miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

Clinical Implication of the Effect of the Production of Neutralizing Antibodies Against SARS-Cov-2 for Chronic Immune Thrombocytopenia Flare-Up Associated with COVID-19 Infection: A Case Report and the Review of Literature.

Previous studies have demonstrated that the appropriate production of serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) neutralizing antibody (nAb) plays a critical role in the recovery from coronavirus disease 2019 (COVID-19); however, the role of nAb production in the recovery from a flare-up of chronic immune thrombocytopenia (ITP) has been unknown. We here report the first retrospectively investigated case of serum anti-SARS-Cov-2 nAb production during chronic ITP flare-up triggered by COVID-19. A 79-year-old woman with a history of corticosteroid-refractory ITP visited our hospital complaining of fever, cough, and sore throat for 4 days. Although chronic ITP was controlled by 12.5 mg of eltrombopag (EPAG) every other day, laboratory tests showed a decreased peripheral blood platelet count of 15.0 × 109/L, which indicated worsening thrombocytopenia. Meanwhile, PCR testing of a nasopharyngeal swab revealed that the patient was positive for SARS-Cov-2, and a computed tomography scan revealed bilateral pneumonia. On the basis of the flare-up of chronic ITP associated with COVID-19 pneumonia which was determined as a moderately severe status according to the WHO clinical progression scale, intravenous immunoglobulin therapy for 5 days (days 0-4) and antiviral therapy were added on top of EPAG, which only resulted in a transient increase in the platelet count for several days. After decreasing to 8.0 × 109/L on day 13, the platelet count increased from day 16, coinciding with a positive detection for serum nAb against SARS-Cov-2. Although the increased dose up to 50 mg/day of EPAG was challenged during the clinical course, rapid dose reduction did not cause another relapse. In addition, no thrombotic or bleeding event was seen. These collectively suggest the vital role of the production of anti-SARS-Cov-2 nAb and improvement of clinical symptoms for recovery from a flare-up of chronic ITP in our case.

Successful treatment of paraneoplastic pemphigus and bronchiolitis obliterans associated with follicular lymphoma with obinutuzumab and bendamustine.

We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.

[B-cell acute lymphoblastic leukemia with glycophorin A expression].

This study reports a case of a 49-year-old woman having B-cell acute lymphoblastic leukemia with glycophorin A, a representative erythroid marker, expression. According to the WHO criteria for mixed phenotype acute leukemia (MPAL), erythroid lineage is not defined, and to the best of our knowledge, only one other case with erythroid/B-cell biphenotypic acute leukemia has been reported previously. To establish the disease entity and clarify the pathophysiology of erythroid/lymphoid MPAL, additional cases need to be analyzed.

Gastric lymphoma complicated by phlegmonous gastritis and Guillain-Barré syndrome: A case report.

INTRODUCTION: Complications such as severe infection may occur during the chemotherapy of malignant lymphoma. Phlegmonous gastritis (PG) is a rare acute bacterial infection associated with high mortality, requiring early diagnosis, and prompt management. In addition, Guillain-Barré syndrome (GBS) occasionally requires early treatment and intensive care management due to the occurrence of severe neuropathy and respiratory failure. PATIENT CONCERNS: A 70-year-old male was diagnosed with primary gastric diffuse large B-cell lymphoma (DLBCL) after the detection of several polypoid tumors with ulcers. The patient underwent chemotherapy for DLBCL and exhibited adverse effects (i.e., fever, vomiting, epigastric pain, and neutropenia). Computed tomography indicated widespread thickening in the gastric wall. Furthermore, approximately 2 weeks later, the patient presented with gradual symmetric lower extremity weakness and respiratory failure due to paralysis of the respiratory muscle. DIAGNOSES: DLBCL was diagnosed through a gastric tumor biopsy. On the basis of the computed tomography findings, a culture of gastric juice, nerve conduction studies, and clinical symptoms, this case of gastric lymphoma was complicated with PG and GBS. INTERVENTIONS: The patient was treated with antimicrobial therapy and administration of granulocyte colony-stimulating factor for PG, and with intravenous immunoglobulin and intensive care management for GBS. OUTCOMES: Despite the aggressive progress of the condition, the patient improved without relapse of DLBCL. CONCLUSION: PG was regarded as a precedent infection of GBS. In this article, we present the first reported case of gastric lymphoma complicated with PG and GBS.

