[Modified Premedication of Infusion Reaction with Obinutuzumab Therapy].

Obinutuzumab frequently triggers an infusion reaction(IR). In the GALLIUM study, despite the use of corticosteroids, antipyretic analgesics, and antihistamines to prevent IR, IR occurred at a high frequency of 68.2% for all Grades and 12.4% for Grades 3 or higher. The dose of methylprednisolone was increased from 80 mg administered in the GALLIUM study to 125 mg, and the development of IR was investigated in 30 patients with follicular lymphoma who received the initial dose of obinutuzumab. The incidence of IR was 43.3% for all Grades and 0% for Grades 3 or higher, and no serious IR was observed. It also had no effect on infectious diseases. Increased doses of corticosteroids were well tolerated and suggested as an effective method for reducing the frequency of IR.

Increased Monocyte Chemotactic Protein-1 Accompanying Pro-Inflammatory Processes are Associated with Progressive Hearing Impairment and Bilateral Disability of Meniere's Disease.

BACKGROUND: The progression of hearing impairment and the bilateral involvement of Meniere's disease (MD) may depend on the disease duration and aging. Recent studies reported that MD might involve dysfunction of the microvascular circulation damaged due to inflammatory changes. OBJECTIVES: The aim of this study was to determine that the progress of the MD's hearing impairment and bilateral disability may be associated with the pathogenesis of several pro-inflammatory processes. PATIENTS AND METHODS: We recruited 30 unilateral MD patients (56.8 ± 14.7 years old), 7 bilateral MD patients (65.3 ± 13.9 years old), and 17 age-matched control subjects (53.5 ± 14.4 years old, p > 0.05). We measured the plasma vascular endothelial growth factor (VEGF), plasma interleukin-6 (IL-6), plasma tumor-necrosis factor α (TNFα), and plasma monocyte chemotactic protein-1 (MCP-1). RESULTS: The bilateral MD group and the unilateral MD group had higher plasma MCP-1 (204.7 ± 41.0 pg/mL and 169.5 ± 32.0 pg/mL) than the control group (149.2 ± 30.7 pg/mL) (p < 0.05). There was no significant difference in plasma TNFα, IL-6, and VEGF among 3 groups (p > 0.05). There was a strong correlation between the plasma MCP-1 and age in MD patients (r = 0.58, p < 0.01); however, no significant correlation between the plasma MCP-1 and age was found in control subjects (p > 0.05). The plasma MCP-1 significantly correlated with the average hearing level of 500, 1,000, 2,000, and 4,000 Hz, and the maximum slow phase eye velocity in caloric test in the better side (p < 0.05). Also, the plasma MCP-1 showed significant positive correlations with the plasma IL-6 (r = 0.49, p < 0.01) and plasma TNFα (r = 0.32, p < 0.05) in MD group. CONCLUSIONS: Our results suggest that the increased plasma MCP-1 accompanying pro-inflammatory processes are associated with the progression of the hearing impairment and the bilateral disability of MD.

Niclosamide's potential direct targets in ovarian cancer†.

Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. Although niclosamide has previously been identified by high-throughput screening platforms as a potential effective compound against several cancer types, no direct binding interactions with distinct biological molecule(s) has been established. The present study identifies key signal transduction mechanisms altered by niclosamide in ovarian cancer. Using affinity purification with a biotin-modified niclosamide derivative and mass spectrometry analysis, several RNA-binding proteins (RBPs) were identified. We chose the two RBPs, FXR1 and IGF2BP2, for further analysis. A significant correlation exists in which high-expression of FXR1 or IGF2BP2 is associated with reduced survival of ovarian cancer patients. Knockdown of FXR1 or IGF2BP2 in ovarian cancer cells resulted in significantly reduced cell viability, adhesion, and migration. Furthermore, FXR1 or IGF2BP2 deficient ovarian cancer cells exhibited reduced response to most doses of niclosamide showing greater cell viability than those with intact RBPs. These results suggest that FXR1 and IGF2BP2 are direct targets of niclosamide and could have critical activities that drive multiple oncogenic pathways in ovarian cancer.

Efficacy of upfront hepatectomy without neoadjuvant chemotherapy for resectable colorectal liver metastasis.

