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Background Axillary staging is important for predicting prognosis, and for local control in early breast cancer. Sentinel lymph node biopsy (SLNB) is a widely accepted method to avoid unnecessary axillary lymph node dissection (ALND). Since the ACOSOG Z0011 trial was published, we have refrained from ALND for selected patients with positive SLNB results. However, some cases have shown regional lymph node recurrences after SLNB without axillary dissection. The purpose of this study is to identify risk factors for recurrences, to ensure a safe axillary surgery. Methods A retrospective review of 1011 patientswho underwent SLNB without ALND between June 2004 and March 2017 was performed. Since October 2012, we have not performed ALND in patients (a) with 1 or 2 positive sentinel lymph nodes (SLNs), (b) with positive SLNs that are unmatted or not gross extra nodal extension, (C) in whom clinical tumor size is Results Of the 1011 patients, 969 had negative and 42 had positive SLNs. The median age of patients was 59 years (range 21-88). The median invasive breast tumor size was 15 mm (range 0.05-85), with 1.9% tumors being pathological T3 lesions; 127 patients (12.3%) developed lymphatic vessel invasion. SLNs identification rate was 99.4%. The median number of SLNs removed per patient was 2 (range 1-7). After follow-up of a median 78.5 months, 10 patients (1.0%) had an axillary recurrence and all of them had negative SLN metastasis. The median time to axillary recurrence was 26 months (range 9-94). The hormone receptor (HR) status was significantly related to axillary recurrence (p=0.008). While triple negativity had a tendency to relate (p=0.06), human epidermal growth factor receptor 2 (HER2) status did not correlate with axillary recurrence (p=0.13). Tumor subtypes and axillary recurrence SLNB without ALND (n=1011)Axillary recurrenceP valueHR positive72650.009HR negative1615 HER2 positive12130.13HER2 negative7667 Triple Negative10030.06Not Triple Negative7877 DCIS1240 DCIS: Ductal carcinoma in situ Conclusions As reported previously, the axillary recurrence rate after SLNB was low. Our results show that HR negativity was a significant factor for axillary recurrence. Although the ACOSOG Z0011 trial criteria focused on ALNB positive cases, they do not mention the tumor subtypes. Our findings show that HR negative patients without ALND have to follow up carefully. Citation Format: Sekine C, Nakano S, Mibu A, Otsuka M, Oinuma T. Hormone receptor status is a predictive factor for axillary lymph node recurrence after sentinel lymph node biopsy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-15.

Highlights • Spontaneous cancer remission without treatment is a known phenomenon with various types of cancer. • Although spontaneous breast cancer remission has been thought to be a rare, this may occurs at a certain rate(not rare phenomenon). • When cancer was not detected in the pathological specimen and there were no known biological markers to provide information for the decision regarding adjuvant therapy, observation without further treatment can be option., Introduction Spontaneous breast cancer remission is a rare phenomenon. We report the disappearance from the remaining breast of a new primary carcinoma that had been confirmed through cytology of a pathological specimen, in a case that is strongly suspected to be spontaneous remission. Presentation of case A 44-year-old woman underwent breast-conserving surgery for a tumor located on the border between the upper-outer and lower-outer quadrants of the left breast (T2, N1, M0; Stage IIB). Eleven years after surgery, computed tomography indicated a mass in the upper-inner quadrant of the left breast. Excisional biopsy was initially planned for treatment following the definitive diagnosis because cytology revealed malignancy. The patient had noticed tumor regression one month after fine-needle aspiration and repeat ultrasonography performed the day before excisional biopsy confirmed the tumor reduction. On pathological examination, no tumor cells were observed in the mass. Discussion There was a discrepancy between FNA cytology and pathological diagnosis in our patient. The cytological findings indicated malignancy, but the pathological findings did not. When a tumor’s pathological diagnosis is not malignant even though its FNA cytology diagnosis was malignant, sampling error, cytological over-diagnosis or some other error may have occurred. In this case, however, these were not detected. Because fibrosis was visible on pathological examination, we believe that these events corresponded to spontaneous remission. Conclusion We report a rare case of spontaneous remission in which the cancer disappeared on pathological examination although the cytological diagnosis had been malignant.

