大城 久

We previously investigated the utility of mu-oxo N,N'-bis(salicylidene) ethylenediamine iron (Fe(Salen)) nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen) nanoparticles should rapidly heat up in an alternating magnetic field (AMF), and we hypothesized that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy. Conventional hyperthermic particles are usually made of iron oxide, and thus cannot exhibit anticancer activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in cultured cancer cells, and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically guided delivery of the nanoparticles to the tumor, and AMF-induced heating of the nanoparticles to induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen) nanoparticles per se inhibited tumor growth before the other two modalities were applied. This inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue. When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor masses were dramatically reduced. These results indicate that our strategy of combined hyperthermia-chemotherapy using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a powerful new approach for cancer treatment.

A 57-year-old female was diagnosed as having primary breast cancer (invasive carcinoma of no special type), which was immunohistochemically negative for oestrogen receptor, androgen receptor and human epidermal growth factor receptor Type 2. The main tumour was 54 × 35 mm in size and was located in the internal upper area of the left breast. The tumour had markedly invaded the skin and a daughter nodule was observed in the external upper area of the ipsilateral breast. An enlarged lymph node measuring 12mm in diameter was present in the axilla and an affected parasternal lymph node was also observed. A blood test showed no abnormalities and the patient was negative for tumour markers. We performed three sessions of transcatheter arterial chemoembolization with docetaxel-loaded HepaSphere™. The treatment procedure was successfully performed in all the three sessions. No adverse events higher than Grade 3 were observed. The sizes of the primary lesion and axillary lymph node decreased to 26 × 14 mm (37% reduction) and 10mm, respectively. The parasternal lymph node completely resolved. 2 months later, left total mastectomy and axillary lymph node dissection were performed. The histopathological post-therapy effect was considered to be a mild response (Grade 1a) in the breast lesion and a complete response (Grade 3) in the axillary lymph node. The mean±standard deviation of the minor axis of the vessels embolized with spherical particles was 183.0±96.5 μm. Our results indicate that transcatheter arterial chemoembolization used together with HepaSphere can be an alternative and effective therapy for locally advanced breast cancer.

Despite exhaustive efforts to detect early-stage ovarian cancers, greater than two-thirds of patients are diagnosed at an advanced stage. Although diaphragmatic metastasis is not rare in advanced ovarian cancer patients and often precludes optimal cytoreductive surgery, little is known about the mechanisms and predictive factors of metastasis to the diaphragm. Thus, as an initial step toward investigating such factors, the present study was conducted to characterize the pathological status of ovarian cancer patients who underwent debulking surgery in combination with diaphragmatic surgery. This is a retrospective and cross-sectional study of patients who underwent debulking surgery in combination with diaphragmatic surgery at our institution between January 2005 and July 2015. Clinicopathological data were reviewed by board-certified gynecologists, pathologists, and cytopathologists. The rates of various pathological findings were investigated and compared by Fisher exact test between 2 groups: 1 group that was pathologically positive for diaphragmatic metastasis (group A) and another group that was pathologically negative for diaphragmatic metastasis (group B). Forty-six patients were included: 41 patients pathologically positive and 5 pathologically negative for diaphragmatic metastasis. The rates of metastasis to the lymph node (95.8% vs 20%, P = 0.001) and metastasis to the peritoneum except for the diaphragm (97.6% vs 60.0%, P = 0.028) were significantly increased in group A compared with group B. However, no significant differences between the 2 groups were found for rates of histological subtypes (high-grade serous or non-high-grade serous), the presence of ascites, the presence of malignant ascites, exposure of cancer cells on the ovarian surface, blood vascular invasion in the primary lesion, and lymphovascular invasion in the primary lesion. Our study demonstrated that metastasis to the lymph node and nondiaphragmatic metastasis to the peritoneum are significantly associated with metastasis to the diaphragmatic peritoneum, indicating that these factors may be pathological predictors of diaphragmatic metastasis in patients with ovarian cancer. However, as the data available are not sufficient to demonstrate the predictive power of these factors, a further comprehensive, large-scale study should be performed.

We present a case of a 67-year-old man with intussusception of the right ureter associated with a fibroepithelial polyp. The concentric sign and line sign are characteristic radiological findings in intussusception, and these findings could be seen in the present case. Although this entity is rare, its radiological findings are specific. Multidetector row computed tomography and its multiplanar reconstruction make the diagnosis feasible, although the qualitative diagnosis of the tumor was difficult. (C) 2015 Elsevier Inc. All rights reserved.

The concept of the retrograde lymphatic spread of cancer cells appears to account for a subset of the essential mechanisms of cancer metastasis in various organs. However, no adequate data currently exist to illustrate the pathology of the retrograde lymphatic metastasis of cancer cells in human bodies. To shed light on this phenomenon, we report a case of a 63-year-old Japanese man who underwent an esophagectomy and lymph node dissection for early-stage esophageal cancer.The patient's clinical information was evaluated by board-certified surgeons and internists. Surgically excised materials were histopathologically evaluated by attending pathologists.Postoperative pathological examination revealed that the patient's tumor was a well-differentiated squamous cell carcinoma with negative surgical margins (T1N0M0, stage I). Apart from the primary lesion, a single lymphatic vessel invasion was found between the lamina propria and lamina muscularis of the esophagus where intralymphatic cancer cells had spread against the direction of backflow prevention valves and skipped beyond these valves without destroying them.The present case demonstrated that the retrograde lymphatic spread of cancer cells can occur in valve-equipped lymphatic vessels. Our study may not only provide a scientific basis for the concept of retrograde lymphatic metastasis but also explain a portion of the complexities associated with the lymphogenous metastasis of esophageal cancer.

