Prolonged SARS-CoV-2 infection associated with long-term corticosteroid use in a patient with impaired B-cell immunity.

Corticosteroids are widely used to treat severe COVID-19, but in immunocompromised individuals, who are susceptible to persistent infection, long term corticosteroid use may delay viral clearance. We present a case of prolonged SARS-CoV-2 infection in a man with significantly impaired B-cell immunity due to non-Hodgkin lymphoma which had been treated with rituximab. SARS-CoV-2 shedding persisted, despite treatment with remdesivir. Viral sequencing confirmed the persistence of the same viral strain, ruling out the possibility of reinfection. Although SARS-CoV-2 IgG, IgA and IgM remained negative throughout the treatment period, after reduction of the corticosteroid dose, PCR became negative. Long-term corticosteroid treatment, especially in immunocompromised individuals, may result in suppression of cell-mediated immunity and prolonged SARS-CoV-2 infection.

[A Case of Anastomotic Recurrence 10 Years after Excision of Sigmoid Colon Cancer with Submucosal Invasion].

A 72-year-old woman underwent sigmoid colon resection plus D2 lymph node dissection in 2008, with additional resection after endoscopic mucosal resection(EMR). Histopathological examination revealed only atypical ducts in the EMR scar, with no invasion below the submucosa. No lymphatic, venous, or nerve invasions were confirmed, and oral and anal stumps and lymph node metastases were negative. She was followed up for 5 years after the surgery, and no recurrence was detected. In 2018, she visited our hospital with the chief complaint of diarrhea and constipation. Colonoscopy revealed a circumferential lesion around the anastomosis. She underwent laparoscopic low anterior resection for suspected anastomotic recurrence, which was confirmed by histopathological diagnosis. The anastomotic recurrence 10 years after surgery for SM cancer of the colon with negative lymph node metastasis and vascular factor was extremely rare. We recognized the importance of surveillance 5 years after surgery.

CD33+ Immature Myeloid Cells Critically Predict Recurrence in Advanced Gastric Cancer.

BACKGROUND: It is elusive which subtypes of immune cells are pivotal in cancer progression and prognosis in gastric cancer (GC). The aim of this study is to clarify clinical impact of immature myeloid-derived immune cells in patients with GC who underwent curative gastrectomy with curative lymphadenectomy and treated with S-1 (tegafur/gimeracil/oteracil) postoperatively. METHODS: The prognostic impact of recruited CD33+ immature myeloid-derived cells were clinicopathologically analyzed in curatively resected stage II and III GC. Correlation of preoperative peripheral leukocyte fractions with recruited CD33+ immature cells was also assessed. RESULTS: Patients with high CD33+ cell counts in primary tumor showed dramatically worse prognosis (5-y recurrence-free survival 29.0%) than that of the counterparts (79.4%). High CD33+ cell counts independently predicted poor prognosis in stage II/III (hazard ratio, 4.34; P < 0.001). In analyses of each stage, high CD33+ cell count was pivotally associated with poor prognosis in both stages. There was no significant correlation of each peripheral leukocyte fraction with CD33+ cell recruitment. Of note, high CD33+ cell count was significantly correlated with hematogenous recurrence. CONCLUSIONS: Recruitment of CD33+ immature myeloid cells critically predict hematogenous recurrences in curatively resected advanced GC. These results give rational to focusing on CD33+ myeloid-derived cells as a novel approach to tackle advanced GC.

[A Case Report of Esophageal Cancer Accompanied with Esophago-Bronchial Fistula Which Treated Using Multimodal Therapy Including Esophageal Bypass Surgery].

