Substitution of methotrexate with corticosteroid for acute graft-versus-host disease prevention in transplanted patients who develop methotrexate toxicity.

Methotrexate (MTX) toxicity can hamper the administration of all planned doses in acute graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic stem cell transplantation. Reduction or omission of MTX doses results in an increased risk of acute GVHD. In this prospective observational study, we compared the incidence of GVHD and the transplant outcomes between patients who received the full treatment course of MTX (group 1), patients in whom MTX doses were omitted if MTX toxicity developed (group 2), and patients receiving corticosteroid instead of MTX if MTX toxicity developed (group 3). The cumulative incidence of grades II-IV acute GVHD at 100 days post-transplantation was 22.2 % in group 1, 43.6 % in group 2, and 25.0 % in group 3 (P = 0.132). The risk of grades II-IV acute GVHD in group 2 was higher than that in group 1 (hazard ratio (HR) 3.262, P = 0.016), but the risk in group 3 was similar to that in group 1 (HR 0.960, P = 0.890). Group 3 also showed a trend towards a lower risk of chronic GVHD compared to the other groups. The cumulative risk of chronic GVHD at 2 years was 73.9, 71.6, and 33.3 % in groups 1, 2, and 3, respectively (P = 0.084). However, a likely higher relapse incidence and infection-related mortality in group 3 produced a trend towards the lowest relapse-free survival (2-year RFS, 46.3, 49.3, and 25.0 % in groups 1, 2, and 3, respectively; P = 0.329) and overall survival (2-year OS, 45, 52.3, and 25 %, respectively; P = 0.322) in group 3. Although the substitution of MTX with corticosteroid ameliorates the increased risk of GVHD in patients in which it is imperative to omit its dose, its negative impact on relapse and infection risk does not result in favorable transplant outcomes.

Ramosetron Versus Ondansetron in Combination With Aprepitant and Dexamethasone for the Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Randomized Phase III Trial, KCSG PC10-21.

BACKGROUND: A combination of serotonin receptor (5-hydroxytryptamine receptor type 3) antagonists, NK-1 receptor antagonist, and steroid improves the complete response (CR) of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. Ramosetron's efficacy in this triple combination regimen has not been investigated. This prospective, multicenter, single-blind, randomized, phase III study compares a combination of ramosetron, aprepitant, and dexamethasone (RAD) with a combination of ondansetron, aprepitant, and dexamethasone (OAD) to prove the noninferiority of RAD in controlling highly emetogenic CINV. METHODS: Aprepitant and dexamethasone were orally administered for both arms. Ramosetron and ondansetron were intravenously given to the RAD and OAD groups. The primary endpoint was no vomiting and retching and no need for rescue medication during the acute period (day 1); the noninferiority margin was -15%. RESULTS: A total of 299 modified intention-to-treat cancer patients who received RAD (144 patients) and OAD (155 patients) were eligible for the efficacy analysis. The CR rates of RAD versus OAD were 97.2% versus 93.6% during the acute period, 77.8% versus 73.6% during the delayed period (day 2-5), and 77.1% versus 71.6% during the overall period. Furthermore, RAD was noninferior to OAD in subgroups stratified by age, cancer type, chemotherapeutic agents, and schedule. Repeated measures analysis showed that in male patients, RAD was superior to OAD. Profiles of adverse events were similar in both groups. CONCLUSION: RAD is as effective and tolerable as OAD for CINV prevention in patients receiving highly emetogenic chemotherapy. Ramosetron could be considered one of the best partners for aprepitant.

Dual effects of duplex RNA harboring 5'-terminal triphosphate on gene silencing and RIG-I mediated innate immune response.