BACKGROUND: Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. METHODS AND RESULTS: A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 μm in the left pulmonary ligaments and from 2.50 to 12.50 μm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm(2) in the left pulmonary ligaments and from 2 to 18 per mm(2) in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. CONCLUSIONS: Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura.

Morphological detection of cancer cells in the rabbit VX2 allograft transplantation model is often difficult in a certain region such as serosal cavity where reactive mesothelial cells mimic cancer cells and both cells share common markers such as cytokeratins. Therefore, tagging VX2 cells with a specific and sensitive marker that easily distinguishes them from other cells would be advantageous. Thus, we tried to establish a successively transplantable, enhanced green fluorescent protein (EGFP)-expressing VX2 model. Cancer cells obtained from a conventional VX2-bearing rabbit were cultured in vitro and transfected with an EGFP-encoding vector, and then successively transplanted in Healthy Japanese White rabbits (HJWRs) (n = 8). Besides, conventional VX2 cells were transplanted in other HJWRs (n = 8). Clinicopathological comparison analyses were performed between the two groups. The success rate of transplantation was 100 % for both groups. The sensitivity and specificity of EGFP for immunohistochemical detection of VX2 cells were 84.3 and 100 %, respectively. No significant differences in cancer cell morphology, tumor size (P = 0.742), Ki-67 labeling index (P = 0.878), or survival rate (P = 0.592) were observed between the two. VX2 cells can be genetically altered, visualized by EGFP, and successively transplanted without significant alteration of morphological and biological properties compared to those of the conventional model.

Sclerosing angiomatoid nodular transformation (SANT) is a recently recognized and rare, nonneoplastic lesion of the spleen. Some papers have reported an increased SANT diameter during the follow-up period. We present two cases of SANT whose size increased during the follow-up period. Diffusion-weighted magnetic resonance imaging (DWI) findings correlated well with the pathological findings of SANT, the multinodular high-intensity area as the angiomatoid nodules and the peripheral low-intensity area as fibrous tissues. Therefore, DWI may be a useful imaging tool. (C) 2015 Elsevier Inc. All rights reserved.

Purpose: To assess various ultrasound (US) findings, including B-mode, shear-wave elastography (SWE), and contrastenhanced US, in accurately assessing ablation Inargins after irreversible electroporation (IRE) based on radiologic pathologic correlation, and to compare these findings between IRE and radiofrequency (RF) ablation. Materials and Methods: IRE (n = 9) and RF ablation (n = 3) were performed in-vivo in three pig livers. Each ablation zone was imaged by each method immediately after the procedure and 90 minutes later. Ablation zones were evaluated based on gross pathologic and histopathologic findings in samples from animals euthanized 2 hours after the last ablation. The characteristics and dimensions of the histologic ablation zones were qualitatively and quantitatively compared against each US finding. Results: In B-mode US at 90 minutes after IRE, the ablation zones appeared as hyperechoic areas with a peripheral hyperechoic rim, showing excellent correlation (12 = 0.905, P < .0001) with gross pathologic findings: SWE showed that tissue stiffness in the IRE ablation zones increased over time. Contrast-enhanced US depicted the IRE ablation zones as hypovascular areas in the portal phase, and showed the highest correlation (r2 = 0.923, P < .0001) with gross pathologic findings. The RF ablation zones were clearly visualized by B-mode US. SWE showed that tissue stiffness after RF ablation was higher than after IRE. Contrast-enhanced US depicted the RF ablation zones as avascular areas. Conclusions: IRE and RF ablation zones can be most accurately predicted by portal-phase contrast-enhanced US measurements obtained imMediately after ablation.

Great progress has been made in the diagnosis of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) in the last few years due to the use of molecular criteria. This has allowed us to identify a new type of hepatic nodule. In this case report, we present a male patient with a hepatic nodule associated with idiopathic portal hypertension (IPH) pathologically exhibiting not only the morphological features of FNH, such as ductular reactions, dilated sinusoids, major vascular abnormalities and an immunohistochemical "map-like" pattern of glutamine synthetase (GS), but also the immuno-histological features of focal HCA, such as strong expression of serum amyloid A and C-reactive protein and weak expression of GS. As the final diagnosis, the nodule was identified as an FNH-like lesion with focal inflammatory hepatocellular adenoma.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. There have been few case reports on the cytopathologic features of MASC to date. We examined the clinicopathological and cytological features of seven cases of MASC defined by RT-PCR analysis of the ETV6-NTRK3 fusion gene. The cases occurred in three men and four women aged between 39 and 68 years, with a mean of 51.6 years. In five of these seven cases, the tumor involved the parotid gland. Histologically, all cases displayed predominantly microcystic patterns, often a mixture of follicular and papillary-cystic structures. All tumors were immunoreactive for mammaglobin, S-100 protein, and vimentin. Available fine-needle aspiration cytology smears were cellular and exhibited many loosely cohesive syncytial clusters or isolated cells. Many histiocytes, some of which contained hemosiderin pigments, and variously shaped mucinous material were evident in the background or within the epithelial clusters. The majority of cases showed small to medium-sized follicular structures with secreted materials. Papillary clusters were occasionally found. Tumor cells exhibited small to medium-sized round to oval nuclei, with a smooth contour and indistinct or small nucleoli, and vacuolated cytoplasm. No tumor cells had obvious intracytoplasmic zymogen granules. It appeared that clusters of small to medium-sized follicular and papillary configurations consisting of bland tumor cells with vacuolated cytoplasm, but lack of intracytoplasmic zymogen granules, in a mucinous or hemosiderin-laden histiocyte-rich background, were a characteristic cytological feature highly suggestive of MASC. Diagn. Cytopathol. 2014;42:846-855. (c) 2014 Wiley Periodicals, Inc.

