Applicability of artificial intelligence-based computer-aided detection (AI-CAD) for pulmonary tuberculosis to community-based active case finding.

BACKGROUND: Artificial intelligence-based computer-aided detection (AI-CAD) for tuberculosis (TB) has become commercially available and several studies have been conducted to evaluate the performance of AI-CAD for pulmonary tuberculosis (TB) in clinical settings. However, little is known about its applicability to community-based active case-finding (ACF) for TB. METHODS: We analysed an anonymized data set obtained from a community-based ACF in Cambodia, targeting persons aged 55 years or over, persons with any TB symptoms, such as chronic cough, and persons at risk of TB, including household contacts. All of the participants in the ACF were screened by chest radiography (CXR) by Cambodian doctors, followed by Xpert test when they were eligible for sputum examination. Interpretation by an experienced chest physician and abnormality scoring by a newly developed AI-CAD were retrospectively conducted for the CXR images. With a reference of Xpert-positive TB or human interpretations, receiver operating characteristic (ROC) curves were drawn to evaluate the AI-CAD performance by area under the ROC curve (AUROC). In addition, its applicability to community-based ACFs in Cambodia was examined. RESULTS: TB scores of the AI-CAD were significantly associated with the CXR classifications as indicated by the severity of TB disease, and its AUROC as the bacteriological reference was 0.86 (95% confidence interval 0.83-0.89). Using a threshold for triage purposes, the human reading and bacteriological examination needed fell to 21% and 15%, respectively, detecting 95% of Xpert-positive TB in ACF. For screening purposes, we could detect 98% of Xpert-positive TB cases. CONCLUSIONS: AI-CAD is applicable to community-based ACF in high TB burden settings, where experienced human readers for CXR images are scarce. The use of AI-CAD in developing countries has the potential to expand CXR screening in community-based ACFs, with a substantial decrease in the workload on human readers and laboratory labour. Further studies are needed to generalize the results to other countries by increasing the sample size and comparing the AI-CAD performance with that of more human readers.

Analysis of a tuberculosis outbreak in an office: Hokkaido, Japan, 2019-2020.

Background: In August 2018, a male worker (Pt1) in an office was diagnosed with smear-positive pulmonary tuberculosis (TB). This study aims to characterize the cases found in the TB outbreak in the office. Methods: The risks of TB disease or infection were compared among the staff members by seating locations. Results: A total of 116 current and ex-staff members were investigated, among whom 13 patients with active TB, including Pt1, and 20 with latent TB infection were found by the end of 2020. One-third of the seating groups located at one end of the office that Pt1 belonged to had the highest risk of TB disease (30.8%, 95% confidence interval [CI]: 14.3%-51.8%) and infection (61.5%, 95% CI: 40.6%-79.8%) with a high relative risk of TB infection (6.2, 95% CI: 2.0-18.8) compared to another one-third of the seating groups at the other end of the office that had the lowest risk of active TB (0%, 95% CI: 0%-11.6%) and TB infection (10.0%, 95% CI: 2.1%-26.5%). Conclusion: The seating groups that Pt1 belonged to had the highest risk of TB disease and infection because the staff members in the groups were exposed to the air containing TB bacilli from Pt1. Local health offices should initiate active case finding using chest X-rays as soon as they are notified of a sputum smear-positive TB case if the delay of the diagnosis is longer than three months.

Extremely low 18F-fluorodeoxyglucose uptake in the brain of a patient with metastatic neuroblastoma and its recovery after chemotherapy: A case report.

Commonly, physiological 18F-fluorodeoxyglucose (FDG) uptake in the brain can be observed in 18F-FDG positron emission tomography. Abnormal uptake of 18F-FDG in the brain suggests disorders of central nervous system. Here, we present a case of extremely low 18F-FDG uptake in the brain of a 4-year-old girl with whole-body metastatic neuroblastoma. Almost missing of physiological 18F-FDG uptake in the brain was ascribed at least partly to the metastatic neuroblastoma. The brain could regain physiological 18F-FDG uptake after chemotherapy.

The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury.

Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.