BACKGROUND: Hepatectomy for resectable colorectal liver metastasis (CRLM) is recommended. However, the efficacy of upfront hepatectomy without neoadjuvant chemotherapy (NAC) is unclear due to the uncertainty of perioperative systemic chemotherapy. Moreover, it is crucial to predict the prognosis when considering perioperative chemotherapy. This study evaluated the impact of neoadjuvant chemotherapy on the prognosis of patients with resectable CRLM and assessed the usefulness of Beppu's nomogram for predicting prognosis. METHODS: This retrospective study identified 88 consecutive inpatients who underwent primary hepatic resection for CRLM; 58 received neoadjuvant chemotherapy and 30 underwent upfront surgery. Factors associated with recurrence-free survival were identified via univariate and multivariate analysis. Furthermore, propensity score analysis using inverse probability of treatment weighting (IPTW) was performed. RESULTS: On univariate analysis, poor recurrence-free survival was associated with multiple tumors, advanced primary tumor stage, vascular invasion by the primary tumor, a Beppu's nomogram score ≥ 6, and neoadjuvant chemotherapy. On multivariate analysis, a Beppu's nomogram score ≥ 6 and neoadjuvant chemotherapy were independent risk factors for recurrence. Neoadjuvant chemotherapy recipients had a higher incidence of lymph node metastasis and vascular invasion than non-recipients. Propensity score analysis revealed no significant difference in the recurrence-free survival rate between these groups. CONCLUSIONS: Our results show that upfront hepatectomy without neoadjuvant chemotherapy can be considered for resectable CRLM treatment. Beppu's nomogram score can be a tool for predicting the prognosis of patients with CRLM.

Interstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: Interstitial lung disease (ILD) is a rare adverse event in patients receiving adjuvant or neoadjuvant chemotherapy (NAC) for breast cancer. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature. Given these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received epirubicin and cyclophosphamide (EC) and compared their findings with non-ILD cases. METHODS: The present single-center retrospective study included breast cancer patients who underwent adjuvant chemotherapy or NAC at our hospital between January 2014 and January 2021. RESULTS: Thirty-nine patients who had received EC for operable breast cancer were enrolled in this study. ILD developed 5 out of 39 patients (12.8%). The incidence of ILD in patients with non-dose-dense (dd) or dd chemotherapy was statistically significantly different (p = 0.0149). ILD occurred in three patients during dd EC treatment and two during weekly paclitaxel (wPTX) after dd EC. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, in two patients with continuous pyrexia, and in two patients from computed tomography imaging, which was taken to estimate the efficacy of chemotherapy, in two patients. Three of the 5 ILD patients underwent bronchoalveolar lavage, and 2 of these patients were diagnosed with Pneumocystis jirovecii pneumonia (PCP). There were no cases of serious ILD that required steroid pulse therapy. CONCLUSIONS: Dd chemotherapy may be associated with an increased ILD frequency, which may reflect developing PCP. Careful monitoring and a timely diagnosis are useful for detecting early-stage ILD.

Differences in responsiveness of intratympanic steroid injection for intractable vertigo in Meniere's disease.

OBJECTIVES: The efficacy of intratympanic steroid (ITS) injection for intractable Meniere's disease has been reported; however, its differences in responsiveness are not fully understood. This study investigated the clinical characteristics of patients who responded to ITS injection treatment. METHODS: This retrospective study included 32 patients with Meniere's disease who were unable to control frequent vertigo attacks despite conservative treatment for at least 3 months. They received an intratympanic injection of dexamethasone (3.3 mg/mL) in the affected side at least three times. We measured hearing threshold, subjective symptom scores, cervical and ocular vestibular evoked myogenic potential (cVEMP and oVEMP), and performed glycerol and bithermal caloric tests. RESULTS: Satisfactory control of vertigo for 1 year after the first round of injection was found in 18 patients (56.3%; the response group). However, the injections failed to control vertigo in the other 14 patients (43.8%; the non-response group), and they were then treated with middle ear micropressure therapy. The response group showed improvement in low-frequency hearing, whereas hearing acuity did not change in the non-response group. Significantly reduced amplitude of cVEMP on the affected side was found in 62.5% of patients in the response group; however, no patients in the non-response group showed reduced amplitude of cVEMP. CONCLUSIONS: ITS injection significantly improved the subjective symptoms for intractable Meniere's disease; however, the long-term effects were heterogeneous. Our results suggest that reduced amplitude in cVEMP is associated with the effectiveness of ITS injection treatment.