AIM: To evaluate the usefulness of three-dimensional (3D) shear-wave elastography (SWE) in assessing the liver ablation volume after radiofrequency (RF) ablation. METHODS: RF ablation was performed in vivo in 10 rat livers using a 15-gauge expandable RF needle. 3D SWE as well as B-mode ultrasound (US) were performed 15 min after ablation. The acquired 3D volume data were rendered as multislice images (interslice distance: 1.10 mm), and the estimated ablation volumes were calculated. The 3D SWE findings were compared against digitized photographs of gross pathological and histopathological specimens of the livers obtained in the same sectional planes as the 3D SWE multislice images. The ablation volumes were also estimated by gross pathological examination of the livers, and the results were then compared with those obtained by 3D SWE. RESULTS: In B-mode US images, the ablation zone appeared as a hypoechoic area with a peripheral hyperechoic rim; however, the findings were too indistinct to be useful for estimating the ablation area. 3D SWE depicted the ablation area and volume more clearly. In the images showing the largest ablation area, the mean kPa values of the peripheral rim, central zone, and non-ablated zone were 13.1 +/- 1.5 kPa, 59.1 +/- 21.9 kPa, and 4.3 +/- 0.8 kPa, respectively. The ablation volumes depicted by 3D SWE correlated well with those estimated from gross pathological examination (r(2) = 0.9305, P = 0.00001). The congestion and diapedesis of red blood cells observed in histopathological examination were greater in the peripheral rim of the ablation zone than in the central zone. CONCLUSION: 3D SWE outperforms B-mode US in delineating ablated areas in the liver and is therefore more reliable for spatially delineating thermal lesions created by RF ablation. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

The elucidation of the pathogenesis of human diseases requires increasingly relevant and rigorous animal models. Therefore, investigators must select an appropriate mammalian model. Mice and rats are indispensable in the understanding of the mechanisms of human diseases, but other non-rodent mammals are required in certain situations. The rabbit is one such species. The rabbit exhibits greater biological similarities to humans than the mouse or rat, and the rabbit VX2 allograft cancer model has been used in a broad range of oncological studies, such as stromal responses, metastatic behaviors and therapeutic effects. Cancer cells in this model proliferate in a host rabbit that maintains a natural immunity, which makes this model attractive and unique. However, these examples constitute only a small number of advantages of a rabbit model. Numerous reports suggest that the rabbit is an attractive cancer-bearing animal model for the study of cancer metastasis and the lymphatic system. I briefly review the relevant medical literature and compare the rabbit lymphatic system with mice, rats and humans.

背景:胞巣状軟部肉腫(alveolar soft part sarcoma、ASPS)は若年成人の四肢に好発するまれな悪性腫瘍である。今回、肺転移を契機に発見された大腿部原発ASPSの1例を経験したので報告する。症例:35歳、女性。両肺に多発腫瘤を認め、胸腔鏡下肺部分切除術が施行された。肺腫瘤割面の捺印細胞診標本では、類円形核と大型の核小体を有する異型細胞が結合性の緩い細胞集団として、あるいは孤立性に多数出現していた。これらの異型細胞は豊富な細胞質を伴い、細胞質内には針状の結晶構造物を含んでいた。また、免疫細胞化学的にはtranscription factor for immunoglobulin heavy-chain enhancer3(TFE3)が異型細胞の核に陽性であった。これらの細胞学的所見より、ASPSの肺転移が示唆された。病理組織学的検索でもASPSに合致する所見が得られた。電子顕微鏡的には細胞質内に格子状配列を示す結晶が認められた。さらに、RT-PCR法にてASPL-TFE3融合遺伝子I型転写産物が検出された。その後の精査で、右大腿軟部組織に原発巣が発見された。結論:ASPSでは転移巣が原発巣に先行してみつかることがしばしばあるが、転移巣の細胞診材料でも診断を推定することが可能と考えられた。(著者抄録)

OBJECTIVES: Shear wave elastography is a novel noninvasive method for assessing liver fibrosis by measuring liver stiffness. This study was conducted to evaluate how pathologic changes could have an impact on measured elasticity values in both resected hepatocellular carcinomas and adjacent liver tissue. METHODS: Intraoperative shear wave elastography was performed in 7 patients who underwent liver resection at our institution; 7 hepatocellular carcinomas and adjacent liver tissue were subjected to elastographic measurements. A total of 48 circular regions of interest (ROIs; 3-8 mm in diameter) were located in the hepatocellular carcinomas (n = 37) and adjacent liver tissue (n = 11), and mean stiffness values were obtained from each ROI. All of the histologic images corresponding to the 48 ROIs after surgery were transformed into digital microscopic images by a scanning system, and histologic parameters, such as the proportions of nuclear areas, fatty areas, fibrous areas, and vessel areas, were quantitatively assessed. Relationships between the mean stiffness and the histologic parameters were investigated by the mixed effects model. RESULTS: By univariate analysis, the proportions of collagen fiber areas (P = .039), fibrous areas (P = .045), hepatocellular nuclear areas (P = .045), and nuclear areas other than hepatocellular and lymphoplasmacytic areas (P = .039) showed statistically positive associations with mean stiffness values. Multivariate analysis indicated that the proportion of collagen fiber areas was the strongest pathologic determinant of mean stiffness (P = .008), with hepatocellular nuclear areas also having a significant effect (P = .010). CONCLUSIONS: Fibrosis predictably affects elastographic estimation, but hepatocellular density (ie, hepatocellular nuclear areas) also alters elastographic assessment.

