The impact of the coronavirus disease 2019 pandemic on pediatric hospitalization in Kitami, Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has drastically changed the recommended activities and environment for patients worldwide. Our aim was to assess the impact of COVID-19 on pediatric hospitalizations in Kitami, Japan. METHODS: A retrospective, single-center study was conducted on hospitalized patients aged 0-14 years at the Japanese Red Cross Kitami Hospital. We compared the incidence of pediatric patients hospitalized in 2020 with those in 2017-2019. RESULTS: The number of pediatric hospitalized patients dropped significantly in 2020 compared to that in 2017-2019 (median 43.0 vs 78.5 per month, P < 0.001). The patients were significantly older in 2020 (4.3 vs 3.4 years, P < 0.001). Hospitalization from respiratory (8.5 vs 30.5, P < 0.001) and gastrointestinal infections (3.0 vs 6.0, P = 0.004) significantly decreased. Admission due to respiratory syncytial virus (0.0 vs 4.0, P < 0.001), human metapneumovirus (0.0 vs 1.0, P = 0.005), influenza (0.0 vs 0.0, P = 0.009), adenovirus (0.0 vs 1.0, P = 0.003), and rotavirus infection (0.0 vs 0.0, P = 0.025) also decreased significantly. The <1-5 age groups significantly decreased (<1 year old, 6.5 vs 12.5, P < 0.001; 1-3 years old, 13.0 vs 29.5, P < 0.001; 4-5 years old, 5.5 vs 11.5, P < 0.001). Hospitalization due to foreign body ingestions increased significantly in 2020 (1.0 vs 0.0, P = 0.010). CONCLUSIONS: The COVID-19 control measures inadvertently reduced the number of hospitalized pediatric patients, especially younger children with respiratory and gastrointestinal infections.

Lymphomatoid Papulosis Development in Acute Lymphoblastic Leukemia.

Lymphomatoid papulosis (LyP) is a chronic, recurrent benign skin disease characterized by histological features of a CD 30-positive cutaneous T-cell lymphoproliferative disorder. It is rare, with an annual, worldwide incidence of 1.2 - 1.9 per million, and accounts for 16-47% of pediatric cutaneous lymphoproliferative disorders. It often occurs on the extremities or the trunk and rarely affects the face or genitals. Its onset may be triggered by irradiation therapy, immunomodulating agents, infection or atopic dermatitis. It has a benign course but is associated with certain hematological malignancies. Mycosis fungoides and primary cutaneous anaplastic large cell lymphoma are the most commonly associated hematological malignancies. The incidence of lymphoma in children with LyP has been reported to be 8.5% at most. Most patients who develop lymphomas do so within 4 years of the LyP onset; therefore, patients with LyP should be carefully followed up. Herein, we report a case in which tumors appeared in the left scrotum and under the left lip during maintenance therapy for precursor B-cell acute lymphoblastic leukemia. We needed to distinguish the tumor from extramedullary recurrence of ALL or de novo other cutaneous lymphoma; however, the histological findings of a tumor biopsy resulted in a diagnosis of LyP.

Safety and efficacy of cold snare polypectomy for small colorectal polyps: A prospective randomized control trial and one-year follow-up study.

TRIAL DESIGN: Elimination of small colorectal polyps with cold snare polypectomy (CSP) is reported to be as safe as hot snare polypectomy (HSP). The effectiveness of CSP has not been clearly defined, and the incidence of long-term recurrence has not been determined. We conducted a randomized control study and one-year follow-up study to assess their safety and efficacy. METHODS: Patients with small colorectal polyps were randomized to receive CSP or HSP. Polypectomy was performed to determine the pathological curability, and patients completed a questionnaire about the tolerability of the procedure. Follow-up colonoscopy was performed to determine the local recurrence of adenoma. The major outcome was the non-inferiority of CSP to HSP in the rate of delayed bleeding and minor outcomes, including the incidence of immediate bleeding and perforation, procedural time, and the resection rate. RESULTS: A total of 119 participants were recruited in this randomized study and underwent polypectomy. Among the 458 polyps, 332 eligible polyps were analyzed. The rate of adverse events was 0.6% (1/175) for CSP and 0% (0/157) for HSP, which showed the non-inferiority of CSP. While the complete resection rate of CSP was very high (100%), the R0 rate was not satisfactory (horizontal margin, 65.5%; vertical margin, 89.1%). Two local recurrences (2.5%) were observed in the follow-up of 80 adenomas treated with CSP. No recurrence was found in 79 lesions in the HSP group, which was not significant (P = .06). CONCLUSIONS: Colorectal polyps were safely resected using CSP, similar to HSP. Most would agree to say that CSP is considered safer than HSP. The main question is then related to efficacy. Our results of the present study demonstrate that recurrence after CSP should be carefully managed for curative treatment.