Duplex RNA harboring the 5'-terminal triphosphate RNA is hypothesized to not only execute selective gene silencing via RNA interference, but also induce type I interferon (IFN) through activation of the retinoic acid inducible gene I (RIG-I). We evaluated gene silencing efficacy of the shRNA containing 5'-triphosphate (3p-shRNA) targeting the hepatitis C virus (HCV) RNA genome in hepatic cells. Gene silencing efficacy of the 3p-shRNA was diminished due to the presence of the 5'-triphosphate moiety in shRNA, whereas the shRNA counterpart without 5'-triphosphate (HO-shRNA) showed a strong antiviral activity without significant induction of type I IFN in the cells. 3p-shRNA was observed to be a better activator of the RIG-I signaling than the HO-shRNA with an elevated induction of type I IFN in cells that express RIG-I. Taken together, we suggest that competition for the duplex RNA bearing 5'-triphosphate between RIG-I and RNA interference factors may compromise efficacy of selective gene silencing.

Is Helicobacter Pylori associated with Her2/neu Overexpression in Gastric Cancer Patients who Underwent Curative Resection?

BACKGROUND/AIMS: Human epidermal growth factor receptor 2 (Her2/neu) is an important target for treatment of gastric cancer using trastuzumab and Helicobacter pylori is a well-known risk factor of gastric cancer. We investigated the association of Her2/neu overexpression with Helicobacter pylori and other clinicopathologic factors in gastric cancer patients who underwent curative resection. METHODOLOGY: Her2/neu immunohistochemistry was performed in gastric cancer patients who underwent curative gastrectomy or endoscopic submucosal dissection. Analysis about its associations with clinicopathologic features such as Lauren histologic types, differentiation, Helicobacter pylori infection, location, depth of invasion, lymph node metastasis, and AJCC tumor stage was performed retrospectively. RESULTS: The incidence of Her2/neu 3+, 2+, 1+ and 0 was 8.9%, 22.1%, 4.4% and 64.6% respectively. Intestinal type of gastric cancer showed higher incidence of Her2/neu 3+ than diffuse type. The score 2+ and 3+ was more common in Helicobacter pylori-positive patients than Helicobacter pylori-negative patients (p = 0.024). 7th American joint Cancer Committee Tumor stage, depth of tumor invasion and lymph node metastasis did not show correlation with the level of Her2/neu expression. CONCLUSIONS: Helicobacter pylori-positive gastric cancer showed more Her2/neu overexpression. Helicobacter pylori eradication may be necessary to avoid Her2/neu overexpression.

Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65 years and younger patients with advanced gastric cancer.

BACKGROUND: A chemotherapy regimen with oxaliplatin, fluorouracil, and leucovorin is commonly used to treat advanced gastric cancer (AGC). This study was designed to compare the efficacy and the safety of oxaliplatin plus fluorouracil/leucovorin administered biweekly (mFOLFOX6) between elderly patients aged over 65 years and younger counterparts with AGC. METHODS: This analysis included 82 AGC patients (≥65:31, <65:51). Patients with previously untreated chemo-naïve advanced adenocarcinoma of the stomach received oxaliplatin 85 mg/m(2), 5-FU bolus 400 mg/m(2) on day 1 and 5-FU 1,500 mg/m(2), leucovorin 75 mg/m(2) 22 h infusion on days 1 and 2 every 2 weeks. The aim of the study was to compare efficacy and safety, including response rate (RR), progression-free survival (PFS), overall survival, and grade ≥3 adverse events, between patients aged ≥65 years and patients aged <65 years. RESULTS: Median progression-free survival (PFS) was not significantly different between both groups (≥65: 5.8 months, <65: 5.7 months, respectively, HR 0.77, 95% CI: 0.44-1.16, P = 0.18). Median overall survival was not significantly different between both groups (≥65: 10.3 months, <65: 9.5 months HR 0.83, 95% CI: 0.50-1.37, P = 0.46). The rate of grade 3 or 4 neutropenia did not differ with age group (≥65: 51.6%, <65: 43.1%); nor did the rates of neutropenic fever (≥65: 16.1%, <65: 5.9%), and infection without neutropenia (≥65: 3.2%, <65: 3.9%). Rates of grade ≥3 toxicities such as thrombocytopenia, nausea/vomiting, or peripheral neuropathy were not significantly different between the two groups. CONCLUSIONS: mFOLFOX6 maintains its efficacy and safety in elderly patients aged over 65 years in comparison with AGC patients aged <65 years. Its judicious use should be considered regardless of age.