Needle biopsy has replaced excisional biopsy as a definitive diagnostic technique for breast tumours, although excisional biopsy is still used for complete tumour removal for therapeutic and/or diagnostic purposes. Many vacuum-assisted breast biopsy (VAB) systems have been made available by several manufacturers since the release of the Mammotome (MMT) by Johnson & Johnson in 1995. Several recent discussions have been conducted to identify whether core needle biopsy (CNB) or VAB, is more appropriate. However, currently available VAB systems differ from the conventional system (i.e. articulate arm type 11-gauge(G) MMT), and the characteristics of both CNB and VAB have been improved. In CNB, a 14-G needle is frequently used to obtain a larger sample. By contrast, VAB is considered easier to perform because it uses a thinner needle and a lighter, non-tethered system. When differentiating CNB from VAB, the type of VAB should also be defined. In this review, we discuss the characteristics of ultrasonography-guided VAB and CNB with a focus on practical issues such as the number of samples and volume of tissue obtained during ultrasonography-guided needle biopsy.

Background In recent years, pathological diagnoses have been increasingly required, especially in small breast lesions, because malpractice lawsuits concerning erroneous cytological diagnoses have been commonly reported. Here, we retrospectively evaluated the significance of FNAC and VAB for small breast lesions using ultrasonography guidance. Patients and Methods A total of 1383 cases for which ultrasonography-guided VAB was performed between June 1996 and December 2012 were reviewed. Of these, 455 small breast lesions (239 nonpalpable and 216 nonmass lesions) were included in the study. Results Ultrasonography-guided FNAC was performed before VAB in 248 cases (54.5%). In 133 cases (53.6%), the results of FNAC were inconclusive. Pathological examinations using VAB revealed malignant and benign lesions in 199 and 256 cases, respectively. Of the 256 benign cases, we performed excisional biopsy in 17 cases (6.6%) and repeated VAB in 8 cases (3.1%). Excisional biopsy revealed malignant lesions in 2 cases. The reason for excisional biopsy was overdiagnosis using FNAC in 6 cases (35%). In all cases of repeated VAB, the pathological diagnosis was benign. The reason for repeated VAB was excision of the lesions in 5 cases (62.5%). The false positive and false negative rates of FNAC were 16.7% and 3.4%, respectively, whereas those of VAB were 0% and 1.0%, respectively. Conclusion Cytology findings for small breast lesions should be considered only when imaging and cytology indicate benign lesions. Therefore, pathological examination without cytological examination should be the initial approach.

A rare case of a woman who presented with an isolated supraclavicular lymph node metastasis 1 year after initial surgery for breast cancer is described. The patient was a 47-year-old woman diagnosed with ductal carcinoma in situ (DCIS) of her left breast under stereo-guided, vacuum-assisted biopsy; she underwent lumpectomy and sentinel lymph node biopsy. The pathological diagnosis was DCIS, 15 × 15 × 33 mm, nuclear grade (NG) 1, estrogen receptor (ER)- and progesterone receptor (PgR)-positive, and surgical margin-negative. The sentinel lymph node was negative for cancer metastasis. She received radiotherapy but no other adjuvant therapy. A supraclavicular lymph node was detected on ultrasonography 1 year after lumpectomy and sentinel node biopsy. A PET scan was performed to rule out metastasis from an organ other than the breast. There was no accumulation except for the supraclavicular lymph node. Excisional biopsy was performed, showing lymph node metastasis from the breast. It was ER-positive, PgR-positive, human epidermal growth factor receptor (Her) 2-negative, and Ki67 80 %. She received radiation to the supraclavicular region and anti-estrogen therapy after the biopsy. Isolated supraclavicular lymph node metastasis was diagnosed only 1 year after initial breast surgery. The key issue was to ensure correct diagnosis in order to provide appropriate treatment, because the metastasis occurred early and was an isolated supraclavicular lymph node metastasis, which might have spread from an organ other than the breast.

In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P

Background Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance. Methods Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17. Results In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL. Conclusions Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3364-8) contains supplementary material, which is available to authorized users.

Adenomatoid odontogenic tumor (AOT) is an uncommon entity of odontogenic origin, characterized by the formation of duct-like structures in the tumor. Although its histogenesis is still uncertain, it is also considered to be a rather hamartoma-like lesion. Here we report a case of AOT in a 22-year-old Japanese woman, the first documented case to have been analyzed for the presence of hard α-keratin (human hair protein). A positive reaction for human hair proteins was noted in the marginal area of calcified material, or at the interface or between areas of dystrophic calcification and columnar epithelial cells. Furthermore, melanin pigment was demonstrated histologically in this case, similar to several previously reported cases of AOT with melanin. This is the first reported case of AOT with hard α-keratin. These findings suggest that AOT may have the potential to differentiate into hair components. (Oral Med Pathol 2008; 13: 7-14 doi: 10.3353/omp.13.7)

