Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Co-occurrence of Epstein-Barr virus-positive nodal T/NK-cell lymphoma and nodal T-follicular helper cell lymphoma of different clonal origins: An autopsy case report.

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL.

Derivation of pancreatic acinar cell carcinoma cell line HS-1 as a patient-derived tumor organoid.

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.

Differences in the prefrontal cortex responses of healthy young men performing either water-based or land-based exercise at light to moderate intensity.

Cerebral blood flow increases more during water-based exercise than land-based exercise owing to the effects of end-tidal CO2 (PETCO2) and mean arterial pressure (MAP) changes due to water immersion. However, it is unclear whether oxygenated hemoglobin (oxy-Hb) concentrations in the prefrontal cortex (PFC) are increased more by water-based or land-based exercise. We hypothesized that oxy-Hb concentrations in the PFC are higher during water-based exercise than land-based exercise when the exercise intensity is matched. To test this hypothesis, 10 healthy participants (age: 24.2 ± 1.7 years; height: 1.75 ± 0.04 m; weight: 69.5 ± 5.2 kg) performed light- to moderate-intensity cycling exercise in water (water-based cycling (WC); chest-high water at 30 °C) and on land (LC). Stroke volume, cardio output, heart rate, MAP, respiratory rate, PETCO2, and oxy-Hb in the PFC were assessed during 15 min of exercise, with exercise intensity increased every 5 min. Both WC and LC significantly increased oxy-Hb concentrations in the PFC as exercise intensity was increased (intensity effect: p < 0.001). There was no significant difference in oxy-Hb concentrations during WC and LC in most prefrontal areas, although significant differences were found in areas corresponding to the left dorsolateral PFC (exercise effect: p < 0.001). Thus, WC and LC increase oxy-Hb concentrations in the PFC in a similar manner with increasing exercise intensity, but part of the PFC exhibits enhanced oxy-Hb levels during WC. The neural response of the PFC may differ during water-based and land-based exercise owing to differences in external information associated with water immersion.

Prognostic significance of p16, p21, and Ki67 expression at the invasive front of colorectal cancers.

Cancer cells at the invasive front are believed to be responsible for invasion/metastasis. This has led to examining various morphological features and protein expressions at the invasive front. However, accurate assessment of the pathological section requires long-time training, and inter-observer disagreement is problematic. Immunohistochemistry and digital imaging analysis may mitigate these problems; however, the choice of which proteins to stain and the best analysis method remains controversial. We used the "go-or-grow" hypothesis to select markers with the greatest prognostic relevance. Importantly, nonproliferating cells can migrate. We used Ki67 as a proliferation marker, with p16 and p21 designating nonproliferating cells. We established a semi-automated quantification workflow to study protein expression in serial pathological sections. A total of 51 patients with completely resected colorectal cancer (stages I-IV) were analyzed, and 44 patients were followed up. Patients with cancer cells with p16-high/p21-low or p21-low/Ki67-low at the deepest invasive front demonstrated a significantly worse prognosis than those who did not display these characteristics. These results suggest that the nonproliferating cancer cells at the invasion front possess invasion/metastatic property with heterogeneity of senescence.

Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis.

The organoid culture technique has been recently applied to modeling carcinogenesis in several organs. To further explore its potential and gain novel insights into tumorigenesis, we here investigated whether pancreatic ductal adenocarcinoma (PDA) could be generated as subcutaneous tumors in immunocompromised nude mice, by genetic engineering of normal organoids. As expected, acute induction of KrasG12Din vitro occasionally led to development of tiny nodules compatible with early lesions known as pancreatic intraepithelial neoplasia (PanIN). KrasG12D-expressing cells were enriched after inoculation in the subcutis, yet proved rather declined during culture, suggesting that its advantage might depend on surrounding environments. Depletion of growth factors or concurrent Trp53 deletion resulted in its robust enrichment, invariably leading to development of PanIN or large high-grade adenocarcinoma, respectively, consistent with in vivo mouse studies for the same genotype. Progression from PanIN was also recapitulated by subsequent knockdown of common tumor suppressors, whereas the impact of Tgfbr2 deletion was only partially recapitulated, illustrating genotype-dependent requirement of the pancreatic niche for tumorigenesis. Intriguingly, analysis of tumor-derived organoids revealed that KrasG12D-expressing cells with spontaneous deletion of wild-type Kras were positively selected and exhibited an aging-related mutation signature in nude mice, mirroring the pathogenesis of human PDA, and that the sphere-forming potential and orthotopic tumorigenicity in syngenic mice were significantly augmented. These observations highlighted the relevance of the subcutis of nude mice in promoting PDA development despite its ectopic nature. Taken together, pancreatic carcinogenesis could be considerably recapitulated with organoids, which would probably serve as a novel disease model.