[A Case of Rocuronium-induced Anaphylaxis in a Man with Kounis Syndrome in which Basophil Activation Test was Valuable in Determining the Causative Agent].

We experienced rocuronium-induced anaphylaxis in a 62-year-old man who was scheduled for laparoscopic ileocecal excision for cecal cancer under general anes- thesia. The patient did not have a preoperative history and examinations suggestive of heart disease, or pre- disposing factors for myocardial infarction. Just after induction of anesthesia, we noticed abnormally low blood pressure and ST segment elevation on his elec- trocardiogram. The surgery was postponed and percu- taneous coronary intervention was performed to treat coronary artery stenosis. Re-operation was planned 73-days after the first operation. The patient suffered cardiac arrest just after induction of general anesthesia At the same time, we noticed systemic erythema all over his body, which led to the diagnosis of anaphy- laxis. Cardiopulmonary resuscitation was performed and the surgery was postponed once again. Cardiovas- cular agents, including adrenaline, noradrenaline, atro- pine and amiodarone, improved his hemodynamics. In addition, steroids and anti-histamines were also admin- istered to treat anaphylaxis. We advised him to undergo skin tests to determine the causative agent of anaphylaxis, but he declined. Instead, a basophil activa- tion test was performed, which showed a positive reac- tion to rocuronium. Therefore, we planned general anesthesia without using muscle relaxants such as rocuronium for the third attempt at surgery. The sur- gery was performed safely with this protocol. It is likely that his symptoms in the first general anesthesia were caused by Kounis syndrome. We conclude that the basophil activation test seems to be valuable in determining the causative agent of anaphylaxis, partic- ularly when a patient does not agree to undergo skin tests.

[Outcomes of Bridge to Surgery for Obstructive Colorectal Cancer after Metallic Stent Placement in Our Hospital].

Recently, the endoscopic placement of self-expanding metallicstents (SEMSs)has become widespread for the treatment of acute malignant colorectal obstruction. This study was designed to evaluate the clinical outcomes of 22 patients with obstructive colorectal cancer who underwent SEMS placement as a bridge to surgery(BTS)from January 2012 to December 2015. The subjects comprised 15 men and 7 women with a mean age of 68.1 years. Placement and decompression were successfully achieved in all cases. No serious complications arose from the placement. After excluding 3 patients for whom preoperative chemotherapy or treatment for another disease was prioritized, the mean interval to surgery for the remaining 19 patients was 18.2 days. Operative anastomosis was performed in all patients except those who had tandem lesions. Although postoperative complications including minor leakage(n=1), surgical site infection(n=1), and ileus(n=1)were observed, the course was effective in most patients. Bridge to surgery is a relatively easy, safe, and effective method for the treatment of obstructive colorectal cancer that enables preoperative intestinal decompression and one-stage resection, preventing stoma creation.

Phase II study of FOLFOX4 with "wait and go" strategy as first-line treatment for metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of FOLFOX4 using "wait and go" strategy in treating metastatic colorectal cancer. METHODS: The conventional FOLFOX4 was repeated every 2 weeks. We waited until the recovery of symptoms from persistent neurotoxicity within an added period of 2 weeks, before performing the next cycle ("wait and go" strategy). RESULTS: We enrolled 58 patients, in whom a total of 481 cycles were administered (median 8 per patient; range 1-16). Toxicity was evaluated in 58 patients and response in 55. The major toxic effect was grade 3/4 neutropenia (33%). Painful paresthesia or persistent functional impairment was observed in 4 patients (7%). The response rate was 40% (95% confidence interval; 27.1-52.9%). The median progression-free survival time was 10.2 months, the 1-year survival rate was 89%, and the median overall survival time was 27.6 months. CONCLUSIONS: These findings indicate that this "wait and go" strategy reduces the frequency of persistent neuropathy while maintaining efficacy against metastatic colorectal cancer.

Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival.