Rare case of fecal impaction caused by a fecalith originating in a large colonic diverticulum: A case report.

BACKGROUND: Fecal impaction is defined as a large mass of compacted feces in the colon and has the potential to induce a serious medical condition in elderly individuals. Fecal impaction is generally preventable, and early recognition of the typical radiological findings is important for making an early diagnosis. The factors that lead to fecal impaction are usually similar to those causing constipation. Few cases with fecal impaction associated with a diverticulum have been reported. CASE SUMMARY: We present the case of a 62-year-old woman who suffered from abdominal pain and vomiting, had a medical history of repeated acute abdomen and was diagnosed with fecal impaction in the descending colon based on X-ray and computed tomography (CT) imaging. After examination by gastrografin-enhanced colonography following colonoscopy and CT colonography, the fecalith was suspected to have been produced at the site of a large diverticulum in the transverse colon. The fecalith was surgically resected, and a histological diagnosis of pseudodiverticulum was made. There was no recurrence during 33 mo of follow-up. CONCLUSION: This case highlights the importance of accurate identification and treatment of a fecal impaction. This case indicated that the endoscopic evacuation and subsequent colonography were effective for identifying a diverticulum that might have caused fecal impaction. A fecal impaction was associated with the diverticulum. Consequently, the planned diverticulectomy was performed. Appropriate emergency medical treatment and maintenance treatments should be selected in such cases to prevent recurrence.

Endoscopic Submucosal Dissection for Depressed-type Early Adenocarcinoma of the Terminal Ileum.

We herein report a rare case of ileal adenocarcinoma that was completely removed by endoscopic submucosal dissection (ESD) without any complications. An 80-year-old man was referred to our hospital to undergo treatment for an ileal tumor. Conventional colonoscopy showed a reddish depressed lesion that was classified as type 0-IIc according to the Paris classification. The ileal tumor was successfully removed en bloc by ESD with a negative surgical margin. The histological findings showed a well-differentiated adenocarcinoma with no submucosal or lymphovascular invasion. Colonoscopy and CT performed one year after ESD showed no local recurrence, stenosis, or lymph node metastasis.

Infection with fully mature Corynosoma cf. validum causes ulcers in the human small intestine.

Corynosoma is a parasite that can normally be found in the intestinal tract of fish-eating mammals, particularly in seals and birds. The present case proposed that Corynosoma could attain full maturity in the human intestine. A 70-year-old female complained of abdominal pain. A computed tomography (CT) scan revealed a swelling of the intraperitoneal lymph nodes with no responsible lesion. Video capsule endoscopy and double-balloon endoscopy detected several ulcerations and one parasite in the ileum, which was tightly attached at the bottom of the ulcerations. The parasite was cylindrical and measured approximately 10 mm (long) x 3 mm (wide). Pathologically, the worm had a four-layered body wall and contained embryonated eggs. The sequences of the parasite-derived nuclear ribosomal DNA fragment and mitochondrial DNA fragment of cox1 were almost identical to those of Corynosoma validum. The patient's abdominal pain immediately improved after the administration of pyrantel pamoate (1,500 mg). Corynosoma was possibly the responsible disease in a patient who complained of abdominal pain and in whom no responsible lesion was detected by CT, gastroduodenoscopy or colonoscopy. Examinations of the small intestines should be aggressively performed in such cases.

Graft-versus-host disease (GVHD) prophylaxis by using methotrexate decreases pre-engraftment syndrome and severe acute GVHD, and accelerates engraftment after cord blood transplantation.

GVHD and graft failure are serious problems in CBT. PES after CBT also occurs frequently and is associated with transplantation-related complications such as acute GVHD. We reviewed medical records for 70 consecutive child CBT recipients between December 1997 and April 2015. Forty-nine patients received prophylaxis against GVHD with CsA or Tac in combination with mPSL from day +7 (mPSL group), and 21 patients received CsA or Tac with MTX on day +1 and day +3 (MTX group). Neutrophil engraftment was detected in 59 patients (84.3%). Neutrophil engraftment rate in the MTX group was significantly higher than that in the mPSL group (21/21 (100%) and 38/49 (77.6%), respectively, p = 0.027). PES developed in 35 patients, and the incidence of PES in the mPSL group was significantly higher than that in the MTX group (p = 0.036). The incidence of severe acute GVHD (grade III or IV) in the MTX group was significantly lower than that in the mPSL group (p = 0.049). Although this study was a small-scale study, the results showed that increase in the rate of engraftment and decrease in the incidence of early immune reactions such as PES and severe acute GVHD could be achieved by early commencement of immunosuppression using MTX.