The minimally important difference for the Japanese version of the health assessment questionnaire in patients with rheumatoid arthritis in daily practice.

OBJECTIVE: To validate the minimally important difference (MID) of physical function using the Japanese version of the Health Assessment Questionnaire (J-HAQ) in a cohort of rheumatoid arthritis (RA). METHODS: Patients who participated in a cohort study in both October 2008 and April 2009 were analyzed. Patients self-rated their change in overall status over 6 months using a 5-point Likert scale ("much better", "somewhat better", "same", "somewhat worse", or "much worse"). The MID for J-HAQ score was defined as the mean J-HAQ score change in patients who rated themselves "somewhat better". An effect size (ES) of 0.2-0.5 was considered to be suitable for MID. RESULTS: A total of 4560 patients were analyzed. The mean (standard deviation [SD]) MID for J-HAQ score was -0.06 (0.29), corresponding to an ES of 0.08. As exploratory analysis, 1999 patients with a J-HAQ score ≥0.5 and 28-joint disease activity score (DAS28) ≥ 2.6 at baseline were assessed. The mean (SD) MID for J-HAQ score of these patients was 0.13 (0.01), corresponding to an ES of 0.21. CONCLUSIONS: The MID for J-HAQ score was 0.13 in patients with baseline J-HAQ score ≥0.5 and DAS28 ≥ 2.6. The MID for J-HAQ score was influenced by disease status and functional disability.

Successful delivery in a patient with clinically amyopathic dermatomyositis during pregnancy despite first-trimester acute exacerbation of interstitial lung disease.

A 37-year-old woman with rheumatoid arthritis and interstitial lung disease (ILD) developed clinically amyopathic dermatomyositis (CADM) after achieving pregnancy through in vitro fertilization. She was given oral prednisolone, which improved her respiratory status, and delivered a healthy baby at 35 weeks' gestation. There are few reports of successful outcomes for CADM during pregnancy; to the best of our knowledge, this is the first report of successful delivery in a patient with both CADM and ILD.

Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients with rheumatoid arthritis based on real-world data from the IORRA observational cohort study in Japan.

OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan.

Profiles of EQ-5D utility scores in the daily practice of Japanese patients with rheumatoid arthritis; Analysis of the IORRA database.

OBJECTIVE: Along with the advances of newly developed medical therapies in rheumatoid arthritis (RA), the number of pharmacoeconomical issues has been paid attention rapidly. For cost-utility analysis and determination of quality-adjusted life years, measurement of the EuroQol 5-dimensional descriptive system (EQ-5D) is essential, and has been used in several clinical studies. However, EQ-5D utility measure in Japanese patients with RA, especially in daily practice has not been fully documented. We analyzed the distribution of EQ5D utility scores and investigated the relationship between other clinical measures based on our Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. METHOD: Among 5,284 outpatients who participated in the IORRA cohort study on October 2007, data from 5,043 patients who completed the EQ-5D questionnaire were cross-sectionally analyzed. EQ-5D scores in each subgroup for baseline feature such as gender, age, disease activity score 28 (DAS28), and Japanese version of health assessment questionnaire (J-HAQ) were evaluated. For the evaluation of variables that influenced EQ-5D score, the contribution of each variable was evaluated by ANOVA. RESULTS: Average EQ-5D score was 0.76 in 5,284 patients (84% females, average age: 59.0 years, average disease duration: 12.4 years) whose average DAS28 was 3.3 and average J-HAQ was 0.74. EQ-5D scores were highly correlated with J-HAQ and DAS28, and were significantly lower in females and rheumatoid factor-positive patients. Older age, longer disease duration, higher DAS28, and higher J-HAQ were also significantly associated with lower EQ-5D scores. In multivariate analysis, the factor that most strongly influenced EQ-5D was J-HAQ (57.6%), followed by pain visual analog score (VAS; 12.5%). CONCLUSION: This study clearly demonstrated the distribution of EQ-5D score in the daily practice of RA patients, and provides important information for the pharmacoeconomical studies in rheumatology.