Impact of an emergency department resident strike during the coronavirus disease 2019 (COVID-19) pandemic in Daegu, South Korea: a retrospective cross-sectional study.

BACKGRUOUND: To prepare for future work stoppages in the medical industry, this study aimed to identify the effects of healthcare worker strikes on the mortality rate of patients visiting the emergency department (ED) at six training hospitals in Daegu, Korea. METHODS: We used a retrospective, cross-sectional, multicenter design to analyze the medical records of patients who visited six training hospitals in Daegu (August 21-September 8, 2020). For comparison, control period 1 was set as the same period in the previous year (August 21-September 8, 2019) and control period 2 was set as July 1-19, 2020. Patient characteristics including age, sex, and time of ED visit were investigated along with mode of arrival, length of ED stay, and in-hospital mortality. The experimental and control groups were compared using t-tests, and Mann-Whitney U-test, chi-square test, and Fisher exact tests, as appropriate. Univariate logistic regression was performed to identify significant factors, followed by multivariate logistic regression analysis. RESULTS: During the study period, 31,357 patients visited the ED, of which 7,749 belonged to the experimental group. Control periods 1 and 2 included 13,100 and 10,243 patients, respectively. No significant in-hospital mortality differences were found between study periods; however, the results showed statistically significant differences in the length of ED stay. CONCLUSION: The ED resident strike did not influence the mortality rate of patients who visited the EDs of six training hospitals in Daegu. Furthermore, the number of patients admitted and the length of ED stay decreased during the strike period.

3D Electrodes for Bioelectronics.

In recent studies related to bioelectronics, significant efforts have been made to form 3D electrodes to increase the effective surface area or to optimize the transfer of signals at tissue-electrode interfaces. Although bioelectronic devices with 2D and flat electrode structures have been used extensively for monitoring biological signals, these 2D planar electrodes have made it difficult to form biocompatible and uniform interfaces with nonplanar and soft biological systems (at the cellular or tissue levels). Especially, recent biomedical applications have been expanding rapidly toward 3D organoids and the deep tissues of living animals, and 3D bioelectrodes are getting significant attention because they can reach the deep regions of various 3D tissues. An overview of recent studies on 3D bioelectronic devices, such as the use of electrical stimulations and the recording of neural signals from biological subjects, is presented. Subsequently, the recent developments in materials and fabrication processing to 3D micro- and nanostructures are introduced, followed by broad applications of these 3D bioelectronic devices at various in vitro and in vivo conditions.

A pilot study of daunorubicin-augmented hyper-CVAD induction chemotherapy for adults with acute lymphoblastic leukemia.

Induction of complete remission (CR) is imperative for long-term survival in adult acute lymphoblastic leukemia (ALL) patients regardless of transplantation eligibility. Hyper-CVAD chemotherapy is a widely-used frontline remission induction regimen for these patients. We conducted a pilot trial of frontline remission induction using daunorubicin-augmented hyper-CVAD regimen (hyper-CVDD) in adult ALL patients (n = 15). The CR rate after this modified regimen was 100% (n = 15). Twelve patients were able to proceed to allogeneic hematopoietic cell transplantation, two patients died before transplantation due to infection, and the remaining one who was ineligible for transplant due to her age received an additional five courses of consolidation chemotherapy. Overall survival (OS) and event-free survival (EFS) of the study patients was 61.0 and 47.5% at 3 years. OS and relapse-free survival of transplanted patients was 66.8 and 55.0% at 3 years. This pilot trial demonstrates the favorable efficacy of the hyper-CVDD chemotherapy as a frontline remission induction regimen. Further clinical trials using this regimen are warranted.

Irinotecan Monotherapy Versus Irinotecan-Based Combination as Second-Line Chemotherapy in Advanced Gastric Cancer: A Meta-Analysis.