We report the case of a patient with esophageal cancer accompanied by esophago-bronchial fistula and pneumonia, who experienced improved quality of life following multimodal therapy that included esophageal bypass surgery. A 56-year-old man was diagnosed with advanced esophageal cancer with an esophago-bronchial fistula on computed tomography scan. He underwent esophageal bypass surgery followed by definitive chemoradiotherapy. He started eating 12 days after the surgery and was discharged home after the completion of chemoradiotherapy. On follow-up, the primary lesion was found to be significantly decreased in size and the esophago-bronchial fistula was closed. Although the patient ultimately died owing to distant metastases, he enjoyed a prolonged period of survival following surgery. Multimodal therapy including esophageal bypass surgery is an useful strategy for treating patients with critical conditions such as esophago-bronchial fistula induced by esophageal cancer.

Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy.

BACKGROUND: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy. PATIENTS AND METHODS: We investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment. RESULTS: Hypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia. CONCLUSION: CDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity.

Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma.

BACKGROUND: OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer. METHODS: OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC). RESULTS: OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance. CONCLUSION: Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer.

BACKGROUND: Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC. METHODS: Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples. RESULTS: Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy. CONCLUSIONS: ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

Effectiveness of clarithromycin in patients with yellow nail syndrome.

BACKGROUND: Yellow nail syndrome (YNS) is a rare disease characterized by the triad of thickened, slow-growing yellow nails, lymphedema, and chronic respiratory manifestations. The cause of YNS is not known; however, it is suggested to be due to a congenital lymph abnormality. Since YNS is accompanied by chronic bronchial infection in more than half of patients, we hypothesized that treatment with clarithromycin (CAM) could be effective. We therefore evaluated the effectiveness of CAM against nail discoloration and respiratory manifestation in patients with YNS. METHODS: We conducted an observational study involving 5 patients with YNS who were treated at our institution between January 2005 and January 2016. CAM was prescribed for every patient. Patient demographic information, comorbidities, medications, chest radiographs, and clinical data such as nail color were extracted to evaluate clinical outcome. RESULTS: Mean patient age was 71.6 years, and 2 patients (40%) were male. Four patients had sinusitis, and 2 had rheumatoid arthritis. Regarding respiratory manifestations, 4 patients had sinobronchial syndrome and 2 had pleural effusion. Nail discoloration improved in every patient after CAM treatment. Four patients also experienced improvement in their respiratory manifestations. CONCLUSIONS: In patients with YNS, the anti-inflammatory activity of macrolides might improve their systemic inflammation. This improvement could help to reduce lymphedema and promote nail growth. TRIAL REGISTRATION: Ethical approval was provided by the institutional review board of the National Center of Global Health and Medicine (NCGM-G-002143-00), in January 2017. This study is retrospectively registered for UMIN Clinical Trial Registry ( UMIN000028514 ) in August 4th, 2017.

DNA diagnosis of peritoneal fluid cytology test by CDO1 promoter DNA hypermethylation in gastric cancer.

BACKGROUND: Minimal residual disease of the peritoneum is challenging for early cancer detection in gastric cancer (GC). Utility of PCR amplification of cancer-derived DNA has been considered feasible due to its molecular stability, however such markers have never been available in GC clinics. We recently discovered cancer-specific methylation of CDO1 gene in GC, and investigated the clinical potential to detect the minimal residual disease. METHODS: One hundred and two GC patients were investigated for peritoneal fluid cytology test (CY), and detection level of the promoter DNA methylation of CDO1 gene was assessed by quantitative methylation specific PCR (Q-MSP) in the sediments (DNA CY). RESULTS: (1) CY1 was pathologically confirmed in 8 cases, while DNA CY1 was detected in 18 cases. All 8 CY1 were DNA CY1. (2) DNA CY1 was recognized in 14.3, 25.0, 20.0, and 42.9%, in macroscopic Type II, small type III, large type III, and type IV, respectively, while it was not recognized in Type 0/I/V. (3) DNA CY1 was prognostic relevance in gastric cancer (p = 0.0004), and its significance was robust among Type III/IV gastric cancer (p = 0.006 for overall survival and p = 0.0006 for peritoneal recurrence free survival). (4) The peritoneal recurrence was hardly seen in GC patients with potent perioperative chemotherapy among those with DNA CY1. CONCLUSIONS: DNA CY1 detected by Q-MSP for CDO1 gene promoter DNA methylation has a great potential to detect minimal residual disease of the peritoneum in GC clinics as a novel DNA marker.