TRIM45 negatively regulates NF-κB-mediated transcription and suppresses cell proliferation.

The NF-κB signaling pathway plays an important role in cell survival, immunity, inflammation, carcinogenesis, and organogenesis. Activation of NF-κB is regulated by several posttranslational modifications including phosphorylation, neddylation and ubiquitination. The NF-κB signaling pathway is activated by two distinct signaling mechanisms and is strictly modulated by the ubiquitin-proteasome system. It has been reported that overexpression of TRIM45, one of the TRIM family ubiquitin ligases, suppresses transcriptional activities of Elk-1 and AP-1, which are targets of the MAPK signaling pathway. In this study, we showed that TRIM45 also negatively regulates TNFα-induced NF-κB-mediated transcription by a luciferase reporter assay and that TRIM45 lacking a RING domain also has an activity to inhibit the NF-κB signal. Moreover, we found that TRIM45 overexpression suppresses cell growth. These findings suggest that TRIM45 acts as a repressor for the NF-κB signal and regulates cell growth.

TRIM6 interacts with Myc and maintains the pluripotency of mouse embryonic stem cells.

The proto-oncogene product Myc is a master regulator of cell proliferation through its specific binding to the E-box motif in genomic DNA. It has been reported that Myc has an important role in the proliferation and maintenance of the pluripotency of embryonic stem (ES) cells and that the transcriptional activity of Myc is regulated by several post-translational modifications, including ubiquitination. In this study, we showed that tripartite motif containing 6 (TRIM6), one of the TRIM family ubiquitin ligases, was selectively expressed in ES cells and interacted with Myc followed by attenuation of the transcriptional activity of Myc. Knockdown of TRIM6 in ES cells enhanced the transcriptional activity of Myc and repressed expression of NANOG, resulting in the promotion of ES cell differentiation. These findings indicate that TRIM6 regulates the transcriptional activity of Myc during the maintenance of ES cell pluripotency, suggesting that TRIM6 functions as a novel regulator for Myc-mediated transcription in ES cells.

TRIM32 promotes retinoic acid receptor α-mediated differentiation in human promyelogenous leukemic cell line HL60.

Ubiquitination, one of the posttranslational modifications, appears to be involved in the transcriptional activity of nuclear receptors including retinoic acid receptor α (RARα). We previously reported that an E3 ubiquitin ligase, TRIM32, interacts with several important proteins including RARα and enhances transcriptional activity of RARα in mouse neuroblastoma cells and embryonal carcinoma cells. Retinoic acid (RA), which acts as a ligand to nuclear receptors including RARα, plays crucial roles in development, differentiation, cell cycles and apoptosis. In this study, we found that TRIM32 enhances RARα-mediated transcriptional activity even in the absence of RA and stabilizes RARα in the human promyelogenous leukemic cell line HL60. Moreover, we found that overexpression of TRIM32 in HL60 cells suppresses cellular proliferation and induces granulocytic differentiation even in the absence of RA. These findings suggest that TRIM32 functions as one of the coactivators for RARα-mediated transcription in acute promyelogenous leukemia (APL) cells, and thus TRIM32 may become a potentially therapeutic target for APL.

TRIM32 promotes neural differentiation through retinoic acid receptor-mediated transcription.

Retinoic acid (RA), a metabolite of vitamin A, plays versatile roles in development, differentiation, cell cycles and regulation of apoptosis by regulating gene transcription through nuclear receptor activation. Ubiquitinylation, which is one of the post-translational modifications, appears to be involved in the transcriptional activity of intranuclear receptors including retinoic acid receptor α (RARα). Mutations in the tripartite motif-containing protein 32 gene (TRIM32; also known as E3 ubiquitin-protein ligase) have been reported to be responsible for limb-girdle muscular dystrophy type 2H in humans, and its encoded protein has been shown to interact with several other important proteins. In this study, we found that TRIM32 interacts with RARα and enhances its transcriptional activity in the presence of RA. We also found that overexpression of TRIM32 in mouse neuroblastoma cells and embryonal carcinoma cells promoted stability of RARα, resulting in enhancement of neural differentiation. These findings suggest that TRIM32 functions as one of the co-activators for RARα-mediated transcription, and thereby TRIM32 is a potential therapeutic target for developmental disorders and RA-dependent leukemias.