Objective: This study aimed to evaluate the usability of peritoneal swabbing cytology (PSC) with cotton swabs as an effective method for the detection of peritoneal metastasis during the staging laparotomy of epithelial ovarian carcinomas and borderline tumours (EOC/BT). Study Design: One hundred and ninety-two patients with EOC/BT who underwent laparotomy at the Yokohama City University Hospital from 2004 to 2010 were analysed retrospectively. The positive rates of the PSC and ascites/peritoneal-wash cytology (A/PWC) were compared. Results and Conclusion: Both A/PWC and PSC were performed during laparotomy (n = 140). The rate of metastasis detection with A/PWC was significantly higher than with PSC (50.0 vs. 20.7%, p &lt 0.001 by χ2 test). The superior detection ability of A/PWC was observed regardless of the presence of macroscopic peritoneal metastasis in 56 cases with macroscopic peritoneal metastasis, with A/PWC detecting 80.3% of cases versus PSC detecting 37.5% (p = 0.013). In 84 cases without macroscopic peritoneal metastasis, A/PWC detected 29.8% of cases versus 9.5% with PSC (p = 0.003). Our results suggest that PSC is insufficient to evaluate the peritoneal metastasis for the surgical staging of EOC/BT. Other procedures such as subdiaphragmatic A/PWC should be included when possible to maximize the accuracy of diagnosis. © 2014 S. Karger AG, Basel.

The present study evaluated the potential clinicopathologic significance of elevated microsatellite alteration at selected tetra-nucleotide (EMAST) in non-small cell lung cancer (NSCLC). Sixty-five NSCLCs (19 squamous cell carcinomas, 39 adenocarcinomas, one adenosquamous cell carcinoma, and 6 large cell carcinomas) were examined for EMAST in the ten selected tetra-nucleotide markers. Traditional microsatellite instability (MSI) in the five mono-or di-nucleotide markers of the Bethesda panel was also examined, and compared with EMAST. The incidence of EMAST was higher than that of traditional MSI, as 64.6% (42/65) and 12.3% (8/65) tumors respectively exhibited EMAST and traditional MSI in at least one marker. EMAST and traditional MSI appear to occur independently, as no significant association in their incidence was found (Fisher's exact test, P = 0.146). Subjects who exhibited EMAST in two or more markers had a significantly higher incidence of history of other malignant neoplasms (42.9% [9/21]), compared to those with less than two markers (16.3% [7/43] (Chi-square test, P = 0.021)). Taken together, impairment of molecular machinery for maintaining stable replication of the tetra-nucleotide-repeating regions, which would differ from machinery for mono-or di-nucleotide-repeating regions, may elevate susceptibility to NSCLCs and certain neoplastic diseases. Elucidation of the potential molecular mechanism of EMAST is expected to lead to a discovery of a novel genetic background determining susceptibility to NSCLC and other multiple neoplasms. This is the first report describing a clinicopathologic significance of EMAST in NSCLC.

Large cell neuroendocrine carcinoma (LCNEC) is the rarest type of urinary tract malignancy. Herein, we report a case of LCNEC that arose in the ureter of a 78-year-old Japanese man with a history of ascending colon cancer that had been excised by a right hemicolectomy. Left-sided hydronephrosis associated with the ureteral tumor was discovered during follow-up. A left nephroureterectomy combined with a partial resection of the urinary bladder was performed because atypical cells were detected using voided urine cytology. A histopathological examination revealed that the ureteral tumor contained large atypical epithelial cells of neuroendocrine morphology without a urothelial carcinomatous component. The neoplastic cells were immunohistochemically positive for synaptophysin, chromogranin A, CD56, and cytokeratins, but they were negative for uroplakin III and thyroid transcription factor-1. The Ki-67 labeling index of the neoplastic cells was 50%. Transmission electron microscopy demonstrated the presence of numerous dense granules in the cytoplasm of the neoplastic cells. The ureteral lesion was finally classified as stage III, pT3 cN0 cM0. The patient's postoperative course was uneventful without chemoradiotherapy, and LCNEC did not recur in the subsequent nine months. This case demonstrates that LCNEC can occur in the ureter, which normally does not contain neuroendocrine cells in the urothelium.

Background. Recent diagnostic imaging tests contribute to improving the diagnosis of pancreatobiliary cancers. However, it is not practical to perform these tests for all patients as screening. Thus, less-invasive and simple screening tests are still required. A method to detect the IgG antibody induced in serum against the p53 protein accumulating due to p53 gene mutation, as a biomarker, was developed around 1990. Method. 35 patients with pancreatic cancer, 12 patients with biliary tract cancer, and 31 patients with benign pancreatobiliary diseases were entered into this study. Measurement of serum anti-p53 antibody was conducted in all patients. In addition, the rate of p53 protein overexpression was examined in those cases that could be examined pathologically. Result. Among all patients in the pancreatic cancer and biliary tract cancer groups, there was no patient with serum anti-p53 antibody positive value that exceeded the standard value. The rate of p53 protein overexpression was 48.0% in the patients with pancreatobiliary cancers and 0% in the benign pancreatobiliary diseases group. Conclusion. Serum anti-p53 antibody measurement does not contribute to the diagnosis of pancreatobiliary cancers. Instead, traditional p53 immunostaining still appears to be valuable in combination with standard procedures. © 2013 Junko Umeda et al.