Hearing loss is associated with hippocampal atrophy and high cortisol/dehydroepiandrosterone sulphate ratio in older adults.

OBJECTIVES: Hearing loss (HL) has been recognised as a prodromal symptom of cognitive disorder with aging. It is still uncertain if HL leads to cognitive impairment directly or through an indirect mechanism. DESIGN: Participants of this study underwent an auditory test, blood tests, and brain MRI. The atrophy rate of the hippocampus (HP) was calculated using voxel-based specific areas. A partial correlation analysis whilst controlling for the effect of age was performed to analyse the factors affecting hearing levels and HP atrophy rate (HP%). STUDY SAMPLE: Thirty-six older adults with hearing impairment. RESULTS: The group of participants with moderate or severe HL (n = 22) had higher cortisol/dehydroepiandrosterone sulphate (C/D) ratio, geriatric depression score (GDS) and HP% than the mild HL or normal hearing group (n = 14, p < 0.05). The HP% showed a significant positive correlation with the C/D ratio, GDS and the hearing level of high frequency (HF) (p < 0.05). The C/D ratio was positively correlated with the HP% and the hearing level of the HF (p < 0.05). CONCLUSIONS: Our results suggest that the HL is associated with the atrophy of HP and high C/D ratios in older adults; however, HL may not be causally related to hippocampal atrophy.

Classification of grazing-incidence small-angle X-ray scattering patterns by convolutional neural network.

Grazing-incidence small-angle X-ray scattering (GISAXS) patterns have multiple superimposed contributions from the shape of the nanoscale structure, the coupling between the particles, the partial pair correlation, and the layer geometry. Therefore, it is not easy to identify the model manually from the huge amounts of combinations. The convolutional neural network (CNN), which is one of the artificial neural networks, can find regularities to classify patterns from large amounts of combinations. CNN was applied to classify GISAXS patterns, focusing on the shape of the nanoparticles. The network found regularities from the GISAXS patterns and showed a success rate of about 90% for the classification. This method can efficiently classify a large amount of experimental GISAXS patterns according to a set of model shapes and their combinations.

Genome-wide association study identifies new loci for albuminuria in the Japanese population.

BACKGROUND: Urinary albumin excretion (UAE) is a risk factor for cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Only a few genome-wide association studies (GWAS) for UAE have been conducted in the European population, but not in the Asian population. Here we conducted GWAS and identified several candidate genes harboring single nucleotide polymorphisms (SNPs) responsible for UAE in the Japanese population. METHODS: We conducted GWAS for UAE in 7805 individuals of Asian ancestry from health-survey data collected by Tohoku Medical Megabank Organization (ToMMo) and Iwate Tohoku Medical Megabank Organization (IMM). The SNP genotype data were obtained with a SNP microarray. After imputation using a haplotype panel consisting of 2000 genome sequencing, 4,962,728 SNP markers were used for the GWAS. RESULTS: Eighteen SNPs at 14 loci (GRM7, EXOC1/NMU, LPA, STEAP1B/RAPGEF5, SEMA3D, PRKAG2, TRIQK, SERTM1, TPT1-AS1, OR5AU1, TSHR, FMN1/RYR3, COPRS, and BRD1) were associated with UAE in the Japanese individuals. A locus with particularly strong associations was observed on TSHR, chromosome 14 [rs116622332 (p = 3.99 × 10-10)]. CONCLUSION: In this study, we successfully identified UAE-associated variant loci in the Japanese population. Further study is required to confirm this association.

[A Case of Rectal Neuroendocrine Carcinoma Treated with Multidisciplinary Therapy but with a Poor Prognosis].

A 70-year-old man presented to our hospital with weight loss. A colonoscopy revealed advanced cancer in the lower rectum. Computed tomography showed a tumor larger than 5 cm in the lower rectum with metastasis to the right lateral lymph node. The patient was diagnosed with advanced locally rectal cancer, and chemoradiotherapy(35 Gy plus S-1)was added after 6 courses of mFOLFOX6, and laparoscopic abdominal perineal resection and right lateral lymph nodes dissection were performed. Histopathological examination revealed endocrine cell carcinoma(pT3[A], pN0, M0, pStage Ⅱa). Four months after the operation, recurrence was found in the pelvis, lymph nodes, and lungs, and he died 9 months after the operation. Neuroendocrine carcinoma is relatively rare, so the further accumulation of cases and establishment of treatment methods are desired.

