Prompt Reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1 and a Relatively Low Basal Ratio of Ferritin/CRP Is Possibly Associated With the Efficacy of Tocilizumab Monotherapy in Severely to Critically Ill Patients With COVID-19.

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.

Expanding application of digital pathology in Japan--from education, telepathology to autodiagnosis.

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.

A novel PAX3 rearrangement in embryonal rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft tissue tumor seen in children and young adults, and it can be classified into 2 major histological subtypes, alveolar and embryonal. In the alveolar subtype, 2 recurrent chromosomal translocations, t(2;13)(q35;q14) and its variant t(1;13)(p36;q14), have been identified as the specific cytogenetic abnormalities. These translocations produce the PAX3-FOXO1 and PAX7-FOXO1 fusion genes, respectively. In the embryonal subtype, however, no recurrent chromosomal abnormalities have been identified. In this study, we analyzed the complex chromosomal translocation in one case with embryonal rhabdomyosarcoma by means of spectral karyotyping (SKY) and identified a novel translocation involving chromosome band 2q35, which is the locus of PAX3 gene. Furthermore, we identified the novel PAX3 rearrangement using fluorescence in situ hybridization (FISH) analysis. Additional identification of the partner gene may help disclose the molecular mechanism of the development of this embryonal subtype.

Use of virtual slide system for quick frozen intra-operative telepathology diagnosis in Kyoto, Japan.

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 full-time 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 x10 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.

Clinicopathological characteristics of esophageal squamous papillomas in Japanese patients--with comparison of findings from Western countries.

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.

A new cancer diagnostic system based on a CDK profiling technology.

A series of molecular pathological investigations of the molecules that stimulate the cyclin dependent kinases (CDK1, 2, 4, and 6) have led to enormous accumulation of knowledge of the clinical significance of these molecules for cancer diagnosis. However, the molecules have yet to be applied to clinical cancer diagnosis, as there is no available technology for application of the knowledge in a clinical setting. We hypothesized that the direct measurement of CDK activities and expressions (CDK profiling) might produce clinically relevant values for the diagnosis. This study investigated the clinical relevance of CDK profiling in gastrointestinal carcinoma tissues by using originally developed expression and activity analysis methods. We have established novel methods and an apparatus for analyzing the expression and activities of the CDK molecules in lysate of tumor tissue in a clinical setting, and examined 30 surgically dissected gastrointestinal carcinomas and corresponding normal mucosal specimens. We demonstrate here that remarkably elevated CDK2 activity is evident in more than 70% of carcinoma tissues. Moreover, a G1-CDK activity profiling accurately mirrored the differences in proliferation between tumor and normal colonic tissues. Our results suggest that CDK profiling is a potent molecular-clinical approach to complement the conventional pathological diagnosis, and to further assist in the individualized medications.

Ki-67 labeling index as a marker of malignancy in ocular surface neoplasms.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These results suggest that Ki-67 LI may be a sensitive marker for ocular malignant tumor grading.

Unusual cytologic findings in low grade papillary transitional cell carcinoma.

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 celllular 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.

Successful treatment of congenital systemic juvenile xanthogranuloma with Langerhans cell histiocytosis-based chemotherapy.

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.

Clinicopathologic study of conjunctivochalasis.

OBJECTIVE: To clarify the structural features of conjunctivochalasis histopathologically. METHODS: A biopsy of redundant conjunctiva from the same anatomic location of 44 +/- 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.

Perinodal involvement of cancer cells in gastric cancer patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Development of telepathology systems between different types of terminals based on the standard for image collaboration command protocol].

In Japan telepathology systems have been developed in medical or pathological environment such as a shortage and an uneven distribution of pathologists. More than 100 telepathology terminals are working mainly for intraoperative quick diagnosis. They cannot communicate with different types each other. In March 2000 the Medical Information System Development Center(MEDIS-DC) successfully demonstrated the interconnection between different types of telepathology terminals based on the Standard for Image Collaboration Command Protocol (SICCP). Nikon, NTTdata and Olympus had joined the development. In February 2002 MEDIS-DC examined these systems for pathological consultations in the fields of Okinawa-Kyoto, Kyoto-Mie and Mie-Okinawa. These successful examinations let us know that telepathology systems need new observation methodologies for telecytology and teleconsultation in addition to the flow for intraoperative quick diagnosis, new GUI guidelines for telepathology terminal design and, education and support for users of their smooth operation. Outcomes of MEDIS-DC activities encourageed us to challenge the next generation telepathology. We found some new trends in telepathology or pathology informatics such as virtual slide technologies and the internet applications in US and Europe. In order to keep Japanese priority, MEDIS-DC telepathology comittee has started investigations to construct a strategy for development of Japanese next generation telepathology.

Resection of a pelvic schwannoma with partial removal of the sacral nerve root.

Because the symptoms do not appear in most cases until the tumor has grown quite large, schwannomas are often detected incidentally during work-up for some other condition. Benign schwannomas generally do not invade adjacent structures but making the diagnosis preoperatively can be difficult when the tumor is large. We report the case of a benign schwannoma which was diagnosed preoperatively by needle core biopsy under computed tomography guidance. The tumor was removed completely by partially resecting the S1 nerve root, which was subsequently reanastomosed. The postoperative course was uneventful with the exception of minimal left leg pain due to neurologic deficit.