A patient with dura-associated Creutzfeldt-Jakob disease (D-CJD) which occurred about 15 years after a dura mater graft is reported in the present study. The prion protein gene analysis disclosed no mutation. The D-CJD was atypical in: (i), the long interval between the onset of ataxia and the occurrence of dementia; (ii), the presence of transient myoclonus; and (iii), the presence of florid plaques in the brain. The electron-microscopic findings showed bundles of amyloid filaments which radiated from the center of the plaques without degenerating neurites. This case of D-CJD may belong to a new subtype of D-CJD.

これまでに心筋梗塞動物モデルにおける漢方方剤の影響を報告してきたが, とくに柴胡加竜骨牡蛎湯の心筋梗塞巣・拡大阻止に及ぼす影響を明らかにするため, 最終的に実験群として10頭を検討した。雄性ブタの左冠動脈前下行枝 (LAD) の末梢に, 経カテーテル的に自家製金属コイルを塞栓として挿入して, 梗塞を発症させた。その後, 実験群は柴胡加竜骨牡蛎湯エキス末 (0.66g/kg/day, n=10) を造設した胃痩から投与し, 4週間飼育した。対照群は, 同様に経カテーテル的にLAD内に自家製金属コイルを挿入して, 基本食のみで4週間飼育した (n=9)。4週後に心臓を全割面標本として, 梗塞巣と非梗塞巣との重量を計測し, さらに梗塞巣について組織学的検討も加えた。実験群の心重量に対する梗塞巣の割合 (2.9±1.6%, n=10) は対照群梗塞巣の心重量に対する割合 (8.2±4.8%, n=9) よりも有意に低下した。さらに左室重量に対する梗塞巣の割合についても, 実験群 (4.9±2.6%) は対照群 (13.4±8.0%) よりも有意に低下した。よって実験群梗塞巣領域は対照群梗塞巣よりも縮小した。組織学的に対照群梗塞巣と境界領域の炎症細胞浸潤像は高度であり, 実験群梗塞巣は線維化で置換され炎症細胞も少なかった。実験群梗塞巣と境界領域における小血管も対照群より増生していた。以上より, 柴胡加竜骨牡蛎湯は動物モデルにおける梗塞発症後の梗塞巣の進展・拡大を阻止すること, すなわち梗塞巣を制限化することが示唆された。

A celiac artery aneurysm associated with Behçet's disease is extremely rare. We herein present the case of successful surgical treatment for an impending rupture of a large celiac artery aneurysm with a wide proximal neck in a patient associated with Behçet's disease. To our knowledge, this is the first report of a procedure involving extra-anatomic aorto-common hepatic artery (CHA) bypass through the retroperitoneal space implanting a 6-mm expanded polytetrafluoroethylene graft. An 18-month postoperative magnetic resonance angiography scan showed a good patency of the aorto-CHA graft without an anastomotic pseudoaneurysm in a closure of aorta and anastomoses.

ブタ心筋梗塞モデルにおける柴胡加竜骨牡蛎湯, 当帰芍薬散, 木防已湯の影響とくに漢方方剤の心筋梗塞巣拡大阻止の有無について検討した。自家製金属コイルを左冠動脈内に挿入して心筋梗塞誘発後, (1) 柴胡加竜骨牡蛎湯投与群 (n=5), (2) 当帰芍薬散投与群 (n=5), (3) 木防已湯投与群 (n=5), (4) 対照群 (漢方方剤非投与群: n=5) にわけて1ヶ月飼育した。その後, 心筋梗塞巣の定量的解析や組織学的に梗塞巣と正常心筋の境界領域について検討した。木防已湯群の梗塞・心臓重量比は2.45±0.97%, 梗塞・左心系重量比は3.55±1.48%であった。一方, 対照群の梗塞・心臓重量比は3.94±0.52%, 梗塞・左心系重量比は5.61±0.45% (p

Background: The β chain of the interleukin 2/15 receptor (IL-2/15Rβ) is induced by the expression of the EWS–WT1 . A case of desmoplastic small round cell tumour (DSRCT) expressing only an unusual EWS-WT1 treated by us is reported here. Aim: To characterise an unusual form of EWS–WT1 . Methods: Frozen tissue sections of the axillary tumour were examined using a laser-assisted microdissection technique and reverse transcriptase polymerase chain reaction. Results: The novel fusion of exon 8 of EWS and the defective exon 10 of WT1 (− KTS ) was detected. Although it was an unusual form, the coexpression of the present EWS–WT1 , IL-2/15Rβ and Janus kinase ( JAK1 ) mRNA was detected in the tumour cells. IL-2 and signal transducers and activators of transcription ( STAT5 ) mRNA were detected in both tumour and stromal cells. Conclusion: The induction of the IL-2/15 receptor signalling pathway may contribute to tumorigenesis in DSRCT through a paracrine or an autocrine system, even though the EWS–WT1 was an unusual form.

