EGFR mutations between primary and recurrent NSCLC. PATIENTS AND METHODS Twenty-four patients with NSCLC effusions and CSF were examined by immunocytochemistry using antibodies specific for the E746-A750 deletion mutation in exon 19 and the L858R point mutation in exon 21. The PNA-LNA PCR clamp assay was used to detect the E746-A750 deletion at exon 19, L858R mutation at exon 21, and T790M mutation at exon 20. RESULTS We were able to identify EGFR mutations in NSCLC effusion and CSF with a sensitivity of 100% (5/5) using the anti-delE746-A750 antibody and 100% (8/8) using the anti-L858R antibody. Furthermore, in samples without these EGFR mutations, immunocytochemistry with the two specific antibodies identified 91% (10/11) as negative for both the deletion and the point mutations in EGFR. Activating EGFR mutations decreased in recurrent NSCLC compared with primary NSCLC, and the T790M mutation was detected in recurrent NSCLC of patients receiving gefitinib treatment. CONCLUSIONS Identification of EGFR mutations is important for patients with primary and recurrent NSCLC. Rapid and sensitive immunocytochemistry using mutation-specific antibodies to detect EGFR mutations will be useful for diagnosing responsiveness to EGFR-targeted drugs.

RECQL1 DNA Repair Helicase: A Potential Therapeutic Target and a Proliferative Marker against Ovarian Cancer

Objective This study analyzed the clinicopathological correlation between ovarian cancer (OC) and RECQL1 DNA helicase to assess its therapeutic potential. Methods Surgically resected OC from 118 retrospective cases, for which paraffin blocks and all clinical data were complete, were used in this study. RECQL1 and Ki-67 immunostaining were performed on sections to correlate RECQL1 staining with subtype and patient survival. Ten OC and two normal cell lines were then examined for RECQL1 expression and were treated with siRNA against RECQL1 to assess its effect on cell proliferation. Results Of the 118 cases of adenocarcinoma (50, serous; 26, endometrioid; 21, clear cell; 15, mucinous; 6, other histology), 104 (90%) showed varying levels of RECQL1 expression in the nuclei of OC cells. The Cox hazards model confirmed that diffuse and strong staining of RECQL1 was correlated with histological type. However, RECQL1 expression did not correlate with overall patient survival or FIGO stage. In vitro, RECQL1 expression was exceptionally high in rapidly growing OC cell lines, as compared with normal cells. Using a time-course analysis of RECQL1-siRNA transfection, we observed a significant inhibition in cell proliferation. Conclusions RECQL1 DNA helicase is a marker of highly proliferative cells. RECQL1-siRNA may offer a new therapeutic strategy against various subtypes of OC, including platinum-resistant cancers, or in recurrent cancers that gain platinum resistance.

Assessment of MR Imaging as a Tool to Differentiate between the Major Histological Types of Uterine Sarcomas

OBJECTIVES We retrospectively compared and quantified magnetic resonance (MR) images to distinguish major histological types of uterine sarcomas and malignant and benign tumors. METHODS MR images were obtained from patients who underwent preoperative examinations. We compared 25 pathologically confirmed uterine sarcomas (8 leiomyosarcomas, 11 carcinosarcomas, 6 endometrial stromal sarcomas) with 25 uterine leiomyomas. MR findings included tumor size, location, contour, signal intensity (SI), and contrast enhancement. Analysis focused on the contrast ratio (CR) of SI in T2-weighted images for the areas of lowest, highest, and main SI of each tumor as well as the contrast-enhanced ratio (CER) for the main solid part of each tumor in contrast-enhanced T1-weighted images. We evaluated diffusion-weighted (DW) images and apparent diffusion coefficient (ADC) values in 18 tumors (4 sarcomas, 14 leiomyomas). RESULTS Uterine sarcomas and leiomyomas differed significantly in tumor location, contour, hemorrhaging, necrotic and cystic components, CR for the area of lowest SI (P < 0.05), CR for the area of main SI (P < 0.01), and CER (P < 0.05). Leiomyosarcomas were larger than carcinosarcomas or endometrial stromal sarcomas, and the CR for the area of lowest SI of leiomyosarcomas (P < 0.05) was significantly lower. The CER for endometrial stromal sarcomas (P < 0.05) showed the most homogeneous enhancement. Hemorrhagic or necrotic and cystic components were found more often in larger tumors, although there was no significant difference in their occurrence between sarcoma types. All uterine sarcomas showed high intensity on DW images. The ADC values were lower of uterine sarcomas than leiomyomas, although the difference was not statistically significant. CONCLUSION Quantitative assessment using the CR or CER was useful for distinguishing benign and malignant uterine tumors as well as major histological types of uterine sarcomas.