TRIM29 negatively regulates p53 via inhibition of Tip60.

Ataxia-telangiectasia (AT) is an autosomal recessive genetic disease characterized by immunological deficiencies, neurological degeneration, developmental abnormalities and an increased risk of cancer. Ataxia-telangiectasia group D (ATDC) was initially described as a gene related to AT. Ataxia-telangiectasia group D, also known as TRIM29, is structurally a member of the tripartite motif (TRIM) family of proteins, some of which have been reported to be highly expressed in some human carcinomas, but the involvement of TRIM29 in carcinogenesis has not been fully elucidated. In this study, we found by using yeast two-hybrid screening that TRIM29 binds to Tip60, which has been reported as a cellular acetyltransferase protein. Overexpression of TRIM29 promoted degradation and changed localization of Tip60 and reduced acetylation of p53 at lysine 120 by Tip60, resulting in enhancement of cell growth and transforming activity. In addition, we found that TRIM29 suppresses apoptosis induced by UV irradiation in HCT116 cell lines. These findings suggest that TRIM29 functions as an oncogene that promotes tumor growth.

Piperacillin/tazobactam plus ceftazidime versus sulbactam/ampicillin plus aztreonam as empirical therapy for fever in severely neutropenic pediatric patients.

BACKGROUND: The efficacy and safety of piperacillin/tazobactam plus ceftazidime (PIPC/TAZ+CAZ) versus sulbactam/ampicillin plus aztreonam (SBT/ABPC+AZT) as empirical therapy for febrile neutropenia were assessed in children with hematologic disease and solid tumor. PROCEDURE: A prospective randomized study was performed to evaluate the clinical response of 70 febrile episodes in the PIPC/TAZ+CAZ arm and 64 evaluable febrile episodes in the SBT/ABPC+AZT arm of the study. Clinical efficacy was evaluated at 120 hours, with treatment outcome criteria defined as follows. Success was defined as disappearance of fever, clinical improvement, eradication of the infecting organism, and maintenance of a response for at least 7 days after discontinuation of treatment. RESULTS: An infection was documented microbiologically in 14 episodes (20%) in the PIPC/TAZ+CAZ arm and in 8 episodes (13%) in the SBT/ABPC+AZT arm. The success rate was 57.1% in the PIPC/TAZ+CAZ arm and 62.5% in the SBT/ABPC+AZT arm (P>0.05). No major adverse effects were observed in the study. CONCLUSIONS: PIPC/TAZ+CAZ and SBT/ABPC+AZT are effective and safe for initial empirical treatment of febrile episodes in neutropenic pediatric patients. The clinical efficacy of SBT/ABPC+AZT is equivalent or superior to that of PIPC/TAZ+CAZ, the effect of which is already proven against febrile neutropenia. Therefore, SBT/ABPC+AZT may be a treatment of choice for febrile neutropenia in pediatric cancer patients.

[Cord blood transplantation for acute lymphoblastic leukemia in children: analysis at a single institution].

We examined the result of cord blood transplantation (CBT) for acute lymphoblastic leukemia (ALL) in children. Fifty ALL patients underwent stem cell transplantation in our hospital. Among these, 23 patients received related bone marrow transplantation and peripheral blood stem cell transplantation (R-BMT/PBSCT), 17 patients received unrelated bone marrow transplantation (U-BMT), and 10 patients received unrelated cord blood transplantation (U-CBT). The 5-year overall survival rates after R-BMT/PBSCT, U-BMT and U-CBT were 64.6%, 32.3%, and 85.7%, respectively. Event-free survivals after 5 years were 59.6%, 14.7%, and 70.0%, respectively. The relapse rate in the U-CBT group was equal to that in the R-BMT/PBSCT group, and the transplant-related mortality of U-CBT was 0%. Our data show that U-CBT should be the first choice for patients with refractory or relapsed ALL who have no related HLA-matched donor.

A prospective, randomized study comparing cefozopran with piperacillin-tazobactam plus ceftazidime as empirical therapy for febrile neutropenia in children with hematological disorders.