冠動脈攣縮モデルにおける当帰芍薬散と木防已湯の影響とくに冠動脈攣縮発生について検討した。雄性ブタの左冠動脈前下行枝 (LAD) をカテーテルで擦過し内膜傷害を起こし, 胃瘻を設置した。実験群は当帰芍薬散群 (ツムラ製, n=6) と木防已湯群 (n=5) に分けて, 各エキス末を胃瘻より投与し4週間飼育した。その後, acetylcholine (ACh) を経カテーテル的に投与し攣縮発生を試みた。対照群 (n=5) は普通食のみで飼育し, 攣縮は冠動脈造影像上で確認した。ACh投与後, 擦過部を含むLADとその末梢枝の限局性ないしはびまん性過収縮像を認めた。ACh投与回数に対する当帰芍薬散群の攣縮発生は5/13, 木防已湯群5/12, 対照群7/13であり, 3群間に差異はなかった。しかし, 実験群全体の攣縮発生率は対照群よりも低下傾向にあった。その機序は明らかではないが, 被検方剤はブタ冠動脈攣縮発生に影響を及ぼす可能性が示唆された。

Atherosclerotic plaque with central depression (depressed lesion) may indicate regression of atherosclerosis in the aorta. Aortic depressed lesions have a solitary elevated area of plaque with a sharply-bordered roung depression in its center and no area ulceration. This may be interpretable as a sign of regression of atherosclerosis. To clarify the pathogenesis of depressed lesion, we studied clinical risk factors such as hypercholesterolemia in patients with depressed lesions that were confirmed at autopsy. The patients were divided into 3 groups according to their total cholesterol level at autopsy: a high-risk group (or = 220 mg/dl), a moderate-risk group (180-220 mg/dl), and a low-risk group (or = 180 mg/dl). Depressed lesions were found in 16.4% of those in the high-risk group, in 14.6% of those in the moderate-risk group and in 69.0% of those in the low-risk group. Severe aortic atherosclerosis was found in 69.8% of the patients; 50.9% of those with severe disease were in the-low risk group. Depressed lesions were also found in those with low levels of low-density lipoprotein cholesterol (or = 140 mg/dl), 58.8% of whom were found to have severe atherosclerosis. There was no relationship between total cholesterol level and the presence of depressed lesions. However, a clinical prevention trial may result in sufficient control of ahterosclerosis among those in the high-risk group and may also lead to regression of aortic lesions.

漢方方剤の体重への影響を研究する前段階として, 肥満マウス (KK-Ay) に対する中国茶の影響を検討した。実験開始時6週齢雄性 KK-Ay 30匹に基本食と Oolong & Tuo Tea あるいは Jasmine Tea を自由に摂取させ16週間飼育した。この間, 定期的に体重測定を行い, 実験終了後に生化学的および各臓器を組織学的に検索した。対照群は tap water を自由に飲水させた。その結果, 両者の実験群体重は対照群よりも実験期間を通して低下し, とくに Jasmine Tea 群は実験開始5週後に最大16.5%の体重減少率を示した。この間の平均食餌摂取量も大であった。体重に関与する要因は多種であり体重減少の機序は今回明らかではなかったが, 成長後のKK-Ay肥満マウスモデルにおいて Jasmine Tea は体重減少に有効であった。

Malignant fibrous histiocytoma (MFH) as soft tissue sarcoma would not be especially noteworthy, but primary hepatic MFH reports are extremely rare. Herein, we report ezrin expression in tumor tissues from two primary hepatic MFH cases with different prognoses. Cases 1 and 2 were both women, ages 45 and 70 years, respectively. Case 1 had an 11 x 10 cm liver tumor in segment (S) 3, and case 2 had two liver tumors, 12 x 8 cm in S5 and 10 x 7 cm in S8. Neither had any other systemic tumors. Cases 1 and 2 survived for two year and ten months and for eight and a half months, respectively, after the initial tumor resection. Microscopically, the tumors of these two cases were similar and showed proliferation of atypical cells, including spindle, pleomorphic and multi-nucleated giant cells arranged in storiform, sheet and/or fascicle patterns, with scattered foci of inflammatory cells, indicating MFH. Ezrin expression in tumor tissue from case 1 was sparse, whereas that of case 2 showed strong ezrin expression in many tumor cells. The present results indicate ezrin immunoreactivity in primary hepatic MFH to correlate possible with prognosis, which is consistent with reports on some other types of malignancies.