PURPOSE: A meta-analysis was conducted to examine the question of whether combination regimens are more effective than monotherapy as a second-line chemotherapy in advanced gastric cancer. MATERIALS AND METHODS: The MEDLINE and the EMBASE databases and the Cochrane Central Register for Controlled Trials were searched using appropriate keywords. Only randomized controlled trials were eligible. RESULTS: Taxane-based study is rare; thus, four irinotecan-based studies were finally included in the meta-analysis. Out of 661 patients, 331 patients were assigned to combination therapy and 330 to monotherapy. Cisplatin or fluoropyrimidine (S-1 or 5-fluorouracil) was used as a combination partner to irinotecan. The pooled hazard ratio (HR) for overall survival (OS) and for progression-free survival (PFS) was 0.938 (95% confidence interval [CI], 0.796 to 1.104; p=0.442) and 0.815 (95% CI, 0.693 to 0.958; p=0.013). In subgroup analysis according to previous exposure to a partner agent, the PFS benefit of combination was observed only in the partially exposed group (HR, 0.784; 95% CI, 0.628 to 0.980; p=0.032). CONCLUSION: Second-line irinotecan-based combination was not associated with increased OS, but with PFS benefit, which seemed particularly significant for patients receiving combination with a new agent.

Regulation of CYP1A1 and Inflammatory Cytokine by NCOA7 Isoform 4 in Response to Dioxin Induced Airway Inflammation.

BACKGROUND: Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, binds to a wide variety of synthetic and naturally occurring compounds. AhR is involved in the regulation of inflammatory response during acute and chronic respiratory diseases. We investigated whether nuclear receptor coactivator 7 (NCOA7) could regulate transcriptional levels of AhR target genes and inflammatory cytokines in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated human bronchial epithelial cells. This study was based on our previous study that NCOA7 was differentially expressed between normal and chronic obstructive pulmonary disease lung tissues. METHODS: BEAS-2B and A549 cells grown under serum-free conditions were treated with or without TCDD (0.15 nM and 6.5 nM) for 24 hours after transfection of pCMV-NCOA7 isoform 4. Expression levels of cytochrome P4501A1 (CYP1A1), IL-6, and IL-8 were measured by quantitative real-time polymerase chain reaction. RESULTS: The transcriptional activities of CYP1A1 and inflammatory cytokines were strongly induced by TCDD treatment in both BEAS-2B and A549 cell lines. The NCOA7 isoform 4 oppositely regulated the transcriptional activities of CYP1A1 and inflammatory cytokines between BEAS-2B and A549 cell lines. CONCLUSION: Our results suggest that NCOA7 could act as a regulator in the TCDD-AhR signaling pathway with dual roles in normal and abnormal physiological conditions.

Pleural Metastasis as Initial Presentation of Occult Gastric Cardia Cancer: A Possible Role of PET-CT in Diagnosis.

We report on a case of malignant pleural effusion as initial metastatic presentation of occult gastric cardia cancer in a young woman. To the best of our knowledge, this is the first report of gastric adenocarcinoma metastasized to pleura as an initial presentation. Location of cardia and signet ring cell histology may contribute to the manifestation. Utilization of positron emission tomography-computed tomography was helpful for proper diagnosis. For patients with such distinct clinical presentations, it would be appropriate to consider gastric cancer as one of the possible primary sites.

RNA sequencing identifies novel markers of non-small cell lung cancer.

INTRODUCTION: The development of reliable gene expression profiling technology increasingly impacts our understanding of lung cancer biology. Here, we used RNA sequencing (RNA-Seq) to compare the transcriptomes of non-small cell lung cancer (NSCLC) and normal lung tissues and to investigate expression in lung cancer tissues. METHODS: We enrolled 88 male patients (mean age, 61.2 years) with NSCLC. RNA-Seq was performed on 88 pairs of NSCLC tumor tissue and non-tumor tissue from 54 patients with adenocarcinoma and 34 patients with squamous cell carcinoma. Immunohistochemistry was performed to validate differential candidate gene expression in a different NSCLC group. RESULTS: RNA-Seq produced 25.41 × 10(6) (± 8.90 × 10(6)) reads in NSCLC tissues and 24.70×10(6) (± 4.70 × 10(6)) reads in normal lung tissues [mean (± standard deviation)]. Among the genes expressed in both tissues, 335 were upregulated and 728 were downregulated ≥ 2-fold (p < 0.001). Four upregulated genes - CBX3, GJB2, CRABP2, and DSP - not previously reported in lung cancer were studied further. Their altered expression was verified by immunohistochemistry in a different set of NSCLC tissues (n = 154). CBX3 was positive in 90.3% (139 cases) of the samples; GJB2, in 22.7% (35 cases); CRABP2, in 72.1% (111 cases); and DSP, in 17.5% (27 cases). The positive rate of CRABP2 was higher in adenocarcinoma than squamous cell carcinoma (p < 0.01). CONCLUSIONS: CBX3 and CRABP2 expression was markedly increased in lung cancer tissues and especially CRABP2 may be promising candidate genes in lung adenocarcinoma.