Promoter DNA methylation of CDO1 gene and its clinical significance in esophageal squamous cell carcinoma.

We have demonstrated that CDO1 methylation is frequently found in various cancers, including esophageal squamous cell carcinoma (ESCC), but its clinical relevance has remained elusive. CDO1 methylation was investigated in 169 ESCC patients who underwent esophagectomy between 1996 and 2007. CDO1 methylation was assessed by Q-MSP (quantitative methylation specific PCR), and its clinical significance, including its relationship to prognosis, was analyzed. (i) The median TaqMeth value of CDO1 methylation was 9.4, ranging from 0 to 279.5. CDO1 methylation was significantly different between cStage I and cStage II/III (P = 0.02). (ii) On the log-rank plot, the optimal cut-off value was determined to be 8.9; ESCC patients with high CDO1 methylation showed a significantly worse prognosis than those with low CDO1 methylation (P = 0.02). (iii) A multivariate Cox proportional hazards model identified only CDO1 hypermethylation as an independent prognostic factor (HR 2.00, CI 1.09-3.78, P = 0.03). (iv) CDO1 hypermethylation stratified ESCC patients' prognosis in cStage II/III for both neoadjuvant chemo(radio)therapy (NAC)-positive and NAC-negative cases. Moreover, the CDO1 methylation level was significantly lower in cases with Grade 2/3 than in those with Grade 0/1 (P = 0.02) among cStage II/III ESCC patients with NAC. Promoter DNA hypermethylation of CDO1 could be an independent prognostic factor in ESCC; it may also reflect NAC eradication of tumor cells in the primary tumors.

Predictive factors for lymph node metastasis in additional gastrectomy after endoscopic resection of cT1aN0 gastric cancer.

PURPOSE: Endoscopic therapy for clinical T1aN0 (cT1aN0) gastric cancer is an excellent therapeutic strategy; however, pathological lymph node metastasis (LNM) occasionally occurs. Patients who have a potential for LNM are subject to additional gastrectomy. Our aim was to identify predictors of LNM in additional gastrectomy. METHODS: One hundred and twelve cT1aN0 gastric cancer patients undergoing additional gastrectomy after endoscopic resection were identified between 1997 and 2013. Predictors for LNM were initially selected by a univariate analysis and applied to a multivariate analysis. RESULTS: (1) Twelve patients (10.7 %) had LNM following additional gastrectomy. (2) Clinicopathological factors significantly associated with LNM were the depth of invasion (SM2 or deeper, designated as SM2) (p = 0.0018) and rigorous lymphatic invasion (ly2,3) (p < 0.001). (3) The univariate predictors for LNM were applied to the multivariate logistic regression model, and SM2 (p = 0.0027) and ly2,3 (p = 0.0028) remained significant predictors. (4) When classified into 2 × 2 subgroups, the predictability for LNM was as follows: SM2 plus ly2,3 (46.7 %), SM2 plus ly0,1 (10.0 %), M,SM1 plus ly2,3 (0 %), and M,SM1 plus ly0,1 (0 %). CONCLUSIONS: In cT1aN0 gastric cancer patients, both SM2 and ly2,3 are significant predictors for LNM that may be important as references for additional gastrectomy after endoscopic resection.

Tuberculous pleurisy diagnosed by medical thoracoscopy in an adalimumab-treated rheumatoid arthritis patient after treatment of latent tuberculosis infection.

A 28-year-old rheumatoid arthritis woman treated with adalimumab was admitted with fever, cough, and right chest pain. X-ray showed right pleural effusion. By medical thoracoscopy, diffuse white nodules were observed, and biopsy specimen demonstrated epithelioid cell granulomas with necrosis and auramine-stained organisms, which suggested a diagnosis of tuberculous pleurisy. Medical thoracoscopy can be a potent diagnostic method when tuberculous pleurisy is suspected. Notably, despite latent tuberculosis treatment, active tuberculosis was not prevented.

