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Background and Aim: Tocilizumab, a humanized anti-IL-6 receptor antibody, has been used to treat severely to critically ill patients with COVID-19. A living systematic review with meta-analysis of recent RCTs indicates that the combination therapy of corticosteroids and tocilizumab produce better outcomes, while previous observational studies suggest that tocilizumab monotherapy is beneficial for substantial numbers of patients. However, what patients could respond to tocilizumab monotherapy remained unknown.Methods: In this retrospective study we evaluated the effects of tocilizumab monotherapy on the clinical characteristics, serum biomediator levels, viral elimination, and specific IgG antibody induction in 13 severely to critically ill patients and compared with those of dexamethasone monotherapy and dexamethasone plus tocilizumab.Results: A single tocilizumab administration led to a rapid improvement in clinical characteristics, inflammatory findings, and oxygen supply in 7 of 11 patients with severe COVID-19, and could recover from mechanical ventilation management (MVM) in 2 patients with critically ill COVID-19. Four patients exhibited rapidly worsening even after tocilizumab administration and required MVM and additional methylprednisolone treatment. Tocilizumab did not delay viral elimination or inhibit IgG production specific for the virus, whereas dexamethasone inhibited IgG induction. A multiplex cytokine array system revealed a significant increase in the serum expression of 54 out of 80 biomediators in patients with COVID-19 compared with that in healthy controls. Compared with those who promptly recovered in response to tocilizumab, patients requiring MVM showed a significantly higher ratio of basal level of ferritin/CRP and a persistent increase in the levels of CRP and specific cytokines and chemokines including IL-6, IFN-γ, IP-10, and MCP-1. The basal high ratio of ferritin/CRP was also associated with clinical deterioration even in patients treated with dexamethasone and tocilizumab.Conclusion: Tocilizumab as monotherapy has substantial beneficial effects in some patients with severe COVID-19, who showed a relatively low level of the ratio of ferritin/CRP and prompt reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1. The high ratio of ferritin/CRP is associated with rapid worsening of pneumonia. Further evaluation is warranted to clarify whether tocilizumab monotherapy or its combination with corticosteroid is preferred for severely to critically ill patients with COVID-19.

Schwannomas are tumors of the peripheral nervous system, consisting of different cell types. These include tumorigenic Schwann cells, axons, macrophages, T cells, fibroblasts, blood vessels, and an extracellular matrix. All cell types involved constitute an intricate “tumor microenvironment” and play relevant roles in the development and progression of schwannomas. Although Nf2 tumor suppressor gene-deficient Schwann cells are the primary tumorigenic element and principle focus of current research efforts, evidence is accumulating regarding the contributory roles of other cell types in schwannoma pathology. In this review, we aim to provide an overview of intra- and intercellular mechanisms contributing to schwannoma formation. “Genes load the gun, environment pulls the trigger.” -George A. Bray

肺癌の大腸転移は剖検の2～3％と比較的稀である．生前に診断され手術を受けた症例の報告はさらに少ないが，予後は不良である．症例は80歳，女性．平成15年6月に肺大細胞癌に対し右上葉切除術を受けた（pT1N0M0 stage1A）．平成16年3月初旬より腹痛と便秘，全身倦怠感あり腸閉塞と診断され3月下旬に当院入院となった．大腸内視鏡検査および注腸造影検査を施行したところ横行結腸に潰瘍を伴う全周性の隆起性病変を認めた．生検にて肺癌の大腸転移が疑われた．入院の約3週間後に横行結腸切除を施行したが，腹水が貯留しており細胞診にて悪性細胞を認めた．また多発性の肝転移を認めた．敗血症を併発し，術後第25病日に失った．

To evaluate the relationships among histopathological type, clinical malignant grade, and Ki-67 labeling index (LI) in sebaceous gland carcinoma (SGC), conjunctival squamous cell carcinoma (SCC), and conjunctival intraepithelial neoplasia (CIN), with pterygium and normal conjunctiva as controls. This retrospective study was conducted at the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. We used tissue specimens obtained from 20 patients (four SGC, four SCC, four CIN, four pterygium, and four normal conjunctiva). Ki-67 immunohistochemical analysis was performed in all 20 cases. The Ki-67 labeling index (LI) was 46.1 ± 3.0% (average ± SD) in SGC, 28.4 ± 4.5% in SCC, 20.0 ± 7.2% in CIN, 9.0 ± 2.2% in pterygium, and 6.8 ± 2.3% in normal conjunctiva. Ki-67 LI was significantly (Mann-Whitney U test, P < 0.05) higher in SGC than in SCC, and higher, but not significantly, in SCC than in CIN. Ki-67 LI was significantly (P < 0.05) higher in SCC and CIN than in pterygium. These results suggest that Ki-67 LI may be a sensitive marker for ocular malignant tumor grading. Jpn J Ophthalmol 2004;48:524–529 © Japanese Ophthalmological Society 2004