症例は41歳の女性，検診で右乳房腫瘤を指摘され当院を受診した．29歳と36歳時に右乳房E領域の乳腺多形腺腫に対して，他院で腫瘍摘出術を施行されている．身体所見では，右乳房EAB領域に境界不明瞭な2.3cmの腫瘤を触知し，針生検では，乳腺多形腺腫の再発が疑われた．病理学的に明らかな悪性所見は認めなかったため，整容性を考慮して乳頭温存乳房部分切除術を施行した．術後2年，明らかな局所再発は認めていない．多形腺腫は唾液腺に多く認める良性腫瘍であるが，乳腺原発の報告は少ない．不十分な切除に起因する局所再発や悪性転化が報告されているため，術前に乳腺多形腺腫と診断された場合は，十分な切除断端距離を確保し，腫瘍被膜を損傷しないように切除する必要がある．

Objectives The purpose of this study was to quantitatively assess the contrast kinetics of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles (BR55; Bracco Suisse, Geneva, Switzerland) compared to clinically used microbubbles (SonoVue; Bracco SpA, Milan, Italy) in both normal liver and human hepatocellular carcinoma xenograft tumors in mice. Methods-Microbubbles were injected intravenously into healthy mice (n = 5) and mice bearing hepatocellular carcinoma xenograft tumors (n = 10). Cine loops of contrast enhancement in normal liver and the tumors were acquired for 10 minutes. Quantitative perfusion parameters were derived by fitting time-intensity curves using a dedicated mathematical model combining a bolus function and a ramp function. Immunohistochemical examinations were also performed for normal liver and tumor specimens to determine the level of VEGFR2 expression. Results-The peak contrast enhancement observed in normal liver with BR55 was comparable to that with SonoVue, whereas a significant difference was observed in late-phase enhancement at 10 minutes (ramp slope: P < .01). In the tumor model, SonoVue was rapidly cleared from the circulation, without any noticeable binding in the tumor, whereas BR55 showed a gradual decline, resulting in a longer wash-out period (mean transit time: P < .01). Immunohistochemical examinations showed that intratumoral vascular endothelial cells had sparse and weak VEGFR2 expression, whereas the sinusoidal capillaries in normal liver had much more diffuse and much stronger expression. Conclusions-Our results suggest that BR55 accurately reflects the VEGFR2 status in human hepatocellular carcinoma xenograft tumors. We showed that quantification applied to molecular ultrasound imaging may provide an objective method for measuring the degree of microbubble binding.

膵疾患における超音波内視鏡(EUS)elastographyについて解説した。EUSの利点とその役割にふれ、elastographyにおける膵疾患の評価、strain ratio(SR)を用いた客観的評価による膵癌と腫瘤形成性膵炎との鑑別について述べた。EUS elastographyは対象物の組織硬度を正確に反映しており、膵癌に対する感度は高かった(98.6% 71/72)。ただし進行慢性膵炎例と膵癌との鑑別は困難であった。膵癌と腫瘤形成性膵炎とのSRは膵癌vs腫瘤形成膵炎=39.08±20.54vs23.66±12.65(p<0.05)であり膵癌で高い傾向を示した。EUS elastographyは今後膵疾患の鑑別における新たな精査法の一つとして期待される。(著者抄録)

Background/Aims: Since there is a difference in the slice thickness between preoperative images of liver metastases (1-3mm slices) and surgical liver pathology specimens (5mm slices), micrometastases may not be detected in these specimens. In addition, the accuracy of preoperative imaging for the detection of metastases degenerated by chemotherapy is unclear. Methodology: Five patients with liver metastases from colorectal cancer who had received adjuvant chemotherapy and undergone hepatectomy were included. The whole resected liver was sliced at approximately 1mm intervals and the slices were examined carefully for gross lesions. The preoperative CT and EOB-MRI findings of each lesion were compared with gross and histopathological findings. Results: The accuracy of EOB-MRI was higher than that of CT for the detection of liver metastases. The number of lesions detected on EOB-MRI was in agreement with that of histopathologically proven liver metastases in 4 of the 5 patients. All lesions that were grossly identified but turned out to be non-neoplastic were regenerative nodules associated with drug-induced liver injury or lobular nodules associated with marked fatty change, measuring about 1mm in diameter. Conclusions: EOB-MRI was the most accurate method for the preoperative detection of liver metastases, enabling the visualization of almost all liver metastases.

Objectives-To determine the relative wash-out of hepatocellular carcinomas and dysplastic nodules using Kupffer-phase sonography with Sonazoid (Daiichi-Sankyo, Tokyo, Japan) enhancement and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging (MM) in the evaluation of the histopathologic grades of individual nodules. Methods-This retrospective study included 66 consecutive patients with 78 histologically confirmed hepatocellular carcinomas and dysplastic nodules. In patients with carcinomas, 33 were well differentiated; 29 were moderately differentiated; and 11 were poorly differentiated; and there were 5 dysplastic nodules. All patients underwent both gadoxetic acid-enhanced Mill and Sonazoid-enhanced sonography. The interval between the two imaging examinations was less than 30 days. Six radiologists independently reviewed both images and rated the degree of relative wash-out between the tumorous and nontumorous areas on Kupffer- and hepatobiliary-phase images using a continuous rating scale. We compared these results with the histopathologic grade of each nodule, and the results were then analyzed with multireader multicase receiver operating characteristic analysis. Results-The average Kupffer-phase (P &lt; .001) and hepatobiliary-phase (P = .004) rating scores increased as the carcinomas became less differentiated (Kruskal-Wallis test). The diagnostic accuracies of the average area under the receiver operating characteristic curve, which were estimated using the confidence levels of the relative wash-out of the Kupffer- and hepatobiliary-phase images, were 0.705 and 0.785 for dysplastic nodules versus well-, moderately, and poorly differentiated carcinomas (P = .517), 0.791 and 0.687 for dysplastic nodules and well-differentiated carcinomas versus moderately and poorly differentiated carcinomas (P = .093), and 0.871 and 0.716 for dysplastic nodules and well- and moderately differentiated carcinomas versus poorly differentiated carcinomas (P = .005), respectively. Conclusions-Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced MRI may be useful in estimating the histologic grade, although Kupffer-phase Sonazoid-enhanced sonography may be more accurate in distinguishing hepatocellular carcinomas, especially moderately and poorly differentiated types.