Cutoff values of serum ferritin and TIBC saturation for the evaluation of gastrointestinal neoplasms in adult anemic patients.

We conducted a retrospective study to find out the optimum values of serum ferritin and other hematologic indices in adult anemic patients who should be referred for thorough gastrointestinal (GI) endoscopic evaluation for GI neoplasms. 544 adult anemic patients were stratified into three groups according to the results of GI endoscopy: benign versus premalignant versus malignant. As compared to non-malignant groups, malignant group demonstrated statistically significant differences in terms of median values of ferritin and total iron-binding capacity (TIBC) saturation. By receiver operating characteristics curve analyses to find out optimum cut-off points of the serum ferritin and TIBC saturation which distinguish between non-malignant diseases and malignant diseases, the cut-off ferritin value of 44.33 ng/mL in male had 72.73 % sensitivity and 70.95 % specificity. The cut-off TIBC saturation value of 9.13 % in male had 73.33 % sensitivity and 70.92 % specificity. The cut-off TIBC saturation value of 6.16 % in female had 69.57 % sensitivity and 65.13 % specificity. It is recommended that adult male patients with anemia undergo thorough endoscopic evaluation to detect GI neoplasms when their serum ferritin levels are ≤44 ng/mL or TIBC saturation values are ≤9 %. For adult female, only TIBC saturation values less than 6 % may contribute to determining whether they undergo GI endoscopic evaluation.

Pneumocystis carinii pneumonia in gastric cancer patients without acquired immune deficiency syndrome: 3 cases report and literature review.

Pneumocystis carinii pneumonia (PCP) has rarely been reported in solid tumor patients. It is a well-known complication in immunosuppressed states including acquired immune deficiency syndrome and hematologic malignancy. PCP has been reported in solid tumor patients who received long-term steroid treatment due to brain or spinal cord metastases. We found 3 gastric cancer patients with PCP, who received only dexamethasone as an antiemetic during chemotherapy. The duration and cumulative dose of dexamethasone used in each patient was 384 mg/48 days, 588 mg/69 days, and 360 mg/42 days, respectively. These cases highlight that the PCP in gastric cancer patients can successfully be managed through clinical suspicion and prompt treatment. The cumulative dose and duration of dexamethasone used in these cases can be basic data for risk of PCP development in gastric cancer patients during chemotherapy.

Slow, but complete, resolution of mitomycin-induced refractory thrombotic thrombocytopenic purpura after rituximab treatment.

Thrombotic thrombocytopenic purpura (TTP) is a critical complication of treatment with mitomycin C. We retrospectively describe the case of a patient with progressive renal cell carcinoma and mitomycin-induced TTP refractory to plasma exchange and glucocorticoids; we describe the clinical course, successful management of TTP with rituximab, and follow-up of this case. Mitomycin-induced TTP resolved completely by a total of 4 infusions of rituximab 375 mg/m(2) on a weekly basis, and it took up to 12 months to obtain a platelet count of >100,000/µL. Rituximab is indicated for the treatment of mitomycin-induced TTP refractory to plasma exchange and glucocorticoids, and it could improve the patient's quality of life despite the presence of underlying malignancy.

The efficacy of the coaxial technique using a 6-Fr introducer sheath in stent placement for treating the obstructions proximal to the descending colon.