[Background] Although advanced imaging technology enables us to detect small breast lesions, it remains a challenge whether it is a benign or malignant tumor with imaging findings alone. A definitive diagnosis is required with cytological or pathological diagnosis under ultrasonography guidance. Excessive examinations and malpractice are also concerned with increased examinations. The purpose of the study was to identify the optimal diagnostic approach for small breast lesions.[Patients and Methods] We reviewed a total of 1532 cases of ultrasonography-guided vacuum-assisted core needle biopsy (VAB) performed at a single institution between June 1996 and December 2013. There were 519 small breast lesions (274 non-palpable lesions and 245 non-mass lesions). Ultrasonographic examinations were performed on a LOGIC 500 (GE Healthcare, Waukesha, WI, USA) using an 11 MHz linear transducer before November 2011, and on Aplio MX (TOSHIBA, Minato, Tokyo, Japan) using an 8 MHz linear transducer since then. We performed VAB under ultrasonography guidance using 11-gauge probes (Mammotome Biopsy system; Biopsys Medical Inc., Irvine, CA, USA) for diagnosis and 8-gauge probes for excision of the lesion.[Results] The mean age of the 519 patients was 52.7 years. Ultrasonography-guided fine needle aspiration cytology (FNAC) was performed before VAB in 269 cases (51.8%). The FNAC revealed 76 malignant, 23 suspected malignant, 92 indeterminate, 47 benign or normal, and 31 inadequate cases. Of these FNAC results, the final pathological diagnosis was benign in 2 of 76 malignant and 6 of 21 suspected malignant cases, and malignant in 4 of 47 benign cases. Accordingly, the true positive, true negative, false positive, and false negative rates for the 146 cases (excluding the indeterminate and inadequate cases) by FNAC were 95.8%, 84.3%, 15.7%, and 4.2%, respectively. The pathological results of the VAB specimens were malignant in 229 and benign in 290 cases. Of the 290 cases classified as benign by VAB, we performed post-VAB excisional biopsy in 20 cases. The reasons for this second pathological examination were malignant or suspicious findings for malignancy by FNAC (8 cases), inconsistent imaging and FNAC findings (5 cases), and others (7 cases). Excisional biopsy revealed malignancy in 3 of these 20 cases. Furthermore, we re-performed VAB in 9 out of the original 290 cases, and these were all diagnosed benign as with the first VAB. Excision of the lesion was the primary reason for the second VAB (6 cases), followed by inconsistencies with the imaging findings (2 cases), and suspected malignancy by FNAC (1 case). The true positive, true negative, false positive and false negative rates of VAB were 98.7%, 100%, 0%, and 1.3%, respectively. The mean follow-up duration was 43 months. [Conclusion] To prevent the excessive examinations, FNAC should be excluded from the initial diagnostic approach for small breast lesions. VAB is a highly reliable technique as the initial diagnosis for small breast lesions with high true positive and true negative rates and a very low false positive rate. The optimal strategy for diagnostic procedures should be adopted in consideration of reducing stress and anxiety in patients and costs. Citation Format: Satoko Nakano, Masahiko Otsuka, Akemi Mibu, Toshinori Oinuma. What is the optimal diagnostic approach for small breast lesions? Fine needle aspiration cytology vs. Vacuum-assisted core needle biopsy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-03-02.

Aims: To determine the expression of Mcl-1 in testicular germ cell tumours in order to clarify the role of this anti-apoptotic factor in these tumours. Various members of the Bcl-2 family have been implicated in the apoptotic mechanisms regulating germ cell apoptosis. Mcl-1 is an anti-apoptotic Bcl-2 family member and has recently been reported to be related to the progression of malignancy; however, the involvement of Mcl-1 in the development of germ cell tumours is still unknown. Methods and results: Mcl-1 expression in testicular germ cell tumours was investigated by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). By immunohistochemistry, overexpression of Mcl-1 was present in all germ cell tumours that were studied, including embryonal carcinoma and yolk sac tumour, as well as choriocarcinoma and teratoma. In teratomas, Mcl-1 was widely distributed in the epithelial, myogenic, neural and mesenchymal components. RT-PCR analysis after microdissection revealed high levels of Mcl-1 mRNA in all tumour variants compared with non-neoplastic germ cells. Conclusion: Overexpression of anti-apoptotic Mcl-1 may function to enhance the viability of testicular germ cells, thereby leading to tumorigenesis.