Prediction of delayed platelet engraftment after autologous stem cell transplantation for B-cell non-Hodgkin lymphoma.

Delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment after autologous peripheral blood stem cell transplantation (auto-PBSCT). To identify risk factors for DPE and to develop a simple and clinically applicable system for predicting the time required for platelet recovery, we conducted a multi-institutional retrospective study in 144 patients with B-cell non-Hodgkin lymphoma who underwent auto-PBSCT. In a median observation period of 930 days (range: 25-5272 days), 139 patients successfully achieved platelet engraftment (≥50.0 × 109/L). The median duration for platelet engraftment was 19 days, and 130 patients had platelet engraftment within 40 days after auto-PBSCT; however, the other 14 patients failed to achieve platelet engraftment within 60 days. These 14 patients with DPE required a significantly greater number of apheresis procedures and had a lower pre-apheresis absolute lymphocyte count (PA-ALC) compared to those without DPE. Importantly, multivariate analysis revealed that the number of transplanted CD34+ cells (≤2.0 × 106/kg), number of required apheresis procedures (≥3 days), and PA-ALC (≤1.0 × 109/L) were independently associated with a longer time for platelet engraftment after auto-PBSCT. By incorporating these three independent factors as variables, we generated a new scoring system for prediction of the time and probability for platelet engraftment after auto-PBSCT.

Association between sarcopenia and sleep disorder in older patients with diabetes.

AIM: In the present study, we aimed to examine the association between sarcopenia and sleep disorder in older patients with diabetes using the Japanese version of SARC-F (SARC-F-J). METHODS: Outpatients with diabetes (aged ≥65 years) at the Ise Red Cross Hospital were included in the present study. We used the Japanese version of the Pittsburgh Sleep Quality Index, which is a self-administered questionnaire, to measure sleep disorder. To evaluate sarcopenia, we used SARC-F-J, a self-administered questionnaire, comprising five items. For multiple logistic regression analysis, the dependent variable was sleep disorder and the explanatory variable was sarcopenia, and these were used for calculating the odds ratios of sarcopenia with regard to sleep disorder. RESULTS: In total, 318 patients were included in this study (189 men and 129 women). The prevalence of sarcopenia was 22.5% and that of sleep disorder was 44.8%. Adjusted odds ratios of sarcopenia and sleep disorder were 6.04 in men (95% CI 1.71-21.36, P = 0.005) and 6.33 in women (95% CI 1.91-20.97, P = 0.003). CONCLUSIONS: We found a statistically significant association between sarcopenia and sleep disorder in older patients with diabetes using SARC-F-J. Therefore, older patients with diabetes should be cautioned regarding sleep disorder if they are diagnosed with sarcopenia. Geriatr Gerontol Int 2019; 19: 399-403.

[Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis subsequent to rabbit antithymocyte globulin administration and successfully treated with rituximab in a patient with aplastic anemia].

Rabbit antithymocyte globulin (ATG) is an effective immunosuppressive therapy for patients with aplastic anemia (AA). However, Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is a rare but serious complication of the therapy. An 81-year-old man was diagnosed with severe AA on the occasion of melena. Because cyclosporine monotherapy did not improve his condition, rabbit ATG was additionally administered. Thirty-one days after the administration of rabbit ATG, the patient presented with fever and general malaise. His liver and renal function tests showed rapid decline, and the patient went into shock. Although atypical lymphocytes in the peripheral blood, hepatosplenomegaly, and lymphadenopathy were not detected, the peripheral blood EBV-DNA load and serum ferritin levels were high, and his bone marrow aspiration specimen revealed hemophagocytic findings, leading to a diagnosis of EBV-LPD. He was treated with rituximab and recovered immediately. A total of 480 days have passed since the patient was administered the rabbit ATG, and he remains in AA remission without EBV-LPD relapse. This case suggests that rituximab is an effective therapy for EBV-LPD manifesting as EBV-associated hemophagocytic lymphohistiocytosis and indicates that monitoring the EBV-DNA load contributes to the diagnosis.

Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma.

Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC.

[Strangulation Ileus Caused by Incarcerated Esophageal Hiatal Hernia after Laparoscopic Total Gastrectomy - A Case Report].

Laparoscopic total gastrectomy(LTG)is one of the most increasing surgeries among gastric cancer surgery. Although LTG has many advantages on the patient, we should be more careful of its specific complications. Here we report a case of 72- year-old man with the complaint of severe acute upper abdominal pain due to strangulation ileus caused by incarcerated esophageal hiatal hernia(EHH)after LTG. Emergent operation has performed on the patient and total 180 cm length of necrotic small intestine was resected. EHH after gastrectomy was thought to be rare complication. However, some literature reported that EHH after gastrectomy, especially after LTG has more possibility than it has ever thought to be. Laparoscopic surgery has more advantages than open surgery in terms of less invasiveness, rapid postoperative recovery, and less intraabdominal adhesion. One of the causes for EHH after LTG is ironically thought to be its less intraabdominal adhesion. We concluded that crus repair is one of the effective methods for the prevention of EHH after LTG through experiencing this case.

Granulocyte colony-stimulating factor-producing hepatocellular carcinoma with abrupt changes.

Granulocyte colony-stimulating factor (G-CSF)-producing tumor is one of the rare types of cancer clinically characterized by an elevated fever and white blood cell (WBC) increment. Although G-CSF producing tumors have been reported in several types of cancer including those of the lungs, cervix and bladder, G-CSF producing hepatocellular carcinoma is extremely rare. Here, we report the case of a rapidly growing and poorly differentiated hepatocellular carcinoma producing G-CSF. The patient showed symptoms of continuous high fever, stomach pain and cough, and high serum WBC counts, C-reactive protein (CRP) and G-CSF levels were found in laboratory tests. After a radical hepatectomy, the patient completely recovered from the above symptoms and inflammatory state. The serum levels of G-CSF were reduced to normal levels after radical surgery. An immunohistochemical analysis revealed the overexpression of G-CSF in the cytoplasm of certain hepatocellular carcinoma (HCC) cell. The patient's serum WBC, CRP and G-CSF levels remained within normal levels in the six months after surgery without recurrence. This is the 9th case report of G-CSF producing hepatocellular carcinoma in English literature. We review the clinical characteristics of the G-CSF producing HCC and discuss a possible treatment strategy.

Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer.

BACKGROUND: Recently, circulating microRNAs have been reported to be stably detectable in plasma/serum and to function as potent non-invasive biomarkers in various cancers. We hypothesized that miR-18a could contribute to a novel plasma biomarker in patients with gastric cancer (GC). METHODS: We focused on miR-18a, which is a component of miR-17-92 cluster and has been reported as highly expressed in GC tissues. The study involved three steps: (1) confirmation of the higher miR-18a expression in primary GC tissues and GC cell lines than in normal gastric tissues and a fibroblast cell line; (2) evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing 104 GC patients and 65 healthy volunteers; (3) evaluation of monitoring tumor dynamics by the plasma miR-18a assay. RESULTS: (1) The miR-18a expressions were significantly higher in GC tissues than in normal gastric tissues (P = 0.0286) and higher in all examined GC cell lines than in the fibroblast cell line. (2) The plasma miR-18a concentrations were significantly higher in GC patients than in healthy controls (P < 0.0001). The value of the area under the receiver-operating characteristic curve was 0.8059. (3) The plasma miR-18a levels were significantly reduced in postoperative samples compared to in preoperative samples (P = 0.0002). In an miR-18a overexpressing cell line, the miR-18a concentration of cultured medium increased in both cell number and time-course dependent manners, suggesting microRNA might be released from cancer cells into the surrounding environment. CONCLUSIONS: Circulating miR-18a could be a useful biomarker for screening GC and monitoring tumor dynamics.