Objective: To clarify the structural features of conjunctivochalasis histopathologically. Methods: A biopsy of redundant conjunctiva from the same anatomic location of 44 eyes with conjunctivochalasis was examined histologically. All patients, 9 men and 35 women, aged 66.6 ′ 7.5 years (mean ′ SD, 50.87 years), underwent conjunctivoplasty (termed tear meniscus reconstruction). Results: In all 44 cases, histologic examination disclosed normal conjunctival epithelium and negligible inflammation and lymphocyte infiltration; 39 patients manifested microscopic lymphangiectasia. Elastica van Gieson staining demonstrated elastic fiber fragmentation and sparsely assembled collagen fibers in all 44 cases. There was no discernible difference between specimens from patients with and without complications including tear-deficient dry eye, meibomian gland dysfunction, and clinically observable lymphangiectasia and/or pinguecula. Conclusion: Based on our histopathologic findings, we hypothesize that mechanical forces between the lower lid and conjunctiva gradually interfered with lymphatic flow. Chronic, prolonged mechanical obstruction of lymphatic flow may result in lymphatic dilation and eventually give rise to clinical conjunctivochalasis.

En-bloc resection for cancer has been a standard procedure based on the concept that there may be a small number of "invisible" cancer cells around the primary tumor and metastatic lymph nodes. However, there are few histopathologic studies of this issue.Perinodal involvement of cancer cells, defined as existence of cancer cells in the attached fatty tissue around the dissected lymph nodes, was assessed in 123 node-positive and 15 node-negative gastric cancers by both hematoxylin-eosin staining and immunohistochemistry.Perinodal involvement was found in 79 (57%) of the 138 patients. The incidence was higher in patients with tumors invading the deeper layer, the macroscopic diffuse type, the presence of lymphatic or vascular invasion (P.05), and advanced disease (stage I, 17%; II, 62%; III, 67%; IV, 80%). Survival of patients with perinodal involvement was less than that of patients without perinodal involvement (46% vs 87%; P.005). Perinodal involvement was found, by multivariate analyses, to be a significant prognostic factor.Perinodal cancer cells are observed frequently in gastric cancers with lymph node metastases, and the involvement appears to be a reliable prognostic factor for gastric cancers.

OBJECTIVE: To describe cases of low grade papillary transitional cell carcinoma (LG-pTCC) with a low nuclear cytoplasmic (N/C) ratio and unusual cytologic patterns with many isolated, single neoplastic cells. STUDY DESIGN: We defined the following unusual cytologic findings as isolated, single cell pattern: (1) numerous single cells sometimes with a few flat cell clusters; (2) very low N/C ratio; (3) angulation of cytoplasmic contour; (4) pale, homogeneous cytoplasm; (5) hyperchromatic nuclei with an uneven contour; (6) monotonous cytologic appearance; and (7) clear background. We studied 2,956 cytologic specimens of voided urine from 114 LG-pTCC patients at our university hospital during a 10-year period. RESULTS: Thirty-six specimens had the isolated, single cell pattern. The isolated, single cell pattern showed less cellular atypia than does the typical pattern of LG-pTCC. On histology the cases with the isolated, single cell pattern showed a papillary structure with an erosive surface and were composed of mildly atypical neoplastic cells with very low N/C ratios. CONCLUSION: Some LG-pTCCs show many single, atypical transitional cells.

横行結腸に発生した進行癌の根治切除後6年経過し, 胃所属リンパ節への単独転移再発を認めた症例を経験した. 症例は66歳の男性で, 1989年5月に横行結腸癌による腸閉塞で右半結腸切除術を受け, 外来通院中であった. 1994年5月よりCEA の上昇を認めはじめ, 1996年1月には胃内視鏡検査にて胃体下部大彎側に粘膜下腫瘍と考えられる隆起性病変を認めた. その後, 増大傾向を認めたためCT・腹部血管造影などを施行し, 切除可能な大腸癌再発病変と診断して1996年11月19日手術を施行した. 手術所見にて胃大彎側のNo.4dリンパ節への転移再発と診断し, 幽門側胃切除にて切除郭清した. 術後経過は良好で, 再切除後6年7か月を経過したが無再発生存中である. 初回手術後5年以上経過した横行結腸癌の胃所属リンパ節への単独転移は, 再発形式としてもまれなため, 若干の文献的考察を含めて報告する.

We encountered a case of gastric cancer that was initially detected as a deep hemorrhagic ulcer without surrounding irregular elevation, followed by rapid protrusion in less than 1 month. Using endoscopic images in the follow-up study, we estimated the doubling time (DT) of this unusual tumor as 9.2 days. Since the doubling time of gastric cancer is generally fairly long due to exfoliation of many cancer cells into the gastric lumen, this cancer presented with extremely rapid growth. Besides, this case reinforces that follow-up study is important in terms of clinical management of ulcerative lesions.