Salivary gland tumors are relatively uncommon and there exists a considerable diagnostic difficulty owing to their diverse histological features in individual lesions and the presence of a number of types and variants, in addition to overlapping histological patterns similar to those observed in different tumor entities. The classification is complex, but is closely relevant to the prognostic and therapeutic aspects. Although hematoxylin-eosin staining is still the gold standard method used for the diagnosis, immunohistochemistry (IHC) can enhance the accuracy and be a helpful tool when in cases to investigate the subjects that cannot be assessed by histological examination, such as the cell nature and differentiation status, cell proliferation, and tumor protein expression. This review depicts on the practical diagnostic utility of IHC in salivary gland tumor pathology under the following issues: assessment of cell differentiation, focusing on neoplastic myoepithelial cells; discrimination of histologically mimic tumor groups; diagnosis of specific tumor types, e.g., pleomorphic adenoma, adenoid cystic carcinoma, and salivary duct carcinoma; and evaluation of malignancy and prognostic factors. IHC plays a limited, even though important, role in the diagnosis of salivary gland tumors, but is often useful to support the histological assessment. However, unfortunately few tumor type-specific markers are still currently available. For these reasons, IHC should be considered a method that can be used to assist the final diagnosis, and its results themselves do not directly indicate a definitive diagnosis.

45歳男。約3年前から右側頭部皮膚に腫瘤が出現し徐々に増大したため受診となった。腫瘤は直径約2.5cm大の桑実状で表面にびらんを来たしており、PET-CTで結節は不規則な集積を示しているが骨の破壊は認めない所見で、腫瘤から1.5〜2.0cm離して全摘術を施行した。腫瘤は皮膚全層におよび不規則隆起性で充実性であり、表皮は反応性に増殖して淡明な腫瘍細胞に移行している所見で、免疫組織化学的には腫瘍細胞はサイトケラチン7や34βE12で陽性で、P53は約80%以上の腫瘍細胞の核で過剰発現しているのを認める所見でありclear cell hidradenomaと診断した。術後7ヵ月で再発や転移はない。

We report a case of high-grade invasive urothelial carcinoma with plasmacytoid differentiation of the urinary bladder. A 75-year-old woman was referred to our hospital because of macroscopic hematuria. Cystoscopy detected a solid pedunculated bladder tumor, and a transurethral resection of the bladder tumor (TUR-Bt) and the image findings showed pT1N0M0 bladder cancer. The histopathological examination revealed the coexistence of a large component of high-grade invasive urothelial carcinoma and a small component of plasmacytoid carcinoma. Following the TUR-Bt, external beam radiotherapy and chemotherapy with gemcitabine and nedaplatin were carried out. The bladder tumor has not recurred for 2 years after the TUR-Bt.

44歳，男性。平成19年1月より誘因なく頭頂部に腫瘤が出現。同時期に右頸部にも腫瘤を自覚。近医でMRI施行し右耳下腺腫瘍を指摘され当科紹介受診。初診時，頭頂部にドーム状隆起した2.2×1.7 cmの暗紅色腫瘤と右耳下腺に直径1.5 cm大の硬結を認めた。頭部皮膚腫瘤に対して皮膚生検術を施行し，血管肉腫と診断。右耳下腺腫瘍に関し耳鼻科へ併診したが経過観察となった。皮膚悪性腫瘍摘出術，全層植皮術を施行。病理組織学的所見で切除断端陽性であり，放射線治療を追加。右耳下腺腫瘍も針生検術で血管肉腫の転移と診断，放射線を追加照射した。術後2ヵ月で多発肺転移が出現し，術後3ヵ月で肺胞出血による呼吸不全にて永眠される。家族歴で両親に血族婚あり，長兄が30歳で白血病にて他界。既往に両眼の白内障あり。また外見上は鳥様顔貌を認め，頭髪や眉毛に白髪あり。血液検査でヒアルロン酸が高値であり，Werner症候群と診断。

Background: Large cell neuroendocrine carcinoma (LCNEC) of the lung, a subtype of large cell carcinoma (LCC), is characterized by neuroendocrine differentiation that small cell lung carcinoma (SCLC) shares. Pre-therapeutic histological distinction between LCNEC and SCLC has so far been problematic, leading to adverse clinical outcome. We started a project establishing protein targets characteristic of LCNEC with a proteomic method using formalin fixed paraffin-embedded (FFPE) tissues, which will help make diagnosis convincing.Methods: Cancer cells were collected by laser microdissection from cancer foci in FFPE tissues of LCNEC (n = 4), SCLC (n = 5), and LCC (n = 5) with definite histological diagnosis. Proteins were extracted from the harvested sections, trypsin-digested, and subjected to HPLC/mass spectrometry. Proteins identified by database search were semi-quantified by spectral counting and statistically sorted by pair-wise G-statistics. The results were immunohistochemically verified using a total of 10 cases for each group to confirm proteomic results.Results: A total of 1981 proteins identified from the three cancer groups were subjected to pair-wise G-test under p &lt 0.05 and specificity of a protein's expression to LCNEC was checked using a 3D plot with the coordinates comprising G-statistic values for every two group comparisons. We identified four protein candidates preferentially expressed in LCNEC compared with SCLC with convincingly low p-values: aldehyde dehydrogenase 1 family member A1 (AL1A1) (p = 6.1 × 10-4), aldo-keto reductase family 1 members C1 (AK1C1) (p = 9.6x10-10) and C3 (AK1C3) (p = 3.9x10-10) and CD44 antigen (p = 0.021). These p-values were confirmed by non-parametric exact inference tests. Interestingly, all these candidates would belong to cancer stem cell markers. Immunohistochmistry supported proteomic results.Conclusions: These results suggest that candidate biomarkers of LCNEC were related to cancer stem cells and this proteomic approach via FFPE samples was effective to detect them. © 2011 Nomura et al licensee BioMed Central Ltd.