OBJECTIVE: We wanted to evaluate the efficacy of stent placement using the coaxial technique with a stiff, long introducer sheath in patients with technical failure using an angiographic catheter for the obstructions proximal to the descending colon. MATERIALS AND METHODS: Self-expandable metallic stent placement was attempted under fluoroscopy-guidance in 77 consecutive patients who had malignant colorectal obstruction. Stent placement was performed using an angiographic catheter and a guide wire. If the angiographic catheter could not be advanced over the guide wire into the obstructive lesions proximal to the descending colon, then a 6-Fr introducer sheath was used. The technical success rate, the clinical success rate and the complications were analyzed. RESULTS: Successful stent placement was achieved in 75 of 77 patients (97%). The angiographic catheter failed to advance into the obstructive lesions of 11 patients (M:F = 7:4; mean age, 65.5 years) whose lesions were at the level of the splenic flexure or transverse colon. Therefore, the coaxial technique was implemented in all these 11 patients using a 6-Fr stiff introducer sheath and then the stent placement was successful. There were no complications related to the use of a stiff introducer sheath. Clinical success, which was defined as relief of clinical obstructive bowel symptoms, was obtained within 24 hours in all of patients. CONCLUSION: The coaxial technique using a stiff introducer sheath can increase the technical success of fluoroscopy-guided, self-expandable metallic stent placement in patients with colonic obstruction proximal to the descending colon.

Serum prohepcidin levels in Helicobacter pylori infected patients with iron deficiency anemia.

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection appears to subvert the human iron regulatory mechanism and thus upregulates hepcidin, resulting in unexplained iron-deficiency anemia (IDA). We evaluated serum prohepcidin levels before and after eradication of H. pylori in IDA patients to assess whether it plays a role in IDA related to H. pylori infection. METHODS: Subjects diagnosed with unexplained IDA underwent upper gastrointestinal endoscopy and colonoscopy to confirm H. pylori infection and to exclude gastrointestinal bleeding. Blood was sampled before treatment to eradicate H. pylori and again 1 month later. Serum prohepcidin levels were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: Serum prohepcidin levels decreased significantly after oral iron replacement combined with H. pylori eradication (p = 0.011). The reduction ratio of serum prohepcidin levels after the treatment did not differ among the combined oral iron replacement and H. pylori eradication groups, the H. pylori eradication only group, and the iron replacement only group (p = 0.894). CONCLUSIONS: Serum prohepcidin levels decrease after both H. pylori eradication and oral iron administration, with improvement in IDA. Serum concentration of prohepcidin is related to the anemia status, rather than to the current status of H. pylori infection, in IDA patients.

Oligodeoxyribozymes that cleave beta-catenin messenger RNA inhibit growth of colon cancer cells via reduction of beta-catenin response transcription.

Abnormal regulation of Wnt/beta-catenin signaling followed by increased levels of the beta-catenin protein have been identified in enhanced cellular proliferation and development of colon polyps and cancers. To inhibit beta-catenin gene expression in colon cancer cells, RNA-cleaving oligodeoxyribozyme (DNAzyme) was employed to destroy the beta-catenin mRNA. We designed a strategy to identify the cleavage sites in beta-catenin RNA with a pool of random sequences from a DNAzyme library and identified four potential DNAzyme-working sites. DNAzymes were constructed for the selected target sites and were tested for the ability to cleave beta-catenin RNA. When introduced into the cells, the selected DNAzymes decreased the expression of beta-catenin significantly as well as its downstream gene, cyclin D1. Additionally, we designed short hairpin RNA that targets the same cleavage site for the selected DNAzyme. The designed short hairpin RNA also inhibited beta-catenin gene expression in colon cancer cells. Our studies show that RNA-cleaving DNAzymes and RNA interference targeted to beta-catenin significantly reduced beta-catenin-dependent gene expression, resulting in inhibition of colon cancer cell growth. These results indicate that the functional antisense oligonucleotides directed against beta-catenin might have potential as a therapeutic intervention to treat colon cancer.