[Usefulness of thoracoscopy under local anesthesia in the diagnosis of tuberculous pleurisy occurring during infliximab administration: a case report].

We report the case of a 71-year-old man with rheumatoid arthritis. Infliximab administration was started as treatment for rheumatoid arthritis in January 2009. As he showed a positive result for the tuberculin test, he was treated with isoniazid for 9 months. He was subsequently referred to our department in October 2011 with a right-sided pleural effusion. When thoracoscopy was performed under local anesthesia, white and red protruding lesions of various sizes were observed in the pleural cavity. A biopsy revealed fibrous granulation tissue, and tissue culture and all sensitivity tests were positive for Mycobacterium tuberculosis. Therefore, thoracoscopy is useful for not only diagnosis but also determining whether resistant tuberculosis is present.

Massive Hemothorax Caused by Removal of Percutaneous Transhepatic Abscess Drainage Tube for Bile Leak After Subtotal Cholecystectomy: A Case Report.

A 59-year-old man with a past medical history of gallstones was diagnosed with acute cholecystitis and received antibiotic treatment. He was discharged after ten days of hospitalization and was due to undergo laparoscopic cholecystectomy. Three months later, however, he had to be readmitted due to a recurrence of acute cholecystitis. Subsequently, laparoscopic reconstituting subtotal cholecystectomy was performed because Inflammation of the gallbladder was severe. At the first postoperative outpatient visit, the patient reported obstructive jaundice, and computed tomography (CT) scan revealed fluid collection in the hepatic bed and a missed common bile duct stone. Percutaneous transhepatic abscess drainage (PTAD) was performed on admission, and endoscopic stone removal was attempted the following day but was challenging due to a periampullary diverticulum. During laparotomy for stone extraction, the patient experienced prolonged shock and CT showed bleeding from the liver and massive right hemothorax. After open chest drainage and hemostasis, transcatheter arterial embolization (TAE) was performed. Such a case has never been reported before, and the PTAD tube should be handled cautiously.

Examination of the utility of cryobiopsy for tuberculous pleurisy in thoracoscopy: A report of seven cases.

Thoracoscopy under local anaesthesia is effective for the diagnosis of tuberculous pleurisy (TP), mesothelioma and pleural metastases of lung cancer, etc. It has recently been reported that cryobiopsy is useful for obtaining sufficient tissue, achieving a greater depth, and avoiding crush artefact than biopsy forceps. However, the utility of the tissue obtained by cryobiopsy for culture for diagnosing TP is unknown. We compared positivity rates of tissue culture obtained by biopsy forceps and cryobiopsy in seven TP patients. The median tissue size was 2 mm by biopsy forceps and 6 mm by cryobiopsy. The pathological diagnostic rate of pleural tissue was 85.7% with biopsy forceps and 100% with cryobiopsy. However, the positivity rate of tissue culture was 57.1% with biopsy forceps and 28.5% with cryobiopsy. Since rapid freezing with a cryoprobe makes it difficult for bacteria to grow, it is possible that cryobiopsy might not be useful for obtaining a tissue culture in TP cases. However, since the sample size of this study was small, analysis of more cases is required to confirm our results.

Diagnosis of diffuse panbronchiolitis by transbronchial lung cryobiopsy.

A 70-year-old man began to cough. Chest X-ray showed a tumor in the center, pleural effusion on the left side, and diffuse granular shadows on the right side. Chest computed tomography (CT) showed bronchial wall thickening and numerous granular shadows. We suspected diffuse panbronchiolitis. Thus, transbronchial lung biopsy (TBLB) and transbronchial lung cryobiopsy (TBLC) were performed. The tissue size obtained was 1 mm by TBLB and 6 mm at 5 seconds by TBLC. Histological analysis of the TBLB specimen showed lymphocyte infiltration, no fibrosis in Hematoxylin-eosin (HE) staining, and no elastic fibers in Elastica van Gieson (EVG) staining. On the other hand, TBLC specimens showed inflammatory cell infiltration and fibrosis around the bronchioles in HE staining and hypertrophy of elastic fibers in EVG staining. It was diagnosed as diffuse panbronchiolitis (DPB) from clinical and pathological findings. Cryobiopsy is useful in diagnosing DPB as well as interstitial pneumonia and lung cancer.