In July 2003, a 63-year-old man received a low anterior resection for rectal cancer. In February 2006, he underwent a right hepatectomy for a solitary metastatic liver tumor the liver tumor had not invaded the bile duct, and a curative resection was performed. In August 2008, an enhanced computed tomography examination revealed a massive focal lesion at the point of the common bile duct. Endoscopic ultrasonography clearly revealed a hyperechoic polypoid lesion that had spread laterally on the surface of the slightly dilated bile duct and had a smooth outer hyperechoic layer. No lymph nodes were present in this region. Endoscopic retrograde cholangiopancreatography revealed an irregular stricture, and a biopsy was performed through the scope. Microscopic examination revealed a tumor characterized as a moderately differentiated adenocarcinoma resembling the liver tumor. We diagnosed the intrabiliary tumor as a metachronous metastatic bile duct tumor from rectal cancer without involvement of the liver parenchyma. This is a very rare case, with recurrence only in an extrahepatic bile duct after the complete resection of a metastatic liver tumor. This is the first clinical, pathological, and radiological description of this rare condition. © Springer 2011.

背景．稀ではあるが，臓側胸膜浸潤のない肺癌症例でも，術中に存在する胸水中に癌細胞が証明されることがある．臨床病理学的にも病期診断に極めて重要な所見であり，癌進展の自然史としても興味深い病態であるが，その機序は明らかでない．症例．血痰を契機に発見された左上葉原発，肺腺癌の68歳・男性．臨床病期はstage IAであった．術中所見では，少量の漿液性胸水を認めた他は，臓側胸膜面の変化や播種巣などはなく，sT1bN0M0D0E1（+）少量・漿液性PL0PM0：stage IAと診断した．術後病理診断では葉気管支間リンパ節に転移を認めた．癌組織の臓側胸膜浸潤は認めなかったが，胸水細胞診にて癌性胸水と診断され，最終的にpT1bN1（#11）M1a（E+）：stage IVの診断となった．結論．癌性胸水の存在は，病期診断，術後の治療戦略上，極めて重要な所見である．術中に臓側胸膜表面に変化のない症例であっても洗浄細胞診を，また少量でも胸水が存在すれば胸水細胞診を積極的に施行すべきである．<br>

Primary hepatic lymphoma is a very rare condition, and the majority of the cases reported are of B-cell origin. We report a case of a 65-year-old man with primary hepatic peripheral T-cell lymphoma, not otherwise specified (PTCL-nos) who presented with 15% weight loss and general fatigue over the previous 9 months. Imaging studies and bone marrow examination could not confirm a diagnosis of lymphoma. Liver biopsy was performed because of an elevated soluble interleukin-2 receptor (sIL-2R) level (17,000 U/I) and hepatomegaly. After the diagnosis of primary hepatic PTCL-nos, treatment with low-dose corticosteroid was initiated, and the sIL-2R level decreased. Discontinuation of corticosteroid treatment resulted in the re-elevation of the sIL-2R level, and subsequently, treatment with low-dose corticosteroid was reinitiated. The sIL-2R level decreased rapidly, and the patient is alive with no evidence of lymphoma for 50 months after diagnosis. Thus, we found that a low-dose corticosteroid was effective in the long-term control of the disease, whereas many previous studies reported that primary hepatic PTCL-nos has a poor prognosis.

Background. A large body of accumulated data has now revealed that podocytes play a major role in the development of proteinuria. However, the mechanisms of podocyte injury, leading to foot process effacement and proteinuria, are still unclear partly due to the current lack of an appropriate strategy for preparing podocytes. In this study, we have developed a novel method of rapid isolation of podocytes from mice using magnetic activated cell sorting with an anti-nephrin antibody. Methods. After endothelial cell depletion using anti-CD31 antibody, nephrin-positive cells were prepared from mouse kidneys using magnetic activated cell sorting with polyclonal rabbit anti-nephrin antibody. Purity of the positively sorted cells was determined by confocal microscopy and fluorescence-activated cell sorting (FACS) analysis. Expression profiles of podocyte-specific molecules in the sorted fractions were characterized by qualitative PCR and immunoblot analysis. Results. Nephrin-positive cells, isolated from mouse kidneys within 6 h, showed dual positivity for synaptopodin and rabbit IgG on confocal microscopy. FACS analysis revealed that the purity of the positively sorted fractions was similar to 75%. The nephrin-positive cells sorted by this approach showed a significantly higher expression of podocyte-specific molecules compared with nephrin-negative fractions. Conclusions. These data strongly suggest that our novel method for isolating podocytes has great utility for various downstream applications such as genomic analysis, proteomics and transcriptomics to elucidate molecular profiling of podocyte biology in vivo compared with conventional methods as our approach requires only several hours to complete and no tissue culture.