Peroxisome proliferator-activated receptors (PPARs) play an important role in vascular events during progression of atherosclerosis, associated with lipid metabolism, inflammatory response and others. To clarify relationships between the expression of PPARs subtypes and regression, we studied mRNA expression of PPARs subtypes with reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, especially in centrally depressed atherosclerotic plaques (depressed plaque) in the aortas of elderly patients, and proposed morphological feature of atherosclerotic regression. Samples were separated from the depressed plaque, atheromatous plaque, and diffuse intimal thickening (DIT) in the aortas of elderly patients at autopsy and they were analyzed for RT-PCR. The depressed plaques obtained were divided into two parts: depressed area and surrounding elevated area. Total RNA was prepared, using the TRIzol Reagent, and was reverse transcribed using random hexamer primers and Thermoscript kit for RT-PCR. Immunohistochemical analysis was processed for mouse anti-PPAR gamma antibody, detected by the ABC method. 1) Decreased foam cells were found in the depressed area than in the surrounding elevated area of the depressed plaque. These foam cells were immunohistochemically positive for HAM56 and strong reactivities for PPAR gamma were found in the nuclei of macrophage-derived foam cells. PPAR gamma was also detected in the nuclei of endothelial cells and smooth muscle cells. 2) Expressions of PPAR alpha and PPAR gamma were found in the depressed plaques with RT-PCR. These expressions were found both in the depressed area and the surrounding elevated area without significant differences. 3) PPAR gamma mRNA expression both in the depressed area and the surrounding elevated area, was greater than in DIT, and was less than in the atheromatous plaque. 4) Expression of PPAR gamma mRNA was intense and increased in the surrounding elevated area than in the depressed area. 5) A significant increase of PPAR gamma expression was found in the atheromatous plaque than in the DIT. 6) There was no significant difference of PPAR alpha mRNA expression between the depressed area and the surrounding elevated area. The depressed plaque has been considered to be a morphological characteristic of regression in recent studies. Expression of mRNA for PPARs was detected in the depressed plaque as well as the atheromatous plaque, furthermore, there were different expressions and intensity of PPARs between the depressed area and the surrounding elevated area of the depressed plaque. These findings suggest that the expression of PPARs may be involved not only in the progression of atherosclerosis but also in regression.

Sclerosing encapsulating peritonitis (SEP) is characterized by the diffuse appearance of marked sclerotic thickening of the peritoneal membrane. We experienced a case with SEP accompanied by regional changes of peritoneum. A 37-year-old woman with end-stage renal failure was started on continuous ambulatory peritoneal dialysis in 1985 and was transferred to hemodialysis in 1997. She was admitted because of ileus in 1998 with SEP and died of septicemia. The diagnosis of SEP was confirmed via the autopsy. The root of the mesentery was retracted and shortened. Since the peritoneal change was marked in the regions with free margin of mesentery and was less apparent in the regions not adhered to mesentery, it is indicated that mechanical stress also contributes to the occurrence of SEP. Since calcification and ossification were only seen in a free margin of small bowel from mesentery, it is suggested that there is a close relationship between calcification and ossification. Since fibrosis invaded into the muscle layer, dysfunction of bowel movement as well as bowel obstruction contributed to the appearance of ileus. It is suggested that mechanical stress by the root of mesentery which is retracted and shortened also contributes to the appearance of SEP.