BACKGROUND: Claudin, occludin, and zonula occludens (ZO)-1 are known as tight-junction-associated proteins. The aim of this study was to examine the expression of these proteins in gastric carcinoma. METHODS: Gastric cancer tissues (n = 124) were obtained from 124 patients who underwent gastrectomy at our hospital between January 2000 and December 2004. The expression of the above tight-junction-associated proteins in carcinoma, normal mucosa, and metaplastic epithelium was examined using immunohistochemistry. In addition, the expression of claudin-4 mRNA was examined in fresh frozen tissue obtained from 34 patients. RESULTS: Significant correlations were seen between the expression of claudin-4, occludin, and ZO-1. In regard to claudin-4, significant correlations were seen between the expression of claudin-4 evaluated by immunohistochemistry and the expression of claudin-4 mRNA. Claudin-4 expression was significantly decreased in tumors with undifferentiated-type adenocarcinoma, advanced T stage, lymph node metastasis, and peritoneal metastasis. Occludin and ZO-1 expression was significantly decreased in tumors with undifferentiated-type adenocarcinoma. Overall survival was significantly shorter in patients with low claudin-4 expression. Cox multivariate analysis revealed that low claudin-4 expression was independently associated with significantly decreased overall survival. CONCLUSION: Tight-junction-associated proteins, particularly claudin-4, may play important roles in determining invasiveness, metastatic potential, and survival in gastric cancer.

Traffic of infused bone marrow cells after genetically-labeled syngeneic bone marrow transplantation following lethal irradiation in mice.

UNLABELLED: Bone marrow (BM) cells are considered the source of stem cells for various organs. However, how quickly BM cells can penetrate and constitute lymphoid organs remains elusive. In the present study, we addressed this issue in a model using genetically-labeled syngeneic BM transplantation (BMT). METHODS: Donor BM cells were obtained from "green mice", transgenic mice with enhanced GFP. Lethally irradiated C57BL/6 mice were infused with 1 x 10(6) BM cells from the green mice through the tail vein. BM chimerism was analyzed by FACS and the presence of donor BM cells in thoracoabdominal organs was assessed by fluorescence microscopy. The commitment of BM cells was examined by immunohistochemical staining using epithelium-, macrophage-, B and T-lymphocyte, and endothelium-specific antibodies. RESULTS: BM chimerism reached 40+/- 18.5%, 82.6 +/- 23.4%, and 72 +/- 18% (mean +/- SD) at 1, 4, and 12 wks after BMT, respectively. GFP-positive cells were detected in all organs in the course of chimeric formation. Most GFP-positive cells were T and B lymphocytes in lymphoid systems including spleen, thymus, mesenteric lymph nodes and microvilli, and some were positive for macrophage and endothelial cell markers. CONCLUSIONS: Our results indicate that BM-derived cells migrate rapidly into various thoracoabdominal organs after BMT, and that lymphoid tissues are predominantly replaced with infused BM in lethally-irradiated mice. This confirmed the previous finding by others and suggests high interest of this model for further studies to characterize kinetics and roles of infused cells.

Usefulness of intraoperative esophagogastroduodenoscopy in a patient with lupus enteritis.

A 19-year-old Japanese woman had melena 2 months after systemic lupus erythematosus was diagnosed. Colonoscopy showed diffuse ulceration with bleeding in the ileum, suggesting that the melena was due to ischemic enteritis associated with lupus enteritis. Because treatment with high doses of steroid, anticoagulants, and cyclophosphamide pulse was ineffective, surgical intervention was planned. On exploration, it was impossible to determine the extent of resection visually. Intraoperative esophagogastroduodenoscopy clearly revealed the border between the ulcer and normal area, permitting successful resection of the ileum and ileostomy. This is the first report to document the usefulness of esophagogastroduodenoscopy in surgical treatment of ischemic enteritis in a patient with systemic lupus erythematosus.

Ornithine decarboxylase activity as a prognostic marker for colorectal cancer.

Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines, which are essential for cell proliferation. ODC activity was measured in 47 colorectal cancer patients, 5 patients with adenoma of colorectum and 4 healthy volunteers. Mean ODC activities of cancer tissue, non-cancerous mucosa from cancer-bearing colorectum, adenoma tissue, and normal mucosa from healthy volunteers were 435+/-392, 154+/-173, 295+/-202, 103+/-60 pmol CO2/h/mg protein, respectively. ODC activity of cancer tissue or adenoma tissue was significantly higher than that of the others. Among colorectal cancer patients, ODC activity in cancer tissue was correlated with T factors, lymph node metastasis and stages. Patients with tumors that had high ODC activity (> or =350 pmol CO2/h/mg protein) showed a poor 10-year survival rate. These results suggest that ODC activity may be a useful marker for patients' prognosis after surgery.