Sebaceous carcinoma is the rarest type of oral malignancies. We report a case of primary sebaceous carcinoma of the tongue. Systemic imaging studies revealed that the patient had a T2N2cM0 (International Union Against Cancer guidelines) primary lingual tumor. Histopathological examination revealed neoplastic sebocytic and basaloid cells, and Sudan III staining and electron microscopy revealed intracytoplasmic lipid droplets. The neoplastic cells stained positive for adipophilin; epithelial membrane antigen; epithelial antigen; and cytokeratins 7, 8, and 15, but negative for cytokeratins 5/6, 18, 19, and 20; the androgen receptor; and carcinoembryonic antigen. Superselective intraarterial chemotherapy was administered via the superficial temporal artery concurrent with daily radiotherapy. Multiple biopsies confirmed a complete response of the primary lesion. The patient then underwent neck dissection followed by pathological examination, which revealed lymph nodes metastases. After postoperative radiotherapy to the neck, distant metastases were identified in the mediastinal lymph nodes and the lung. The patient died 17 months after completing the initial course of chemoradiotherapy. Our case demonstrates that superselective intraarterial chemotherapy combined with concurrent radiotherapy can be effective in treating the primary lesion of patients with a sebaceous carcinoma of the tongue. However, an effective strategy to eradicate metastases has yet to be established.

Background. Childhood-onset systemic lupus erythematosus (SLE) is frequently complicated with lupus nephritis (LN), which is characterized by the deposition of DNA-containing immune complex to the glomerulus. Toll-like receptor 9 (TLR9), capable of recognizing the microbially derived CpG oligonucleotide, plays a crucial role in the innate immunity. TLR9 is also assumed to be related to the aetiology of SLE in the recognition of anti-DNA antibody-containing immune complex, but this remains controversial. We conducted a study to elucidate the association between TLR9 and LN in childhood-onset SLE. Methods. We compared the expression and localization of TLR9 and the slit membrane-related protein in the biopsied kidney sample by immunostaining in four children with active or inactive LN. We also evaluated their laboratory findings, such as anti-DNA antibody, complement and proteinuria at biopsy, to assess the correlation to the findings of the immunostaining. Results. TLR9 is not expressed in a normal control kidney. However, TLR9 develops in podocytes only in active LN but disappears in remission. Meanwhile, the slit membrane-related proteins such as nephrin, podocin and synaptopodin in podocytes express clearly and uniformly in remission, but their expression is markedly diminished in active LN, which results in podocyte injury. When TLR9 is expressed in podocytes, all the patients simultaneously showed hypocomplementaemia, high titre of anti-double-stranded DNA (dsDNA) antibody and proteinuria. Conclusion. Injured podocytes in active LN express TLR9. This expression could be associated with proteinuria and increased anti-dsDNA antibody. This is the first report indicating that TLR9 is involved in the aetiology of LN and that it may play some role in podocyte injury.

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1 alpha (HIE-1 alpha)-mediated VEGF-A expression. The EGR-1 modulator,.NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1 alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1 alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. (Am J Pathol 2010, 177:70-83; DOI: 10.2353/ajpath.2010.091164)

Background Little is known about urine cytology of large cell neuroendocrine carcinoma (LCNEC) of the bladder. We report a case of primary LCNEC of the bladder, focusing on urinary cytology. Case A 76-year-old woman who had a history of transurethral resection for urothelial carcinoma of the bladder visited our hospital because of intermittent gross hematuria. Urinary cytology on this visit identified atypical cells, interpreted initially as urothelial carcinoma. Cystoscopy detected a tumor apart from the previous bladder urothelial carcinoma. The diagnosis of LCNEC was pathologically confirmed after the transurethral resection; subsequently radical cystectomy and bilateral pelvic lymphadenectomy were performed. Based on the review of urine cytology for this tumor, neoplastic cells possessed rosette and nuclear molding arrangements with finely or coarsely granular, hyperchromatic nuclei. The average nuclear size of the neoplastic cells was 10.3 mu m, whereas the average cell size was 14.9 mu m. These cells were immunocytochemically positive for synaptophysin, consistent with LCNEC. The postoperative course for this patient was uneventful, and LCNEC had not recurred in the 48 months since cystectomy. Conclusion Our observations suggest that urinary cytology in combination with morphometry and immunocytochemistry may be a potentially useful method for the detection of LCNEC of the bladder. (Acta Cytol 2010;54:303-310)

A 73-year-old female was operated with radical nephrectomy and cholecystectomy for renal cell carcinoma and suspected gallstones after 9 courses of sunitinib treatment. Gallbladder specimen showed gallbladder metastasis originating from the renal cell carcinoma. Gallbladder metastasis from renal cell carcinoma is rare. Here, we discuss a case of gallbladder metastasis from renal cell carcinoma. Copyright © 2010 S. Karger AG.

The case was a 67-year-old male who visited our hospital with a major complaint of macroscopic hematuria. A bladder tumor was found. When a transurethral resection of the bladder tumor was performed, the histopathological diagnosis was neuroendocrine bladder cancer. After chemotherapy with cisplatin and etoposide a partial shrinkage of the tumor was observed however, the patient expired 7 months after the first visit. Copyright © 2010 S. Karger AG.

Extraskeletal osteosarcoma is an uncommon high-grade malignant soft tissue sarcoma. Well-differentiated extraskeletal osteosarcoma is thought to have a better prognosis than classical extraskeletal osteosarcoma, but dedi fferentiation after recurrence has also been reported. We present a case of a primary retroperitoneal extraskeletal osteosarcoma in a 62-year-old Japanese woman. Abdominal CT revealed a large mass with diffuse calcification in the right retroperitoneal space and tumor resection was performed. The histopathological diagnosis was well-di fferentiated retroperitoneal extraskeletal osteosarcoma. She was followed up by CT every 6 months without adjuvant radiotherapy and chemotherapy for 31 months until anaplastic highgrade spindle cell sarcoma recurred in the retroperitoneum. Our case is the seventh reported description of well-differentiated extraskeletal sarcoma, and the first to arise in the retroperitoneum and recur as an entirely dedifferentiated spindle cell sarcoma. Copyright © 2010 Hiromasa Arai et al.