Ileal Na+-dependent bile acid transporter (ISBT) constituting a gateway to enterohepatic circulation of bile acids occurs exclusively at the distal site of the small intestine. In the present study, we examined colonic tumorigenesis promoted by deoxycholic acid in relation to the expression of the ISBT. For this purpose, the small intestine of a Fischer-344 rat was resected a length of 20 cm above the ileo-cecal valve (ileal resection) or below the duodenum (jejunal resection). Then, rats were treated with an intraperitoneal injection of azoxymethane (15 mg/kg body wt.) once a week for 3 weeks and fed a 20% casein diet supplemented with 0.2% deoxycholate for 39 weeks. Northern blot analysis demonstrated that the ISBT mRNA was hardly detectable in ileum-resected rats. The excretion of fecal bile acids was 1.5-fold higher in the ileum-resected group than in the jejunum-resected group (P < 0.05). On the contrary, the serum bile acids concentration of ileal-resected rats was about one-half of that of jejunum-resected animals (P < 0.05). The tumor incidence and the total tumor number were significantly higher in the ileum-resected group than in the jejunum-resected one (P < 0.05). Interestingly, no tumor was found at the proximal colon in the jejunum-resected group while tumors developed frequently at the proximal site as well as mid and distal colon in the ileum-resected group. These observations demonstrate that malabsorption of bile acids owing to the lack of ISBT enhanced colon tumorigenesis.

We investigated the histogenesis of hyperplastic polyps of the stomach, in terms of cellular proliferation, by studying endoscopically removed and gastrectomized human gastric polyps either labeled with bromodeoxyuridine (BrdU) by in vitro flash labeling techniques or labeled in an isolated organ circulation system, in both of which, perfluorochemical artificial blood was employed. Immunohistochemistry with antibodies against BrdU and proliferating cell nuclear antigen (PCNA) was simultaneously employed. The generative cell zone of pedunculated and semipedunculated polyps was markedly expanded compared with that of the background mucosa, and this change also appeared in sessile polyps, although to a lesser degree. Enhanced proliferative activity was observed in both epithelial and stromal cells in areas of erosion. Our results demonstrate that the initial change in the histogenesis of hyperplastic polyps is an expansion of the generative cell zone, followed by interstitial edema and stromal cell proliferation, and that erosion can facilitate these changes. No correlation was found between the size of the polyps and the labeling indices. This finding explains, in part, the diversity of chronological changes in the size and shape of hyperplastic polyps.

It has recently come to be thought that cases of juvenile polyposis have a natural tendency to develop adenoma and/or carcinoma. Here we present a case of juvenile polyposis coli with adenomatous change in a 21-year-old male, with a review of 34 cases of juvenile polyposis in the Japanese literature, and discuss the pathogenetic development of the polyps and their malignant potential. In this case, focal or entire adenomatous areas were found in large part of the polyps in the resected sigmoid colon and rectum, though these findings had not been recognized in 23 polypectomy specimens from the rectum 10 months prior to the operation. It was suggested that adenomatous change developed quickly in a very short time.

We investigated the basic diagnostic processes used in telepathology with our robotic still-image system, OLMICOS, by analysing the steps and patterns used in 20 consecutive tissue section diagnoses. Three basic approaches were recognized. One was magnifying a suspect finding in a low-powered microscopic image. This approach was used mostly for confirming or characterizing a tumour. The second approach was scanning over a low-powered image by magnifying square images to form a mesh. This was found to be useful to confirm the presence or absence of signs and was mostly used as the initial step in judging the surgical margin of malignant cases or diagnosing lesions. The third approach was a combination of these two and was used for delineating the surgical margin, confirming the absence of metastases or diagnosing difficult lesions. Recognition of these three basic diagnostic approaches is important in making a rapid and correct remote diagnosis.

The thickness of Brunner's glands was measured with an ocular micrometer in 75 cases of surgically resected duodenal ulcer and in 75 autopsy cases (control group). Endoscopic findings before operation were also studied. Maximum mean thickness of Brunner's glands in the control group was 1.54 +/- 0.38 mm (mean +/- SD), and no regional difference in thickness was noted. The thickness of Brunner's glands in the duodenal ulcer group was widely distributed, from 0.5 mm to 5.0 mm, and the average value was 3.0 +/- 1.0 mm, with a statistically significant difference from that of the control group. In most duodenal ulcer cases Brunner's glands were thickest within 1 cm from the center of an ulcer. Only six cases of duodenal ulcer (8.0%) showed a diffusely thin layer of Brunner's glands, less than 1.5 mm thick. These results show that the Brunner's glands become hyperplastic in duodenal ulcer patients, especially near the ulcer. In the healed ulcer Brunner's glands were thin at the center of an ulcer scar, and the average thickness was 0.42 +/- 0.26 mm. This histologic finding corresponded to the depressed scarred area observed endoscopically, suggesting a decreased mucosal resistance at this area.

Bromodeoxyuridine (BrdU) immunohistochemistry has recently been introduced for the visualization of DNA-synthesizing nuclei. To determine the optimal conditions for detecting BrdU-incorporated nuclear DNA in formalin- or ethanol-fixed, paraffin-embedded human gastric tissues, we tested several different pretreatment procedures of hydrolysis with HCl and enzymatic digestion with actinase before the immunohistochemical staining. Three cases of surgically resected stomachs were perfused with artificial blood containing BrdU and fixed in formalin, ethanol or with their combination for different durations. The results of BrdU-immunohistochemical stainings were checked and the labeling indices were compared. As for hydrolysis, treatment with 2N HCl at 25°C for 90min was sufficient to detect the immunoreactivity in the stomach irrespective of fixative conditions tested. However, to obtain the most suitable stainings an additional enzymatic digestion was needed, and the optimal condition with actinase was different according to the fixation time in formalin- and/or ethanol-fixed tissues. There are also a few differences in the demonstrability of nuclear BrdU among various kinds of cells, i.e. normal epithelial cells, immunoblasts in the lymphoid follicle and cancer cells. Our method could extend the range of application of BrdU immunohistochemistry for cell kinetic studies using human surgically resected organs.