Multicenter phase II study of biweekly CAPIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer (JSWOG-C3 study).

BACKGROUND: Triweekly capecitabine plus irinotecan (CAPIRI) was not a replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the treatment of metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy. METHODS: Patients with mCRC who had received prior chemotherapy, including oxaliplatin-based regimens, were eligible for this study. The treatment protocol administered capecitabine at 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan at 150 mg/m2 on day 1, and bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study were progression-free survival (PFS) and safety. Secondary endpoints were overall survival (OS), time to treatment failure, response rate (RR), and disease control rate (DCR). RESULTS: Fifty-one patients were enrolled in this study. Median PFS was 5.5 months [95% confidence interval (CI) 4.23-7.40 months], and median OS was 13.5 months (95% CI 11.57-20.23 months). The RR was 14.6% (95% CI 6.5-28.4%), and the DCR was 66.7% (95% CI 51.5-79.2%). Hypertension was the most common Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two patients suffered from grade 3 hand-foot syndrome. CONCLUSIONS: In mCRC patients, biweekly CAPIRI + bevacizumab appears effective and feasible as a second-line chemotherapy with relatively low toxicities, and has potential as a useful substitute for FOLFIRI + bevacizumab.

[A Case of Laparoscopic Abdominoperineal Resection of Anorectal Malignant Melanoma].

A 56-year-old woman with complaints of anal bleeding and pain visited our hospital, and an elastic soft mass was detected in the anal canal on digital examination.Colonoscopy showed a black Isp polypoid lesion with a black pit from the anal canal to the lower rectum(P-Rb).She was diagnosed with malignant melanoma based on colonoscopic biopsy.Tumor marker levels(CEA, CA19-9)were not increased.No distant metastasis was detected on abdominal CT.No direct invasion was detected on MRI of the pelvis.The patient underwent laparoscopic abdominoperineal resection and D2 lymph node dissection. Histopathology showed a malignant melanoma(pT4b, N0, M0, pStageⅡC).The patient received interferon therapy as adjuvant therapy.There is no sign of recurrence 2 years and 1 month after the surgery.Anorectal malignant melanoma is relatively rare, so establishment of therapy by the accumulation of cases is desired.

[Twenty-Five Cases of Locally Advanced Rectal Cancer That Underwent Laparoscopic Surgery after Preoperative Chemotherapy].

Several recent reports have described the administration of preoperative chemotherapy for locally advanced rectal cancer. In our hospital, preoperative chemotherapy based on oxaliplatin was administered for locally advanced rectal cancer with a tumor diameter of 5 cm or more and half semicircularity or more, and curative resection with laparoscopic surgery was performed after tumor shrinkage. We have experienced 25 cases that underwent preoperative chemotherapy for local advanced rectal cancer in our hospital from May 2012 to April 2016. No tumor increased in size during preoperative chemotherapy and there were no cases where R0 resection was impossible. In addition, no distant metastasis during chemotherapy was observed. Postoperative complications were observed in 3 cases(12%), and anastomotic leakage was observed in 1 case (4%), but conservative treatment was possible. Multidisciplinary treatment of preoperative chemotherapy and surgery should be considered as a therapeutic strategy for locally advanced rectal cancer, mainly in medical institutions without radiation treatment facilities.

MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters.

Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes.

Grazing-incidence small-angle X-ray scattering from Ge nanodots self-organized on Si(001) examined with soft X-rays.

Grazing-incidence small-angle X-ray scattering (GISAXS) measurements with soft X-rays have been applied to Ge nanodots capped with a Si layer. Spatially anisotropic distribution of nanodots resulted in strongly asymmetric GISAXS patterns in the qy direction in the soft X-ray region, which have not been observed with conventional hard X-rays. However, such apparent differences were explained by performing a GISAXS intensity calculation on the Ewald sphere, i.e. taking the curvature of Ewald sphere into account.

Impact of the COVID-19 Infection on Head and Neck Cancer Treatment During Hospitalization.