To clarify the involvement of peroxisome proliferator-activated receptors (PPARs) in atherosclerotic plaque formation, we investigated the expression patterns of mRNA and protein of PPARalpha and PPARgamma in human aorta. Atheromatous plaque, fatty streak, and diffuse intimal thickening (DIT) were separated macroscopically, and each sample was divided into halves. Half of them were used for analysis of mRNA expression with reverse transcription-polymerase chain reaction and the others were used for histologic analysis. Both PPARalpha and PPARgamma mRNA were detected in all atheromatous plaques, all fatty streaks, and in some DIT. However, expressions of PPARalpha and PPARgamma were obviously less frequently found in DIT than in atheromatous plaques, and the intensity of these expressions was stronger in the atheromatous plaques than in the DIT. Compared with PPARalpha, PPARgamma mRNA was expressed more frequently in atheromatous plaques. In atheromatous plaques, PPARgamma mRNA was expressed independently, whereas PPARalpha mRNA was coexpressed with PPARgamma. PPARgamma protein was obviously found in the nuclei of endothelial cells, macrophages, mononuclear cells, and smooth muscle cells in the aortic intima. These results suggest that expressions of PPARalpha and PPARgamma in human aortic wall are involved in atherogenesis from the early stages.

We investigated the influence of glycated low density lipoprotein (LDL) for vascular smooth muscle cell (SMC) proliferation or injury. We utilized glycated, slightly oxidized LDL (GLDL-LOX), glycated, auto-oxidized LDL (GLDL) and glycated, metal-induced extensively oxidized LDL (GLDL-OX) to examine the effect of glycation itself or combined glycation and oxidation on SMC. GLDL-LOX induced SMC proliferation and migration, and increased the number of platelet-derived growth factor receptor, beta subunits, (PDGF-R) positive SMC. Also, GLDL-LOX promoted protease activity, compared with the other groups including native LDL (control). GLDL and GLDL-OX demonstrated SMC injury with apoptosis and Bax protein expression, compared with native LDL and GLDL-LOX. These results suggested that LDL glycation contributed to the progression of atherosclerosis by promoting SMC migration and proliferation, with little dependence on oxidative modification. Secondary auto-oxidation adding to glycation induced SMC apoptosis, and SMC injury occurred in the state of strong oxidation with glycation. We concluded that LDL glycation might play a key role in the progression of atherosclerosis in diabetes, and glycated LDL promoted atherosclerosis, even with little assistance from oxidation.

Atherosclerotic plaque with central depression (depressed lesions) have been proposed as one morphological feature of atherosclerotic regression in the elderly. We have also revealed that depressed lesions have been found not only in the aorta of elderly human but also in rabbit aorta. In this study a relationship between apoptosis and atherosclerotic regression was immunohistochemically studied to clarify the possibility of the pathogenesis of depressed lesion in rabbit aorta. Twenty male New Zealand White rabbit (NZW) were fed with a 1.0% cholesterol diet during a 12-week atherogenic induction period. Then they were fed only with a basic diet for 36-week (n = 6) and 48-week (n = 6, experimental group) regression periods. A control group was fed with 1.0% cholesterol diet for 12-week (n = 2) and 60-week (n = 6). They were killed and aortas were fixed with formalin. Sections obtained from aortas were processed for histological and immunohistochemical studies including the TUNEL method, staining with Ki-67 and others. Several depressed lesions were found in the aortas of NZW animal, but none were noted in control aortas. Results of surface involvement in the experimental groups were significantly lower than in the control, and the aortas of the experimental group had atherosclerotic regression. Apoptosis was found in the depressed lesions, which had more apoptotic cells than non-regressed atherosclerotic plaques. Furthermore, the apoptotic cells were significantly greater in the center of depressed lesions than in marginal areas. Ki-67 staining was positive in the atherosclerotic plaque, but negative in the depressed lesions. It appears that the NZW aortic atherosclerotic plaques may transform to depressed lesions with apoptosis. Atherosclerotic regression has been associated with apoptosis.

Atherosclerotic plaque with central depression (depressed lesion) has been hypothesized to be a morphological feature of atherosclerosis regression. We tested this hypothesis in New Zealand white rabbits. After the animals were fed a diet containing 1% cholesterol for three months, they were changed to a normal diet for 6 to 9 months. Several aortas had centrally depressed lesions similar to those found in elderly people, and the animals had low serum cholesterol levels. Immunohistochemical study showed that the depressed lesions contained more smooth muscle cells and collagen type IV, and fewer macrophage-derived foam cells than did common atherosclerotic elevated lesions found in rabbits. We know of no other report of depressed lesions in rabbits with atherosclerosis. Thus we believe that the centrally depressed lesion is a histological characteristic of regression of atherosclerosis.