Application of microwave irradiation has been explored both in fresh and fixed frozen sections and in metallic stainings. The results showed a combination of irradiation alone followed by further irradiation immersed in any reagent containing about 50% alcohol made better microscopic-image quality in fresh frozen sections, but lesions of lymphoid tissues and lipid-rich brain tissues required further technical consideration for making better nuclear details and reducing spongy appearance. Fixed frozen sections had disappointing results with insufficient fixation and various degrees of freezing and mechanical damage. Standardization of fixed frozen sections may be a future problem. Metallic staining was time-saving and produced exellent results. A microwave oven can be a useful tool in surgical pathology.

A 65-year-old man who presented with adrenal insufficiency was admitted on Feburuary 9, 1988. CT scan showed bilateral swelling of adrenals; open biopsy of the tumor revealed non-Hodgkin's lymphoma. The serum level of catecholamines and calcitonin was elevated. A combination chemotherapy was started. After 3 courses of the treatment remission was achieved, following recovery from adrenal insufficiency. In November, 1988, he had pulmonary infiltration and high fever, resolved by the administration of antibiotics and antifungal drugs. On January 27, 1989, he underwent emergency operation because of perforation of gastric ulcer. In Feburuary, tumor increased in size, and the disease became progressive. On April 2, 1989, he died of respiratory failure. Autopsy revealed a definite diagnosis of malignant lymphoma, diffuse large cell type. Immunohistological studies revealed B cell origin of the cells based on positive LCA and pan B markers.

私達の近年の開発研究に基づく顕微測光と画像解析の結合解析法を応用し, 顕微蛍光測光法による細胞増殖動態の解析単独では鑑別の困難な, 甲状腺の腺腫様過形成5例濾胞腺腫12例および濾胞癌12例を検索した.単離採取した一つひとつの細胞について, 細胞測光による核DNA定量と細胞核の形態解析 (面積, 周囲長, 核DNA濃度, 形状係数など) を対応させて行った.各症例について細胞周期の全ての時期の細胞 (全細胞) 群に対して形態解析を行うとともに, 細胞周期に基づく形状変化の影響を除外して客観的に形態学的特性を評価するために, 2倍体細胞 (G0-G1期細胞) 群に限定した解析も行った.その結果, 検索した腺腫様過形成, 濾胞腺腫および濾胞癌の核DNA量分布パタンは類似していたが, 2倍体細胞の核形態の不規則さは, 腺腫様過形成や腺腫よりも腺癌において有意に高度であることが定量的に示された.以上より, 本法が, 甲状腺腫瘍の良・悪性鑑別に, 細胞測光法や画像解析法単独による解析よりも, 有用であると考えられた.

To clarify the characteristics of esophageal squamous papillomas (ESPs) in the Japanese population, we investigated 38 ESPs of 35 Japanese patients from a file with 17,387 upper gastrointestinal endoscopies in our university hospital. ESPs accounted for 0.20% of the total number of endoscopies and comprised 21 females and 14 males with an average age of 59.2 years. More than half of the ESPs (52.6%) were located in the middle esophagus. The ratio of human papilloma virus (HPV) positive ESPs was 10.5% and all were located in the middle esophagus of female patients only. HPV-positive ESP cases were younger (46.8 years) than HPV-negative cases (60.8 years). Based on comparison with the reports from western countries, we attribute the low prevalence in the lower esophagus to the relatively fewer occurrences of severe reflux esophagitis (RE) due to chronic gastritis with low gastric acid secretion among Japanese patients.

We encountered four patients with overt primary sclerosing cholangitis (PSC) which were histologically classified into stage 2 or 3. We examined the expression of stem cell factor (SCF), a ligand of c-kit, in injured bile ducts by immunohistochemistry, and mast cells were identified by immunohistochemistry using anti-HMCT (human mast cell tryptase) and anti-c-kit antibodies to clarify their relation with portal fibrosis coincident with destroyed bile ducts. SCF was detected in the epithelia of most bile ducts in PSC, and many HMCT- and c-kit-positive mast cells were found in portal tracts. Image analysis showed more significant numbers of c-kit-positive mast cells per area of portal tract in PSC than in chronic hepatitis C, and they might increase from stage 2 to 3. c-Kit-positive cells infiltrated into the portal tracts with SCF-positive destroyed bile ducts, and c-kit mast cells should be investigated in detail to make a role for portal fibrosis in PSC.