Clinical usefulness of end-tidal CO2 measured using a portable capnometer in patients with respiratory disease.

INTRODUCTION: This study aimed to evaluate the correlation and agreement between end-tidal CO2 (EtCO2 ) measured with the novel portable capnometer (CapnoEye®) and partial pressure of arterial carbon dioxide (PaCO2 ) levels in patients with respiratory diseases and to compare the efficacy of EtCO2 and PvCO2 in predicting PaCO2 levels. METHODS: We analyzed the correlation and the agreement between EtCO2 and PaCO2 and between PvCO2 and PaCO2 using Pearson's moment correlation coefficient in patients with type 1 and type 2 respiratory failure and both groups overall. RESULTS: A total of 100 samples were included that comprised 67 men (67%). The mean age of the subjects was 77 ± 13 years. Chronic obstructive pulmonary disease (COPD) (43%) was the most common disease. There was a high correlation between EtCO2 and PaCO2 (r = 0.88; p < 0.0001). Sixty-six PvCO2 samples were obtained, and there was a high correlation between PvCO2 and PaCO2 (r = 0.81; p < 0.0001). Regarding type 2 respiratory failure, there was a high correlation between EtCO2 and PaCO2 (r = 0.81). The Bland-Altman analysis between PaCO2 and EtCO2 revealed a bias of 5.7 mmHg, with limits of agreement ranging from -5.1 mmHg to 16.5 mmHg. In contrast, the analysis between PaCO2 and PvCO2 revealed a bias of -6.8 mmHg, and the limits of agreement ranged from -22.13 mmHg to 8.53 mmHg. CONCLUSION: EtCO2 measured by CapnoEye® was significantly correlated to PaCO2 levels in patients with respiratory diseases. Moreover, CapnoEye® may be more useful for predicting hypercapnia conditions in which respiratory diseases are compared with measure PvCO2 .

Examination of the utility of the COVID-19 detection kit, TRC Ready® SARS-CoV-2 i for nasopharyngeal swabs.

The reverse transcription polymerase chain reaction (RT-PCR) offers high sensitivity, but has some drawbacks, such as the time required for the RNA extraction. Transcription reverse-transcription concerted reaction (TRC) Ready® SARS-CoV-2 i is easy to use and can be performed in about 40 minutes. TRC Ready® SARS-CoV-2 i and real-time one-step RT-PCR using the TaqMan probe tests of cryopreserved nasopharyngeal swab samples from patients diagnosed with COVID-19 were compared. The primary objective was to examine the positive and negative concordance rates. A total of 69 samples cryopreserved at -80° C were examined. Of the 37 frozen samples that were expected to be RT-PCR positive, 35 were positive by the RT-PCR method. TRC Ready® SARS-CoV-2 i detected 33 positive cases and 2 negative cases. One frozen sample that was expected to be RT-PCR positive was negative on both TRC Ready® SARS-CoV-2 i and RT-PCR. In addition, one frozen sample that was expected to be RT-PCR positive was positive by the RT-PCR method and negative by TRC Ready® SARS-CoV-2 i. Of the 32 frozen samples that were expected to be RT-PCR negative, both the RT-PCR method and TRC Ready® SARS-CoV-2 i yielded negative results for all 32 samples. Compared with RT-PCR, TRC Ready® SARS-CoV-2 i had a positive concordance rate of 94.3% and a negative concordance rate of 97.1%. TRC Ready® SARS-CoV-2 i can be utilized in a wide range of medical sites such as clinics and community hospitals due to its ease of operability, and is expected to be useful in infection control.