BACKGROUND: The aim of this randomized study was to evaluate the efficacy of cefozopran monotherapy and piperacillin-tazobactam plus ceftazidime (PIPC/TAZ + CAZ) combination therapy in pediatric neutropenic patients. PROCEDURE: A total of 51 patients with 138 episodes of febrile neutropenia received antibiotic therapy. Of these episodes, 95 were considered eligible for the study. The episodes were treated randomly with either piperacillin-tazobactam (125 mg/kg/day) plus ceftazidime (100 mg/kg/day) or with cefozopran (100 mg/kg/day). Success was defined as resolution of fever and clinical signs of infection within 120 hr following initiation of antibiotic therapy. Duration of neutropenia did not differ statistically between the two groups, and resolution of fever in all cases without complication was seen before recovery from severe neutropenia. RESULTS: The overall success rate was 61%. There was no statistically significant difference between the two groups: 53% for PIPC/TAZ + CAZ versus 69% for cefozopran (P = 0.122). Blood cultures were positive in eight episodes (8.4%), but there were not deaths as a result of infection. CONCLUSION: Both cefozopran and PIPC/TAZ + CAZ combination therapy are safe and well tolerated in pediatric neutropenic patients. Our results show that cefozopran is a good candidate for monotherapy for neutropenic fever.

Current approaches to management of cerebral fungal infection in pediatric patients with hematologic disorders.

We report 2 pediatric cases of cerebral fungal infection. A patient with severe aplastic anemia developed an Aspergillus species brain abscess and pulmonary aspergillosis after peripheral blood stem cell transplantation. Despite administration of micafungin, amphotericin B, and flucytosine, the patient died 2 months after the transplantation because of underlying pulmonary aspergillosis. Another patient with acute myelogenous leukemia developed a huge brain abscess with histopathologic findings suspicious of mucormycosis. This patient was cured with combination therapy of antifungal agents and intensive surgery, without sequelae. It is important to perform aggressive multimodality treatment, when indicated, including surgical intervention, even if in myelosuppression.

Functional role of metaplastic paneth cell defensins in Helicobacter pylori-infected stomach.

BACKGROUND AND AIMS: Chronic gastritis is caused by Helicobacter pylori infection, and gastritis is classified as inflammation, atrophy, and intestinal metaplasia. Detailed pathologic studies have shown that H. pylori settles on the surface of gastric mucosa, and that it is eliminated from metaplastic mucosa. However, its mechanism of natural protection is not well known. METHODS: Antimicrobial human enteric defensin expression was determined in the RNA and protein levels. Recombinant enteric defensins were produced with a bacterial expression system and their anti-H. pylori activities were assessed by bactericidal assay. RESULTS: Human enteric defensin (HD)-5 and HD-6 were detected in Paneth cells, which are observed in the gastric metaplastic mucosa as well as small intestinal epithelia. HD-5 protein was coexpressed with trypsin, which is considered to be an activating enzyme of HD-5. Less H. pylori was observed in the intestinal metaplasia with HD-5 expressing Paneth cells. The recombinant defensins showed killing activity against H. pylori at a low concentration in vitro. CONCLUSIONS: The human defensins that are expressed in the metaplastic Paneth cells eliminate H. pylori. Metaplastic change may be a purposive development of the human stomach.

The clinical feature of invasive fungal infection in pediatric patients with hematologic and malignant diseases: a 10-year analysis at a single institution at Japan.

Invasive fungal infections (IFI) are an important complication in hematologic malignancies and stem-cell transplantation (SCT). However, there are limited data characterizing IFI in children. The clinical feature of IFI after chemotherapy and SCT were analyzed in 334 pediatric patients treated at Hokkaido University Hospital from 1997 to 2006. The cumulative incidence of IFI was 6.9%; this comprised cases of proven, probable and possible IFI at rates of 1.2%, 3.0%, and 2.7%, respectively. The infected lesions were lung in 14 patients, liver in 5 patients, brain in 3 patients, fungemia in 2 patients, kidney in 1 patient, and endophthalmitis in 1 patient. The mortality of IFI was 48.2%, excluding patients who died due to relapse and interstitial pneumonitis; in particular, 71.4% patients with a lung lesion (10/14) died due to IFI. Fifty-nine pediatric patients died in our institution over the 10-year period of the study and IFI was the direct cause of death in 18.6% (11/59) of the patients. Risk factors for IFI with chemotherapy and SCT were also analyzed. Univariate analysis showed that age at diagnosis older than 10 years, relapse of original disease, long-term administration of broad-spectrum antibiotics, and acute myelogenous leukemia (AML) were the risk factors for IFI. All patients with IFI received long-term antibiotic therapy. AML was most strongly associated using a multivariate analysis. The prognosis of IFI has been expected poor; therefore, prevention of this condition, especially for older patients with AML, would be important.

Stem cell transplantation in primary immunodeficiency disease patients.

BACKGROUND: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. METHODS: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months-4 years). Five patients had Wiskott-Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. RESULTS: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. CONCLUSION: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.