Juvenile xanthogranuloma (JXG), one of the most common forms of non-Langerhans cell histiocytosis (LCH), usually presents in young children as spontaneously regressing cutaneous lesions. However, the systemic type of JXG is difficult to treat in newborn infants, and fatal cases have been reported. In the patient described here, solid masses were discovered by fetal sonography during the 38th gestational week. At birth she had multiple tumors on the back, cheek, and hip as well as marked hepatosplenomegaly accompanied by respiratory failure. Laboratory results indicated pancytopenia, obstructive liver dysfunction, and coagulopathy. Brain magnetic resonance imaging revealed a tumor at the left pontine angle, and dysmorphic histiocytes were present in her spinal fluid. She was diagnosed with systemic JXG by histopathologic findings of the hip mass. The LCH-based multiagent chemotherapy including cytarabine, vincristine, methotrexate, and prednisolone ameliorated the symptoms rapidly. She was treated for 12 months and is currently doing well as a normally developing 2-year-old.

Fisher-344 rats, whose ileum or jejunum had been surgically removed to change the influx of bile acids into the colon, were intraperitoneally administered with azoxymethane and fed on a diet containing deoxycholate for 39 weeks to induce colon cancer. Fecal bile acids in the ileum-resected group were 1.5-times and serum bile acids were about half of those in the jejunum-resected group. As a result, the incidence and number of tumors were higher in the ileum-resected group. In the total of 59 colon tumors (40 were in the ileum-resected group and 19 in the jejunum-resected group), 56 were carcinomas, including two well-differentiated invasive and two mucinous carcinomas found in the ileum-resected rats. However, only three carcinomas, two invasive and one non-invasive, had the K-ras mutation. These results demonstrate that the K-ras mutation was not essentially involved in deoxycholate-promoted colon carcinogenesis.

A 53-year-old woman had extraskeletal osteosarcoma that developed from a soft tissue bony mass present on the volar aspect of the left wrist for 4 years. Initially, the bony mass was soft and movable, but during the first year it became hard and fixed. The patient had no history of trauma. Because the lesion did not grow or cause any symptoms, the patient did not come to the hospital until 4 years after she first noticed the lesion. Radiologically, the bony mass had features characteristic of mature myositis ossificans, showing "eggshell" ossification. A nonmineralized soft tissue mass occurred between the surface of the radius and the bony shell. Histologically, a high-grade osteosarcoma was present between the surface of the radius and the well-differentiated bone tissue, which included fatty and hematopoietic marrow. All the findings indicated that our patient had an extremely rare case of malignant transformation of myositis ossificans.

A 66-year-old man with chronic obstructive lung disease was admitted to our hospital, presenting with mesenteric volvulus and mild liver injury. A superior mesenteric angiogram revealed that the arteries supplying the small intestine were twisted in the arterial phase, while the portal vein was not visualized in the late phase. A celiac angiogram demonstrated that portal blood flow from the splenic venous return was maintained. The patient's symptoms had almost resolved the day after admission, and his serum transaminases level had gradually decreased to normal with conservative therapy. A superior mesenteric angiogram on the 13th hospital day showed a normal arteriogram and the portal vein demonstrated blood flow from the superior mesenteric vein. Liver biopsy revealed hemorrhagic necrosis around the central veins, which was compatible with ischemic hepatitis. Since the patient's O2 saturation level on admission was not low enough to have caused ischemic hepatitis by itself, we suspect that a sudden decrease in portal blood flow was the additional factor that allowed the threshold for the initiation of ischemic liver damage to be reached.

A case of right frontal pleomorphic xanthoastrocytoma that occurred in a 7-year-old boy is reported clinicopathologically. The patient underwent surgery on September 29, 1988. Histologic diagnosis of pleomorphic xanthoastrocytoma was made because, in addition to the unique pleomorphic histologic features, positive glial fibrillary acidic protein in immunohistochemical staining and characteristic ultrastructural features, i.e., cytoplasmic intermediate fibrils and lipid vacuoles, basal lamina, and abundant reticulin networks were demonstrated. The DNA cytofluorometric analysis of the nuclei of the tumor cells disclosed the main mode to be diploid with polyploid classes (4, 8, 16, and 32C) without any aneuploidy. Despite the presence of many pleomorphic nuclei, DNA histogram of the tumor disclosed very few DNA synthetic cells indicating a biologically inactive nature of the tumor. The patient is still alive and totally asymptomatic 20 months postoperatively.

Signet-ring-cell carcinomas were induced in the stomach of 12 beagle dogs by p.o. administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), and the morphology and modes of cell proliferation in an incipient stage of cancer growth were studied with bromodeoxyuridine (BrdUrd) incorporation. From 5 to 27 months after the completion of 8 months' carcinogen treatment, minute carcinomas were found in the stomachs of 9 dogs. Before sacrifice, the dogs were given a single or repeated i.v. injections of BrdUrd for 1-3 days. Minute signet-ring-cell carcinomas were found to form a layered structure, in which the cancer cells proliferated in the lamina propria at the gland-neck level and differentiated to postmitotic signet-ring cells at the upper and lower levels of the mucosa. From repeated injections of BrdUrd, the time required for all the proliferative cells to be labelled with BrdUrd (reflecting the maximum cell-cycle time) was estimated to be 1.7 days for the normal glands, and 2.7 days for minute signet-ring-cell carcinomas. From the labelling index with BrdUrd as well as from the morphology, earliest carcinomas were identified in the single gland. There remained atrophic normal epithelium commonly in the single-gland lesions. Proliferative atypical cells appeared to be shed into the stroma passively through the atrophy and subsequent collapse of the gland rather than through active invasion. This may be a reason why cancer cells in minute signet-ring cell carcinomas preserved the normal pattern of cell renewal movement to form the layered structure.