Objective The after-effects of coronavirus disease 2019 (COVID-19) infection are still unknown; therefore, we investigate the possibility that COVID-19 may interrupt cancer treatment and impact prognosis. Methods We examined the characteristics, prognosis, and changes in treatment options before and after COVID-19 in 11 head and neck cancer patients who were infected with COVID-19 after admission for cancer treatment at Gifu University Hospital. These patients were compared to 110 patients unaffected by COVID-19 during the same period. To identify the effects of COVID-19 on the cancer treatment sequence, we examined the rates of overall survival, progression-free survival, and completion, as well as radiation dosage in radiotherapy and cisplatin dosage in chemoradiotherapy. Results All 11 patients with COVID-19 had their planned cancer treatment postponed or interrupted. There was no significant difference in overall or progression-free survival compared to patients without COVID-19. Notably, only 3/6 of the COVID-19-affected patients completed radiotherapy compared to 42/46 unaffected patients. The ratio of actual radiation dose to planned dose was significantly impaired in COVID-19 affected patients group (98.3% vs. 88.6%). Cisplatin dosage in chemoradiation was not significantly different in either the radical (100 mg/m2, every three weeks) or adjuvant (40 mg/m2, every one week) treatment groups. Conclusion COVID-19 infection in head and neck cancer patients had no apparent impact on cancer prognosis. However, when restricted to irradiation, the treatment completion rate and the ratio of planned to actual dose decreased significantly, underscoring the impact of COVID-19 infection on cancer treatment. The difference in irradiation may affect the success of patients' treatment going forward, and it should be explored whether irradiation can be continued without delay.

Analysis of the Bacterial Flora of Substrates Used for the Cultivation of Agaricus bisporus: Relationship between Clostridia and Yield.

Agaricus bisporus has a high nutritional value and health benefits and its popularity is increasing among vegans and health-conscious consumers, indicating the need for its stable production. Therefore, we examined the bacterial flora of the substrates used to produce A. bisporus using a 16S rRNA gene ana-lysis and discussed the relationship between the bacterial flora and yield. The results obtained showed that A. bisporus yield slightly decreased with an increase in the abundance of Clostridia in substrates after primary fermentation. Lactobacillus showed little or no relationship with A. bisporus yield. Clostridia was identified as an indicator of A. bisporus yield.

Analysis of Critical Current Dependence on Specimen Length and Crack Size Distribution in Cracked Superconductor.

In order to describe the dependence of critical current on specimen length and crack size distribution in the superconducting tape with cracks of different sizes, a Monte Carlo simulation and a model analysis were carried out, employing the model specimens of various lengths constituted of multiple short sections with a crack per each. The model analysis was carried out to evaluate the effects of the two factors on the critical current of a specimen. Factor 1 is the size of the largest crack in a specimen, and Factor 2 is the difference in crack size among all sections at the critical voltage of critical current. Factors 1 and 2 were monitored by the smallest ligament parameter among all sections constituting the specimen and by the number of sections equivalent to the section containing the largest crack at the critical voltage of the critical current of the specimen, respectively. The research using the monitoring method revealed quantitatively that the critical current-reducing effect with increasing specimen length is caused by the increase in the size of the largest crack (Factor 1), and also, the critical current-raising effect is caused by the increase in the difference of crack size (Factor 2). As the effect of Factor 1 is larger than that of Factor 2, the critical current decreases with increasing specimen length. With the present approach, the critical current reducing and raising effects under various crack size distributions were evaluated quantitatively as a function of specimen length, and the specimen length-dependence of critical current obtained by the Monte Carlo simulation was described well.

[Decomposing a Beam Profile Constancy into Energy and Symmetry Components and Its Evaluation Using an Ionization Chamber Array].

PURPOSE: We have proposed a new formulation that can decompose the profile constancy defined in the AAPM TG 142 into energy and symmetry constancies by measuring beam profiles using an IC profiler (ICP). METHODS: Measured profiles were laterally inverted to calculate averaged profiles in the lateral direction, thereby cancelling asymmetric components. Validation tests were performed by comparing the proposed calculation and measured results under various experimental conditions. Calculated profile constancies were further compared to decomposed energy and symmetry constancies. RESULTS: The energy constancy calculated from the averaged beam profile by lateral inversion and the measured PDD(10) constancy agreed within 0.1% when only symmetries were varied. The calculated energy and symmetry constancies, and the measured results agreed within 0.2% when both energies and symmetries were varied. CONCLUSION: The linac beam profile constancy has been decomposed into energy and symmetry terms. The proposed formulation has been validated by comparing the calculations and the direct measurements using the ICP. We have shown that QA/QC for profile constancy tests can be efficiently performed using the proposed formulation.