Changes in virus detection in hospitalized children before and after the severe acute respiratory syndrome coronavirus 2 pandemic.

The impact of strengthening preventive measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the prevalence of respiratory viruses in children was examined. After the SARS-CoV-2 pandemic, the rate of multiple virus detection among hospitalized children decreased. Immediately after the SARS-CoV-2 pandemic, respiratory syncytial and parainfluenza viruses were rarely detected and subsequently reemerged. Human metapneumovirus and influenza virus were not consistently detected. Non-enveloped viruses (bocavirus, rhinovirus, and adenovirus) were detected to some extent even after the pandemic. Epidemic-suppressed infectious diseases may reemerge as susceptibility accumulates in the population and should continue to be monitored.

Planned Safety Analysis of the ACTS-CC 02 Trial: A Randomized Phase III Trial of S-1 With Oxaliplatin Versus Tegafur and Uracil With Leucovorin as Adjuvant Chemotherapy for High-Risk Stage III Colon Cancer.

BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.

Surgery and imatinib therapy for liver oligometastasis of GIST: a study of Japanese Study Group on GIST.

We conducted a multicenter prospective study to clarify the efficacy and safety of surgery and imatinib for liver oligometastasis of gastrointestinal stromal tumors. Eligible gastrointestinal stromal tumor patients were enrolled in the surgery trial or the imatinib trial. Primary endpoints were recurrence-free survival and progression-free survival, respectively. The trials were prematurely terminated due to amendment of guidelines for adjuvant imatinib therapy and low patient accrual. In the surgery trial, all the six patients showed hepatic recurrence: median recurrence-free survival was 145 days (range: 62-1366 days). Of the five patients receiving salvage imatinib therapy, two showed progressive disease although no death was observed. Of the five patients enrolled in the imatinib trial, one died of pneumonia after progressive disease, and four had not shown progressive disease as of last visit. The results suggest that liver oligometastasis of gastrointestinal stromal tumor may not be controllable by surgery alone and require concomitant imatinib therapy.

A case of gastrointestinal bleeding due to right hepatic artery pseudoaneurysm following total remnant pancreatectomy: A case report.

INTRODUCTION: Pseudoaneurysm is a serious complication after pancreatic surgery, which mainly depends on the presence of a preceding pancreatic fistula. Postpancreatectomy hemorrhage following total pancreatectomy is a rare complication due to the absence of a pancreatic fistula. Here we report an unusual case of massive gastrointestinal bleeding due to right hepatic artery (RHA) pseudoaneurysm following total remnant pancreatectomy. PRESENTATION OF CASE: A 75-year-old man was diagnosed with intraductal papillary mucinous carcinoma recurrence following distal pancreatectomy and underwent total remnant pancreatectomy. After discharge, he was readmitted to our hospital with melena because of the diagnosis of gastrointestinal bleeding. Gastrointestinal endoscopy was performed to detect the origin of bleeding, but an obvious bleeding point could not be detected. Abdominal computed tomography demonstrated an expansive growth, which indicated RHA pseudoaneurysm. Emergency angiography revealed gastrointestinal bleeding into the jejunum from the ruptured RHA pseudoaneurysm. Transcatheter arterial embolization was performed; subsequently, bleeding was successfully stopped for a short duration. Because of improvements in his general condition, the patient was discharged. DISCUSSION: To date, very few cases have described postpancreatectomy hemorrhage following total remnant pancreatectomy. We suspect that the aneurysm ruptured into the jejunum, possibly because of the scarring and inflammation associated with his two complex surgeries. CONCLUSION: Pseudoaneurysm should be considered when the fragility of blood vessels is suspected, despite no history of anastomotic leak and intra-abdominal abscess. Our case also highlighted that detecting gastrointestinal bleeding is necessary to recognize sentinel bleeding if the origin of bleeding is undetectable.

Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.

A multicenter phase II trial of mFOLFOX6 plus bevacizumab to treat liver-only metastases of colorectal cancer that are unsuitable for upfront resection (TRICC0808).