Vibratome sections of hippocampus of adult rabbits were stained by a modified Hortega's silver-carbonate method. Impregnated materials were examined by electron microscopy to decide fine-structural characteristics of the resting microglia. Comparing their characteristics with those of macrophages, we came to the following conclusions: (1) Impregnated resting microglia in the hippocampus of adult rabbits can be identified as cells having distinct fine structures. (2) Resting microglia are morphologically different from macrophages or their precursor cells, and, therefore, seem not to be hematogenous cells sojourning in the normal brain parenchyma.

Rat brain was obtained on the 4th day after its damage by a stab wound. The injured and the normal control brain tissues were stained by the immunofluorescence technique using anti-granulomonocytic rabbit serum. After the fluorescence observation the same tissues were further stained by hematoxylin and eosin (HE) and studied comparatively by light microscopy. The following results were obtained: (1) The normal adult rat brain lacks the cells which react with the antiserum, thus the resting microglia occurring in the normal adult brain are antigenically different from the cells of the monocyte-macrophage system. (2) In the injured brain tissues monocytes extravasate, enter-brain parenchyma, and take ameboid forms or become macrophages. (3) Among the reactive cells in the injured brain, all of the brain macrophages and most of the ameboid cells were reactive with the antiserum thereby indicating their monocytic origin.

The healing process of cysteamine-induced duodenal ulcer was studied by [3H]thymidine autoradiography. After the development of ulcer in the duodenum, cell proliferation was markedly activated not only in the crypts but also in the Brunner's glands near the ulcer. In the initial stages of ulcer healing, they both contributed to form the surface covering regenerating epithelium. Granulation tissue also proliferated at the base of the ulcer. In later stages of ulcer healing, new crypts were formed in the floor of the ulcer. New villi regenerated from these crypts and Brunner's glands regenerated by proliferation in situ. The ulcer base then was completely covered with new villi and granulation tissue was replaced by dense fibrous connective tissue. The present study suggested that the Brunner's glands, together with the crypts of Lieberkühn, play an important role in the healing process of cysteamine-induced duodenal ulcer.

Signet ring cell carcinoma was induced in canine stomachs by N-ethyl-N'-nitro-N-nitrosoguanidine, and modes of cell proliferation and turnover in the carcinoma were studied by 3H-thymidine autoradiography in conjunction with morphometric analysis. From 2 to 15 months after the cessation of 8 months carcinogen treatment, carcinomas in an early stage were obtained. Most of the cancer tissues confined to the lamina propria showed a layered structure. This comprised three layers; the superficial and the deep layer were composed of signet ring cells, and the middle layer was composed of small round cells. The dogs were labeled with 3H-thymidine by s.c. injection and by local infusion of the celiac artery. Flash-labeled autoradiographs revealed that most 3H-thymidine incorporating cancer cells were located around the middle layer, with a small amount of mucin. Using a pulse labeling experiment, those labeled carcinoma cells were shown to migrate from the middle layer towards the surface. Morphometric analysis of the autoradiographs showed that the small cells in the middle layer migrated upwards and produced mucin to become full-blown signet ring cells by 5.5 days. In 15 days, most labeled cancer cells in the superficial layer had disappeared. This mode of cellular turnover appeared to mimic a cell renewal system of the normal gastric mucosa. If the cancer cells turn over in this way, the tumor must grow slowly, remaining as an intramucosal cancer for a relatively long period.

A moderately differentiated tubular adenocarcinoma of human stomach, named SY86B, was successfully transplanted subcutaneously to nude mice of different genetic backgrounds (BALB/CA/PBI-nu, C57BL/6J.615/PBI-nu and ICR.BALB/CA/PBI-nu). The tumor has been passaged for 13 generations and the transplantability was 100%. The SY86B cells retained the capacity of invasive and metastatic growth in the nude mice and showed a high rate of metastasis to the regional lymph nodes and to such distant organs as the lungs, liver and pancreas. The overall rate of metastasis was 77.7%. The species of the nude mice, their age and sex apparently did not significantly affect the occurrence of metastasis. Tumor-bearing time and the aggressive character of the tumor cells themselves appeared important for the genesis of metastasis. This experimental model can provide a new approach to basic and clinical studies of cancer metastasis.