[A case of advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy using CPT-11 plus S-1].

Adjuvant chemotherapy for advanced gastric cancer has not yet been established. We report a patient with advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy consisting of CPT-11 and S-1. The patient was a 69-year-old woman diagnosed with large type 3 advanced gastric cancer with esophageal invasion and having No.3 lymph node metastasis (cT3, cN1, cM0, cStage IIIA), treated with 2 courses of CPT-11 plus S-1 as neo-adjuvant chemotherapy. Computed tomography after neo-adjuvant chemotherapy showed improvement of gastric wall thickness and reduction of lymph node metastasis. Subsequently, she underwent an operation. There was no lymph node swelling,so we performed curative surgery consisting of total gastrectomy, splenectomy, cholecystectomy, and D 2 lymph node dissection. Histological diagnosis was pT2 (MP), pN1, pStage II, and estimation of the histological change by chemotherapy was Grade 2. The course after surgery was good, and she was treated by S-1 after discharge. To date, 8 months after surgery, there is no evidence of recurrence. Combination chemotherapy consisting of CPT-11 plus S-1 can be performed safely as a neo-adjuvant treatment, and may be an effective treatment modality for advanced gastric cancer.

[Comparisons of standard treatments for colorectal cancer between Japan and Western Countries].

In order to distinguish the differences in standard treatment for colorectal cancer between Japan and Western countries, we compared several issues in clinical practice guidelines (guidance) of Japan, the United States and the United Kingdom. Endoscopic resection is not common in Western countries, so its feasibility and efficacy should be determined in Japan. Laparoscopic resection, however, is applied to more advanced diseases. Expansion of the indication is now also under consideration in Japan a waiting the results from clinical trials. Although with chmeotherapy for advanced or metastatic diseases, the use of molecular targeting agents is recommended in the United States, it is not in the United Kingdom mainly because it is not cost-effective. The indication of adjuvant chemotherapy is similar in Japan and Western countries. Patients with Stage III disease and high-risk Stage II are good candidates for adjuvant chemotherapy. Enrollment in clinical trial should be considered for remaining Stage II patients. Surgery is considered to be the major treatment modality in Japan for the treatment of liver and lung metastases and advanced rectal cancer. However, neo-adjuvant chemo (-radio) therapy is considered to be the standard treatment in Western countries. Development of a new treatment modality for colorectal cancer has progressed very rapidly, and the standard treatment has changed dramatically. While guidelines should be revised frequently according to new evidence, the standard treatment must be cautiously determined based on cost-effectiveness.

Detection of cancer cells disseminated in bone marrow using real-time quantitative RT-PCR of CEA, CK19, and CK20 mRNA in patients with gastric cancer.

BACKGROUND: To determine the significance of bone marrow disseminated tumor cells in gastric cancer, we investigated the mRNA expression levels of carcinoembryonic antigen (CEA), cytokeratin 19 (CK19), and cytokeratin 20 (CK20) using the real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR). METHODS: Bone marrow samples were aspirated from the sternum at the time of surgery in 65 patients with resectable gastric cancer. Total RNA was extracted from bone marrow; and the expression levels of CEA, CK19, and CK20 mRNA were determined by RQ-PCR using an ABI PRISM 7000 and quantified against the GAPDH mRNA level. RESULTS: The detection limits of these genes were determined in the gastric cancer cell line MKN-45 and the colon cancer cell line C-1, which had been serially diluted in peripheral blood mononuclear cells (PBMCs). A rate of 1 cancer cell/million PBMCs was obtained by detecting CEA and CK19 mRNA in MKN-45 and by detecting CK20 mRNA in C-1. In the clinical samples, only 1 of the 65 gastric cancer patients (1.5%) who had stage IV disease was positive for CEA, CK19, and CK20 mRNA; none of CEA, CK19, or CK20 mRNA was positive in the remaining 64 patients. No significant correlation was observed between disseminated cancer cells in bone marrow and clinicopathological features, including simultaneous or metachronous hepatic metastasis and patient survival. CONCLUSION: The incidence of disseminated cancer cells in bone marrow in our study appears low, unlike that in previous reports. The significance of disseminated cancer cells in bone marrow may also be quite low in gastric cancer.