Growth inhibitory effect of an injectable hyaluronic acid-tyramine hydrogels incorporating human natural interferon-α and sorafenib on renal cell carcinoma cells.

UNLABELLED Immunotherapy including interferon-alpha (IFN-α) is one of the treatment options for metastatic renal cell carcinoma (mRCC) patients. Despite clinical benefits for the selected patients, IFN-α therapy has some problems, such as poor tolerability and dose-limiting adverse effects. In addition, the frequent injections reduce a patients quality of life and compliance. Recently, an injectable and biodegradable hydrogel system to prolong drug release is reported. In this study, we investigated the anticancer effect of IFN-α (Sumiferon®)-incorporated hyaluronic acid-tyramine (HA-Tyr) hydrogels in human RCC-xenografted in nude mice. We also evaluated the synergistic efficacy of IFN-α-incorporated HA-Tyr hydrogels+sorafenib in this model. IFN-α-incorporated HA-Tyr hydrogels+sorafenib most effectively inhibited tumor growth on human RCC cells xenografted in nude mice. In addition, IFN-α-incorporated HA-Tyr hydrogels+sorafenib inhibited the proliferation of tumor in nude mice by inducing apoptosis and the suppression of angiogenesis. Our results suggest a possibility that HA-Tyr hydrogel drug delivery system prolongs the biological half-life of natural human IFN-α and enhances its anticancer effects on human RCC cells. STATEMENT OF SIGNIFICANCE The scope of this study is to provide an alternative approach to improve the anticancer efficacy in renal cell carcinoma (RCC) treatment by using hyaluronic acid-tyramine (HA-Tyr) hydrogel drug delivery system. We investigated the anticancer effect of natural interferon-α (IFN-α)-incorporated HA-Tyr hydrogels in RCC cells. We also evaluated the synergistic efficacy of natural human IFN-α-incorporated HA-Tyr hydrogels+sorafenib. We demonstrated that HA-Tyr hydrogel system is able to release natural human IFN-α in sustained manner and enhances its anticancer effects on human RCC cells. In addition, we suggested that IFN-α-incorporated HA-Tyr hydrogels+sorafenib exhibited most effectively anticancer effects. Hence, we believe that this approach could be applied to treatment with RCC in the future.

Clinical significance of patterns of increased [ 18 F]-FDG uptake in the thyroid gland: a pictorial review

In the diagnosis and staging of oncologic patients, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is well recognized as an important functional imaging modality. FDG-PET also has been used for cancer screening in healthy individuals. In general, the normal thyroid gland shows absent or low uptake on FDG-PET, which is often identified as an incidental finding on PET. Today, thyroid FDG uptake can be seen in three patterns: diffuse; focal; and diffuse-plus-focal. Diffuse thyroid uptake is mainly considered an indicator of chronic thyroiditis. Focal thyroid uptake has been associated with malignancy (range 25–50%). Diffuse-plus-focal uptake is not well recognized and might also indicate a risk of malignancy. Understanding the patterns of thyroid FDG uptake is thus important for nuclear medicine physicians or radiologists when giving recommendations to the referring physician. In this pictorial review, we show the clinical significance of different patterns of thyroid uptake on FDG-PET [PET/computed tomography (CT)], including ultrasonography (US) findings.

Des-γ-carboxyprothrombin (DCP) and NX-DCP expressions and their relationship with clinicopathological features in hepatocellular carcinoma.

Aim Des-γ-carboxyprothrombin (DCP) has been used as a tumor marker for hepatocellular carcinoma (HCC). Recently the DCP/NX-DCP ratio, calculated by dividing DCP by NX-DCP, has been reported useful in detecting HCC. The purpose of this study is to clarify the significance of DCP and NX-DCP expression in HCC tissues. Methods HCC and non-HCC tissue samples were obtained from 157 patients and were immunohistochemically examined for DCP and NX-DCP expression using anti-DCP antibody and anti-NX-DCP antibody. DCP and NX-DCP expression scores were calculated by multiplying staining intensity grade by percentage of stained area. Serum DCP and NX-DCP levels were determined in 89 patients. We evaluated the relationship between tumor expression, serum level, and pathomorphological findings. Results Intrahepatic metastasis (im) was significantly more frequent in cases with high DCP expression than in cases with low DCP expression. High NX-DCP expression was associated with significantly lower histological grade, and less frequent im or portal vein invasion (vp) than low NX-DCP expression. Serum DCP was correlated with DCP expression, but serum NX-DCP was not correlated with NX-DCP expression. DCP-positive (≥40 mAU/L), NX-DCP-positive (≥90 mAU/L), and DCP/NX-DCP ratio-positive (≥1.5) cases were associated with significantly larger tumor size and more frequent vp than negative cases. DCP was rarely expressed, but NX-DCP was frequently expressed in non-cancerous liver tissues. Patients with NX-DCP expression-negative tumors showed a lower survival rate than those with NX-DCP expression-positive tumors (p = 0.04), whereas the survival in serum NX-DCP-positive cases was lower than that of serum negative cases (p = 0.02). Conclusions DCP and NX-DCP were produced in HCC tissues, but differed in expression level and biological properties. DCP expression, serum DCP or NX-DCP level, and DCP/NX-DCP ratio were closely related to malignant properties of HCC.