A 61-year-old woman, who had a past history of Behcet disease, underwent emergency laparotomy because of hemorrhagic shock due to massive intestinal bleeding from an intestinal ulcer which perforated the iliac artery, and her life could be saved. In 1971 she had been admitted to another hospital complaining of melena and diagnosed as Behcet disease by aphtous stomatitis, genital ulceration, uveitis and nodular erythema, then had experienced three episodes of melena with Behcet symptoms which disappeared without treatment. Emergency laparotomy at our hospital revealed that the ileum adhered to the right external iliac artery; on ileal ulcer perforated the right external-iliac artery and formed a fistula between the ileum and artery and formed a fistula between the ileum and the iliac artery; resulting in massive bleeding from iliac artery to the intestinal canal. Partial ileal resection and paching of the arterial wall were performed. The resected ileum exhibited non-specific penetrating ulcer (3.5×2.0cm) without malignancy. The wall of the iliac artery was markedly thickened. Microscopically panangitis was noted. As mentioned above, this case is rare in the association of intestinal Behcet with angio-Behcet disease.

A case of bleeding duodenal varix which was treated successfully with endoscopic injection sclerotherapy (EIS) is reported. The patient developed a hemorrhage from a varix in the descending portion of the duodenum two months after EIS for esophageal varices, and hemostasis was achieved using EIS with an intravericeal injection of 1% polidocanol. The duodenal varix decreased in size after EIS. Two months after EIS, a splenectomy was performed. During a 14-month follow up period after the EIS for the duodenal varix, there was no recurrent bleeding.

42例の末期癌難治性腹水に対し計199回の自家腹水濾過濃縮再静注法を施行したところ, 腹水穿刺排液法に比較して腹水再貯留の傾向は少なく本法の有用性が認められた. 本法の最大の副作用である発熱に対して, Pall社製SQ40S screen filterを使用することにより, 有意に発熱の頻度が減少した. そこで使用後のscreen filterをエネルギー分散型X線装置付走査型電子顕微鏡を用いて分析した結果, 多数のフィブリン様物質とともに, Al, Si, K, Fe, Cu, Znなどの微量元素が検出された. このフィブリン様物質が発熱に対して何らかの関与をしていると推定された. 発熱などの副作用を軽減することにより本法の有用性はさらに向上するものと思われる.

The thickness of Brunner's glands was measured using an ocular micrometer in 297 cases of surgically resected peptic ulcer and in 120 autopsy cases (control group). The mean maximum thickness of Brunner's glands in the control group was 1.55 +/- 0.37mm (mean +/- SD) and no difference in thickness was noted for each decade of age. The mean maximum thickness of Brunner's glands in patients with gastric ulcer, duodenal ulcer and gastroduodenal ulcer was 2.34 +/- 1.06, 3.18 +/- 1.07 and 3.24 +/- 1.05mm, respectively. When an ulcer is within the duodenum, Brunner's glands near the ulcer were thicker than those contralateral to it. In patients with gastric ulcer, Brunner's glands were the thickest in the pyloric ulcer group and negative correlation was noted between the thickness of Brunner's glands and the distance to the ulcer from the pyloric ring. Since gastric acidity is supposed to be lower when an ulcer is located more proximally, these results suggest that Brunner's glands become hyperplastic not only with the presence of an ulcer in the duodenum but also by acid hypersecretion of the stomach.

Adult rabbits received stab wound in the cerebrum and were sacrificed at intervals of 20, 30, and 39h thereafter. Each animal was injected intracere-brally with3H-thymidine 2 h before fixation. Altered brain tissues of the stratum radiatum of hippocampus were taken for examination. Response of “resting microglia” to stab wounding was investigated by electron microscopic autoradiography and by autoradiography applied on silver-impregnated materials. Following results were obtained: (1) Resting microglia undergo marked swelling shortly after the brain damage. We designate these cells as “swollen microglia”. (2) Swollen microglia form the only cell population that proliferate actively in the initial stage of glial response to the brain injury, and (3) astroglia do not proliferate during the same experimental periods, in the rabbit hippocampus.

Cardiac lesions induced in rats by isoproterenol, a potent beta-agonist, and by repeated stress of restraint and water immersion, in which sensitization of beta-adrenergic receptors would be expected to be induced, were investigated morphologically and following facts were revealed. 1) Cardiac lesions induced by isoproterenol, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were more analogous to cardiomyopathy than myocardial infarction or cardiac hypertrophy. 2) Cardiac lesions induced by repeated stress of restraint and water immersion, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were similar to those induced by isoproterenol. These results suggest that the endogenously induced dominant beta-adrenergic stimulating action during stress may play an important role in the pathogenesis of cardiomyopathy, the specific etiology of which is not yet known.

Ploidy patterns of gastric carcinomas of 54 Japanese patients, ranging in age from 28 to 82 years, were determined by cytofluorometry. The gastric cancers were divided into four basic ploidy patterns; the first pattern was a diploid mode, the second was a heteroploid mode, the third was a mosaic pattern of a diploid and a heteroploid mode, and the fourth was a mosaic of two or more different heteroploid modes. The incidence was 68.4%, 14.8%, 12.9%, and 3.7% in the first, second, third, and fourth patterns, respectively. All the cancers contained polyploid populations, whereas the early cancers tended to contain a lesser amount of polyploid cells than the advanced ones. Diffuse-type cancers and well-differentiated, intestinal-type adenocarcinomas were mostly unimodal cancers of the diploidy or heteroploidy, whereas poorly differentiated adenocarcinomas were often mosaic cancers of several different ploidies. There was no correlation between ploidy patterns and ages and sexes of patients. For 11 cases, labeling indices with 3H-thymidine were determined. Labeling indices of the intestinal-type and diffuse-type cancers were 12% to 27% and 7% to 19%, respectively.