Increase in peritoneal recurrence induced by intraoperative hemorrhage in gastrectomy.

BACKGROUND: The association between intraoperative hemorrhage and the type of recurrence was examined, with a focus on peritoneal metastasis. METHODS: A total of 540 patients who underwent macroscopically curative gastrectomy for advanced gastric cancers were reviewed for various clinicopathological characteristics, such as the amount of intraoperative hemorrhage and the pattern of recurrence. Additionally, adhesion assays using gastric cancer cells and mesothelial cells were performed in the presence of blood plasma to assess its effects on cell adhesion. RESULTS: Large intraoperative hemorrhages were correlated with a higher risk of peritoneal metastasis, while small hemorrhages were not. However, there were no significant differences in the incidence of all recurrences or other types of recurrence between both groups. Multivariate analysis of all cases (T2-4) revealed that large intraoperative hemorrhages were not an independent risk factor for peritoneal recurrence (p = 0.144); however, the large hemorrhage group developed peritoneal recurrence more frequently than the small hemorrhage group in each T stage. In the adhesion assay, the ability of cancer cells and mesothelial cells to adhere to each other was enhanced by the addition of plasma to the culture medium. The addition of heparin significantly decreased the plasma-induced enhancement of cell adhesion of Kato III, but not MKN45 or MKN74. CONCLUSIONS: Advanced gastric cancer patients accompanied by a large amount of intraoperative hemorrhage are more likely to develop peritoneal recurrence, and this risk might be due, at least in part, to the increased ability of cancer cells and mesothelial cells to adhere to each other.

Circulating miR-18a: a sensitive cancer screening biomarker in human cancer.

MicroRNAs have been reported to be stably detectable in plasma/serum and to exhibit resistance to endogenous ribonuclease activity because of binding to proteins such as Argonaute-2 and high-density lipoprotein, or being packed by secretory particles such as exosomes. These secretory particles include specific microRNAs and can function as intercellular transmitters. These findings could open-up a new and promising field in the use of circulating microRNAs for cancer treatment. In particular, miR-18a, which is located in the potentially oncogenic miR-17-92 cluster, is a highly expressed microRNAs in several types of cancers. The concentration of miR-18a in plasma/serum of patients with cancer such as esophageal (AUC=0.944), pancreatic (AUC=0.936), hepatocellular (AUC=0.881), colorectal and other types of cancers is much higher than that of healthy volunteers. Such reports provide evidence that circulating miR-18 might be a next-generation biomarker and contribute to cancer screening in non-invasive liquid biopsy, to a clinically-satisfactory degree of sensitivity and specificity.

[Treatment strategy for patients with CY1 gastric cancer using subgroup analyses].

BACKGROUND AND AIMS: Recent advances in anti-cancer drug treatments enable us to improve prognosis in Stage IV gastric cancer. In particular, in recent reports patients with only cytology positive (CY1) non-curative factors have comparatively better prognosis than others. This study was designed to evaluate our outcomes, to allow identification of CY1 gastric cancer patients and to investigate new treatment strategies. PATIENTS AND METHODS: Between 2000 and 2008, 336 patients underwent peritoneal washing cytology for gastric cancer intra-operatively. Of these, 35 patients (10.4%) were diagnosed with CY1 gastric cancer. RESULTS: 1 ) In all CY1 gastric cancers, 1-year, 3-year, and 5-year survival rates were 49%, 11%, and 5.7%, respectively. Clinical factors such as number of non-curative factors (p=0.008) and gastrectomy (p=0.001)were significantly related to poor prognosis. 2 ) The number of CY1 patients with only CY1 non-curative factors (Group C) and multiple non-curative factors (Group CM)were 14 and 21, respectively. The number of CY1 patients with gastrectomy and without gastrectomy were 30 (MST 366 days, Group C: 14 Group CM: 16) and 5 (MST: 88 days, Group CM: 5), respectively. 3 ) In CY1 patients with gastrectomy, patients treated with S-1 based chemotherapy had better prognosis in both Group C and Group CM. 4 ) 8 CY1 patients with neoadjuvant chemotherapy (NAC) followed by gastrectomy (MST 501 days, 1-year survival rate 62.5%) tended to have better prognosis than those without NAC (MST 132 days, 1-year survival rate 25.0% (p= 0.055). CONCLUSIONS: Gastrectomy, number of non-curative factor, S-1 based chemotherapy and NAC were keys to improving prognosis by subgroup analyses in CY1 gastric cancer.