BACKGROUND: A phase II clinical trial was conducted on colorectal cancer patients with only liver metastases (focal diameter exceeds 5 cm or the number of liver metastases is ≥5; H2·H3) to evaluate the liver resection rate and safety after 6 cycles of mFOLFOX6+bevacizumab (BV) therapy. METHODS: mFOLFOX6+BV therapy was applied for 6 cycles to the patients with H2·H3 liver only metastasis. Hepatectomy was considered after the sixth cycle as a rule, and was performed if possible. The primary endpoint was the curative hepatectomy rate (R0 resection rate). RESULTS: Forty-six patients were registered and 45 patients were included in the efficacy analysis. Of the 19 patients rated as unresectable before therapy, 18 completed 6 cycles of mFOLFOX6+BV therapy and subsequently underwent hepatectomy (16 were R0-resected). Of the 26 initially unresectable patients, 6 underwent hepatectomy (4 were RO-resected). The overall R0 resection rate was 44.4% (20/45). Chemotherapy-associated grade 3 or higher adverse events included neutrophil decreased (17.4%) and leukocyte decreased (8.7%), fatigue (6.5%) etc. Only hypertension (6.5%) and venous thromboembolism (2.2%) were BV-associated grade 3 or higher adverse events. Among the 25 patients who underwent hepatectomy, intraoperative/postoperative complications included grade 3 wound infections (2 cases), biloma, delayed wound healing and intraperitoneal abscess (each 1 case). CONCLUSIONS: In colorectal cancer patients with liver-only metastases, mFOLFOX6+ BV therapy yielded a high hepatectomy rate and a high percentage of initially unresectable and subsequently resectable cases. The chemotherapy associated adverse events and hepatectomy complications were both within acceptable ranges.

Ezh2 regulates transcriptional and posttranslational expression of T-bet and promotes Th1 cell responses mediating aplastic anemia in mice.

Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-γ-producing Th1 CD4(+) T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4(+) T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases.

The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.

Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.

Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice.

Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4(high)) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4(high) i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4(high) i-DCs were CD11c(+)B220(+)PDCA-1(+), resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4(high) i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4(low)) i-DCs were CD11c(+)B220(-)PDCA-1(-), and had low levels of Jagged1. In vitro assays showed that Dll4(high) i-DCs induced significantly more IFN-γ- and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4(low) i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4(high) i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4(low) i-DCs. Furthermore, Dll4 and Dll4(high) i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4(high) i-DCs.

[Questionnaire survey of efficacy of patient support in outpatient chemotherapy by pharmacist].

The aim of this study is evaluation of the efficacy of the pharmacist in providing support at the ambulatory therapy center (ATC), especially in connection with chemotherapy side effects in patients. The unsigned questionnaire survey was conducted for patients receiving chemotherapy in ATC. 108 patients were enrolled, and 78 patients answered questions. Patients were asked which kind of specialists provide the most ideal support in the ATC, and what do patients suffer in the ATC. Interestingly, more patients chose pharmacists than nurses and doctors. Many of patients suffer hair loss, nausea and peripheral neuropathy, and many people feel time spent in the ATC is not so meaningful.

Kaposiform hemangioendothelioma of the mediastinum in a 7-month-old boy: a case report.

Kaposiform hemangioendothelioma is an aggressive vascular proliferation that has been recognized as a separate entity from other childhood vascular tumors. The authors present an unusual case of hemangioendothelioma arising in the mediastinum of a 7-month-old male infant with acute respiratory distress and Kasabach-Merritt syndrome. This patient with life-threatening lesion showed a dramatic response to interferon alfa-2a. This case had many histologic and clinical features consistent with kaposiform hemangioendothelioma.

Effect of uni-adrenalectomy on blood pressure in a patient with excessive adrenal 18-hydroxy-11-deoxycorticosterone production bilaterally.

A 46-year-old woman was presented with mineralocorticoid excess syndrome and a large mass originating from the right adrenal gland. Clinical examination before right adrenalectomy revealed elevated serum concentrations of 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) both systemically and in the adrenal veins bilaterally. Histopathological and immunohistochemical analyses of the surgical specimen demonstrated adrenal hyperplasia of outer fasciculata cells, and the presence of cystic mass. The adrenalectomy ameliorated her blood pressure (BP) from 156/96 mmHg to 148/87 mmHg with a concomitant increase of serum potassium concentration from 3.1 mEq/l to 3.5 mEq/l. These results suggest that uni-adrenalectomy is, at least in part, effective in ameliorating not only BP but also potassium concentration in a patient of adrenal hyperplasia with excessive bilateral 18-OH-DOC production.