Brains of normal rats ranging in age from newborn to adult were observed with immunofluorescence technique using anti- granulomonocyte antiserum. For the first 10 days after birth, many cells with positive fluorescence were found in the white matter, the subependyma , the extra-parenchymal spaces, and the leptomeninx , but very few in the gray matter. They were mononuclear, rich in cytoplasm, and globular or irregular in shape. After about day 10 p.n., the positive cells decreased in number and became slender. However, there was no change in the distribution pattern. After about 3 weeks of age, no positive cells were detected in the brain parenchyma, except for very rare necrobiotic ones. It was suggested that blood monocytes infiltrate into the brain parenchyma of normal neonatal rat, but only for a while in the limited areas (white matter and subependyma ). They have the morphology and distribution of the "ameboid microglia" of neonatal brain. These monocytes disappear from the brain finally by the end of month 1 p.n.

Chronic gastritis is an important pathological condition of the gastric mucosa because the disease is thought to develop a predisposition to other gastric diseases [1], including, most seriously, gastric carcinomas [2, 3]. Although a large amount of information concerning glandular epithelial changes of the stomach in chronic gastritis has accumulated [4], our knowledge of vascular stromal changes in the diseased condition is surprisingly limited. Since glandular epithelial components and their surrounding vascular stroma have been shown to be structurally and functionally closely related to each other in the normal gastric mucosa [5], it is clearly important to study vascular stromal changes in chronic gastritis where diverse alterations of structures and cellular differentiations of the gastric glands are observed [4].

We started to use virtual slide (VS) and virtual microscopy (VM) systems for quick frozen intra-operative telepathology diagnosis in Kyoto, Japan. In the system we used a digital slide scanner, VASSALO by CLARO Inc., and a broadband optic fibre provided by NTT West Japan Inc. with the best effort capacity of 100 Mbps. The client is the pathology laboratory of Yamashiro Public hospital, one of the local centre hospitals located in the south of Kyoto Prefecture, where a fulltime pathologist is not present. The client is connected by VPN to the telepathology centre of our institute located in central Kyoto. As a result of the recent 15 test cases of VS telepathology diagnosis, including cases judging negative or positive surgical margins, we could estimate the usefulness of VS in intra-operative remote diagnosis. The time required for the frozen section VS file making was found to be around 10 min when we use ×10 objective and if the maximal dimension of the frozen sample is less than 20 mm. Good correct focus of VS images was attained in all cases and all the fields of each tissue specimen. Up to now the capacity of best effort B-band appears to be sufficient to attain diagnosis on time in intra-operation. Telepathology diagnosis was achieved within 5 minutes in most cases using VS viewer provided by CLARO Inc. The VS telepathology system was found to be superior to the conventional still image telepathology system using a robotic microscope since in the former we can observe much greater image information than in the latter in a certain limited time of intra-operation and in the much more efficient ways. In the near future VS telepathology will replace conventional still image telepathology with a robotic microscope even in quick frozen intra-operative diagnosis.

Background Digital pathology, i.e., applications of digital information technologies to pathology practice, has been expanding in the recent decades and the mode of pathology diagnostic practice is changing with enhanced precision. In the present study the changing processes of digital pathology in Japan were investigated and trends to future were discussed. Methods The changing status of digital pathology was investigated through reviewing the records of annual meetings of the Japanese Research Society of Telepathology and Pathology Informatics (JRST-PI) and of the Japanese pathology related medical and informatics journals. The results of the Japanese questionnaire survey conducted in 2008-2009 on telepathology and virtual slide were also reviewed. In addition effectiveness of an experimental automatic pathology diagnostic aid system using computer artificial intelligence was investigated by checking its rate of correct diagnosis for given prostate carcinoma digital images. Results Telepathology played a central role in the development of digital pathology in Japan. Both macroscopic and microscopic pathology digital images were routinely generated and used for diagnostic purposes in major hospitals. Virtual slide (VS) digital images were used first for education then for conference, consultation and also gradually for routine diagnosis and telepathology. The experimental automatic diagnostic aid system achieved the rate of correct diagnosis around 95% for prostate carcinoma and its use for automatic mapping of cancerous areas in a given tissue image was successful. Conclusions Advance in the digital information technologies gave revolutionary impacts on pathology education, conference, consultation, diagnosis, telepathology and also on pathology diagnostic procedures in Japan. The future will be bright for pathologists by the advanced digital pathology but we should pay attention to make the technologies and their effects under our control.

The number of diagnostic pathologists is significantly small in Japan with respect to the large number of clinical cases that require pathological diagnosis. Because of this individual diagnostic pathologists are overloaded in their daily work. To improve the situation development of computer assisted diagnostic system for a pathologist will be one of the effective solutions.