Circulating long non-coding RNAs in plasma of patients with gastric cancer.

BACKGROUND: We examined the levels of long non-coding RNAs (lncRNAs) in the plasma of patients with gastric cancer to assess their clinical significance for diseases diagnosing and monitoring. MATERIALS AND METHODS: We investigated the stability of plasma lncRNAs, and then confirmed the appropriateness of the lncRNA assay with a pre-amplification method. The levels of plasma lncRNAs, H19, HOX antisense intergenic RNA (HOTAIR), and metastasis associated lung adenocarcinoma transcript-1 (MALAT1), were then analyzed in patients with gastric cancer (GC) and healthy controls. RESULTS: Plasma lncRNAs exhibited minimal gradual instability only under several severe conditions. Analysis showed that samples with pre-amplification had a higher level of linearity in the reverse transcription polymerase chain reaction (RT-PCR) assay than those without pre-amplification. Plasma H19 levels were significantly higher in patients than in healthy controls. Plasma H19 levels were significantly reduced in postoperative samples. CONCLUSION: Circulating lncRNAs can be detectable in plasma, and the detection of circulating lncRNAs may provide new complementary tumor markers for gastric cancer.

Prognostic impact of circulating miR-21 in the plasma of patients with gastric carcinoma.

BACKGROUND: MicroRNAs (miRNAs) such as miR-17-5p, miR-21, miR-106a and miR-106b are reported to be highly expressed in gastric carcinoma (GC) tissues. Recently, we reported that these miRNAs were consistently detectable in plasma and reflected tumor dynamics of GC. We hypothesized that these plasma miRNA concentrations could be used as prognostic markers in patients with GC. MATERIALS AND METHODS: Between 2008 and 2009, preoperative plasma samples were collected from 69 consecutive patients with GC at our hospital. We retrospectively examined the association between plasma miRNA concentrations and prognosis. RESULTS: The postoperative cause-specific survival rate of patients with high plasma miR-21 concentration was significantly poorer than those with a low concentration (p=0.0451), as was that of those with high plasma concentration of miR-106a (p=0.1132). There were no prognostic differences according to the plasma concentration of miR-17-5p and miR-106b. Those with high miR-21 concentration had also a slightly higher incidence of vascular invasion (p=0.0311). Multivariate analysis revealed that the presence of a high miR-21 concentration in plasma was an independent prognostic factor (p=0.0133, hazard ratio: 13.4 (95% CI: 1.72-104.4)). CONCLUSION: The level of circulating miR-21 could be a reliable prognostic marker in the plasma of patients with GC. These findings contribute to the stratification of patients in order to identify those who need meticulous follow-up for early detection of recurrence and additional or alternative treatments of GC.

Overexpression of TRIM44 contributes to malignant outcome in gastric carcinoma.

Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which is characterized by a conserved RING finger, B-box, and coiled-coil domains, function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer. We analyzed seven gastric cancer cell lines and 112 primary tumors, which were curatively resected in our hospital between 2001 and 2003. Expression of the TRIM44 protein was detected in gastric cancer cell lines (2/7 cell lines; 29%) and primary tumor samples of gastric cancer (29/112 cases; 25%). Knockdown of TRIM44 expression using several specific siRNAs inhibited the proliferation, migration, and invasion of TRIM44-overexpressing cells. Overexpression of the TRIM44 protein was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.0038, log-rank test) in both intensity and proportion expression-dependent manner. TRIM44 positivity was independently associated with worse outcome in multivariate analysis (P = 0.0233, hazard ratio 3.37 [1.18-9.64]). These findings suggest that TRIM44 plays a crucial role in tumor cell proliferation through its overexpression, and highlight its usefulness as a predictor and potential therapeutic target in gastric cancer.