Understanding the response of dendritic cells to activation by streptococcal preparation OK-432.

BACKGROUND: The streptococcal preparation OK-432 induces maturation of T cells and dendritic cells (DCs). However, the mechanisms by which OK-432 induces DC maturation are not well understood. MATERIALS AND METHODS: The effects of OK-432 and TNF-alpha on peripheral blood mononuclear cells (PBMCs) were compared. Antibody-based approaches were used to detect proteins characteristic of antigen-presenting cells and cytokines. Cytotoxicity was evaluated by measuring the release of LDH after incubation of effector and target cells. The TLR-4 levels were measured by real-time quantitative PCR. RESULTS: Changes in cell surface marker levels were detected in both treatment groups but OK-432 had a greater effect on induction of Th-1-type cytokines. Furthermore, TLR-4 mRNA was up-regulated in cells from two out of five patients in response to OK-432, but not in response to TNF-alpha. CONCLUSION: OK-432 has a more profound effect on human DCs than TNF-alpha and may act through multiple signaling pathways.

Low serum ferritin levels as a clue to colonic cancer detection in two patients with coronary artery disease: a case report.

We diagnosed colonic cancer using low serum ferritin levels as a clue in two patients with cardiac or cardiopulmonary disease. In the course of the follow-up, the serum ferritin levels decreased to less than 18 ng/mL without significant appearance of iron-deficiency anemia. One patient showed positive immunological fecal occult blood test results whereas the other not. Both patients rejected further colonoscopy because of their concern for stress in relation to their cardiac or cardiopulmonary diseases, but instead agreed to positron emission computed tomography (PET) using a F-18 deoxyglucose at their own expense. In both patients, PET documented abnormal tracer accumulation in the colon. From the results of PET imaging, they eventually agreed to colonoscopy. A colonic adenocarcinoma was detected at the site of the positive PET finding in each patient. Both patients underwent curative resection of the cancer. The detection of the levels of serum ferritin may be available for the screening colonic cancer in patients declining colonoscopic examination.

[Experimental study for a combination chemo-immunotherapy using dendritic cells].

This study was designed to seek for the optimal anticancer agents for a combination of chemotherapy and specific immunotherapy using dendritic cells (DC) in gastric cancer. We investigated the immuno-suppressive activity of anticancer agents on human peripheral blood mononuclear cells (PBMC), apoptosis inducing activity on gastric cancer cells and expression of Toll-like receptor (TLR)-4 mRNA on immatureDCs (iDCs) by paclitaxel (TXL) and docetaxel (TXT). We further compared the cytotoxicity of cytotixic T lymphocytes (CTLs) induced by DCs pulsed with tumor cell lysate and apoptotic cells induced by TXT. Although most of the anticancer agents demonstrated the suppression activity on proliferation of PBMC in a dose dependent manner, TXT, doxifluridine and irinotecan did not show the suppressive activity on PBMC even in the highest drug concentration. About 60% of gastric cancer cells demonstrated apoptosis after a 24-48 hour treatment with both TXL and TXT. Expression of TLR-4 mRNA in iDCs was up-regulated by TXT, not by TXL, and peaked at 2 hours after the treatment. CTLs induced by DCs pulsed with tumor cell lysate and apoptotic cells showed a similar killing activity to target cells. These results suggest that TXT appears to be an optimal anticancer agent for a combination therapy with chemotherapy and tumor specific immunotherapy using dendritic cells in gastric cancer.

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer.

BACKGROUND: This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU). METHODS: A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1M tegafur--0.4 M 5-chloro-2,4-dihydroxypyridine--1 M potassium oxonate (S-1 [TS-1]) were also compared, using three human gastric cancer xenografts in nude mice. RESULTS: There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity. CONCLUSION: DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.