Infantile hemangioma of the liver in an adult: A case report and review of the literature

Infantile hemangioma (IH), a representative vascular liver tumor, usually occurs in infancy or early childhood but rarely in adults. In this study, we describe a case of IH in a 47-year-old female and we also review the literature. A plain computed tomography (CT) image revealed five hypoattenuating masses in the liver. A dynamic study revealed the masses appeared to be well-enhanced in the arterial phase, and were considered to be high-flow hemangiomas. The tumors appeared as hypointense tumors on the T1-weighted images and as hyperintensities on fat-suppression T2-weighted images. Following the administration of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), tumors appeared to be well-enhanced in the arterial phase. In the portal phase, tumors demonstrated isointensity compared with the surrounding liver parenchyma, and hypointensity in the equilibrium and hepatobiliary phases. The apparent diffusion coefficient (ADC) values ranged from 2.0 to 2.4x10(-3) mm2/sec. Microscopically, the tumors were composed of numerous capillary-like small vessels lined with plump endothelial cells, arranged in a single layer without mitoses, and small bile ducts were trapped and scattered within the tumor. These findings were considered to be characteristic of IH. To the best of our knowledge, this case is the third report on IH in adults.

Editorial on “Distribution of malignant lymphomas in the anterior mediastinum: a single-institution study of 76 cases in Japan, 1997–2016”

Mediastinal tumors differ in type and frequency depending on the mediastinal compartment. The tumor location, site of origin, area of existence and extension, and inner structure are extremely valuable factors in image interpretation and diagnosis.

Large cell neuroendocrine carcinoma of the maxillary sinus on fine needle aspiration cytology: Report of a rare case with a focus on pitfalls in diagnosis

Head and neck large cell neuroendocrine carcinoma (LCNEC) is a rare high‐grade malignant tumor with neuroendocrine differentiation. We report a case of LCNEC causing difficulty in cytological diagnosis. A 60‐year‐old man with right‐sided face pain presented with a swelling at the right cheek, and he complained of right nasal obstruction and lacrimation. Preoperative fine‐needle aspiration cytology (FNAC) showed high cellularity, with a moderate number of clusters of tumor cells on an abundant necrotic background. The clusters were arranged in sheet structures with palisading, and were cohesive with overlapping. The tumor cells had comparatively abundant cytoplasm, with conspicuous large, irregular nucleoli with a fine granular chromatin pattern. Mitotic figures were observed easily. On immunocytochemistry using LBC smear, tumor cells were negative for p40. High‐grade carcinoma other than non‐keratinizing squamous cell carcinoma was suggested from these findings on FNAC. The pretreatment histological biopsy sample revealed tumor cells with solid growth pattern, necrotic materials and large polygonal cells with abundant cytoplasm, fine granular chromatin, and conspicuous nucleoli. Head and neck LCNEC with abundant cytoplasm, fine granular chromatin patterns, prominent nucleoli, and necrotic background were very characteristic of LCNEC. If considered carefully, these findings can enable us to exclude the majority of non‐keratinizing squamous cell carcinomas, and FNAC using ancillary technique can be very useful for proper diagnosis.

Mature Cystic Teratoma With an Element of Hepatocellular Carcinoma in Anterior Mediastinum: Magnetic Resonance-Pathologic Correlation

A teratoma is a germ cell tumor (GCT) commonly composed of somatic tissues derived from at least 2 of the 3 germ layers, that is, ectoderm, endoderm, and mesoderm. Teratomas account for <10% of all mediastinal masses.1 The frequency of a mature teratoma in mediastinal masses is ∼6% (27/445)2, whereas the presence of hepatic tissues in a mature teratoma is extremely rare.3 Recently, 2 GCTs with hepatocellular carcinoma (HCC) components were reported: one was a testicular teratoma,4 and the other was a germinoma in the brain.5 To the best of our knowledge, this is the first report of a mature cystic teratoma with an element of HCC arising in the anterior mediastinum.