We have investigated the effects of copper-zinc type superoxide dismutase (Cu, Zn-SOD) on the function of oxidized low density lipoprotein, utilizing cultured smooth muscle cells (SMC), obtained from rabbit aorta. We added native LDL (nLDL), minimally oxidized LDL (MmLDL) and copper ion-induced oxidized LDL (OxLDL) to the culture media. No remarkable change was found out by adding nLDL. The numbers of SMC, including migrated SMC, were increased by the addition of MmLDL. Cu, Zn-SOD significantly inhibited the reactions induced by MmLDL. The SMC numbers were markedly decreased by OxLDL addition without recovery by adding Cu, Zn-SOD. Thus, MmLDL significantly promoted the SMC proliferation and migration. OxLDL revealed strong cytotoxicity against SMC. Cu, Zn-SOD inhibited both the migration and the proliferation of SMC induced by MmLDL, and did not alter the effect of OxLDL. In conclusion, Cu, Zn-SOD inhibited some functions of MmLDL, and may play an important role in protecting against the atherosclerotic processes evoked by MmLDL.

The argyrophilic nucleolar organizer regions (AgNOR) are silver stained granules that are thought to correlate with cell proliferation activity. Two AgNOR counting methods: the mean AgNOR count (mAgNOR, the mean number of AgNOR granules in 100 cells) and the AgNOR proliferatlve Index (pAgNOR, the percentage of cells exhibiting five or more AgNOR granules per nuclei) have been proposed. In this study, the two counting methods were applied to 58 cases of normal uterine corpus and uterine corpus tumors and were compared with the Ki-67 labeling Index (Ki-67 Ll) using MIB-1 monoclonal antibody and other hlstopathologlcal criteria. Notable differences In the number of AgNOR and the Ki-67 Ll were observed between benign and malignant smooth muscie tissue. Hlstopathologic features are well correlated to the proliferatlve activity of tumors. Although the most reliable method of predicting malignant potential cannot be determined, the methods outlined by this study are thought to be highly useful In assessing proliferatlve activities.

Atherosclerotic plaque with central depression (depressed lesion) was firstly proposed in our previous report as one of the morphological features of regressed lesions, which was characterized by the presence of isolated, well defined lesions with a centrally depressed area and smooth surface. They were obviously different from atherosclerotic plaques with ulceration (ulcerated plaques) in elderly autopsy cases. In this study, 30 ulcerated plaques obtained from specimens of the elderly aortas were histologically and immunohistochemically investigated to clarify the morphogenesis of the depressed lesion and its correlation to the ulcerated plaque. These depressed lesions were divided into 4 groups according to their derivation; (a) fused lesion of multiple fibrous plaques, (b) regressing lesion of plaques, (c) healed ulcerated plaques, and (d) mixed type of these lesions. Regeneration of endothelial cell was noted in the peripheral zone of ulcerated plaques, and collagen type IV was also increased in the stroma of these ulcerated plaques. These were healed ulcerated plaques. The ulcerated plaques with complete restoration of endothelial cells on the ulcerated surface may become atherosclerotic plaques with central depression. These lesions are one of the histological features of regression in advanced atherosclerosis.

A total of 161 atherosclerotic plaques from 50 aortas in elderly autopsy cases were pathomorphologically investigated to clarify the pathogenesis of atherosclerotic plaque with central depression. Atherosclerotic plaques with central depression, with well defined borders were employed for this study, ulcerated plaques being excluded. Pathomorphological findings showed that plaques with central depression could be divided into four groups according to their derivation respectively; (a) fused lesion of multiple fibrous plaque, (b) regressing lesion of plaque, (c) healing lesion of ulcerated atheromatous plaque, (d) mixed type. Finally, it was suggested that atherosclerotic regression may cause some central depression in the atheromatous plaques.

Alterations in DNA methylation have been implicated in mammalian development. Hence, the identification of tissue-specific differentially methylated regions (TDMs) is indispensable for understanding its role. Using restriction landmark genomic scanning of six mouse tissues, 150 putative TDMs were identified and 14 were further analyzed. The DNA sequences of the 14 mouse TDMs are analyzed in this study. Six of the human homologous regions show TDMs to both mouse and human and genes in five of these regions have conserved tissue-specific expression: preferential expression in testis. A TDM, DDX4, is further analyzed in nine testis tissues. An increase in methylation of the promoter region is significantly associated with a marked reduction of the gene expression and defects in spermatogenesis, suggesting that hypomethylation of the DDX4 promoter region regulates DDX4 gene expression in spermatogenic cells. Our results indicate that some genomic regions with tissue-specific methylation and expression are conserved between mouse and human and suggest that DNA methylation may have an important role in regulating differentiation and tissue-/cell-specific gene expression of some genes.