Cost-effectiveness of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, versus methotrexate in patients with rheumatoid arthritis using real-world data from the IORRA observational cohort study.

OBJECTIVES: To evaluate the cost-effectiveness of tocilizumab in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: The cost-effectiveness was determined using a Markov model-based probabilistic simulation. Data from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study between April 2007 and April 2011 were extracted using a pair-matching method: tocilizumab group (n = 104), patients who used at least 1 disease-modifying anti- rheumatic drug and in whom tocilizumab treatment was initiated; methotrexate group (n = 104), patients in whom methotrexate treatment was initiated for the first time or after an interruption of 6 or more months. Assuming a 6-month cycle length, health benefits and costs were measured over a lifetime and discounted at an annual rate of 3%. RESULTS: Compared with methotrexate treatment, lifetime costs and quality-adjusted life years (QALYs) for tocilizumab treatment were approximately 1.5- and 1.3-times higher, respectively. Incremental cost per QALY gained with tocilizumab was $49,359, which was below the assumed cost-effectiveness threshold of $50,000 per QALY. The probability of tocilizumab being cost- effective was 62.2%. CONCLUSION: The simulation model using real-world data from Japan showed that tocilizumab (at a certain price) may improve treatment cost-effectiveness in patients with moderate-to-severe RA by enhancing quality-adjusted life expectancy.

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice.

OBJECTIVES: To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. METHODS: We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. RESULTS: We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. CONCLUSIONS: Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.

Chronological changes in baseline disease activity of patients with rheumatoid arthritis who received biologic DMARDs between 2003 and 2012.

BACKGROUND/PURPOSE: The use of biologic disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) has been increasing since 2003. In this study, we evaluated changes in the characteristics of patients receiving biologic DMARDs daily, in Japan. METHODS: The characteristics of all RA patients who received any biologic DMARD at the Institute of Rheumatology, Tokyo Women's Medical University, within 1 year after its approval in Japan, were retrospectively evaluated. The periods of patient enrollment for each biologic agent were: infliximab (IFX), 2003-2004; etanercept (ETN), 2005-2006; tocilizumab (TCZ), 2008-2009; adalimumab (ADA), 2008-2009; abatacept (ABT), 2010-2011; and golimumab (GLM), 2011-2012. We retrospectively collected individual patient characteristics, concomitant medication usage, and disease activity assessed by disease activity score 28 (DAS28) at the time of administration, from the medical records. The retention rate for each agent at 6 months after treatment initiation was also assessed. RESULTS: The numbers of patients who received each biologic DMARD at our institute within 1 year after its approval were: IFX, 49; ETN, 50; TCZ, 62; ADA, 52; ABT, 40; and GLM, 77. From 2003 to 2012, the proportion of patients with prior use of any biologic DMARD increased, as did concomitant use and dose of methotrexate (MTX); however, corticosteroid use and doses decreased. DAS28, at the time of treatment initiation, gradually decreased. At the time of IFX administration, 75% and 25% of patients had high and moderate disease activity respectively, compared to 25% and 58% respectively, of patients who received GLM. No significant difference was observed in the retention rate of biologic DMARDs at 6 months (range, 75.0% to 89.6%). CONCLUSION: Baseline disease activity of RA patients who received biologic DMARDs between 2003 and 2012 has changed from high to moderate in daily practice in Japan.

Effect of interleukin-6 receptor inhibitor, tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors.

OBJECTIVES: To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays. METHODS: RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction. RESULTS: Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ. CONCLUSION: TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.

Evaluation of Energy Balance Estimated From Total Energy Expenditure and Body Composition Changes in Junior Sumo Wrestlers: An Observational Study Over Six Months.

Background Sumo is a sport that requires wrestlers to develop their physique from childhood for athletic advantage. However, the energy expenditure and energy balance required for the growth of junior Sumo wrestlers remain unclear. This study aimed to determine the energy balance of junior Sumo wrestlers over six months using doubly labeled water (DLW) and bioelectrical impedance analysis (BIA). Methodology A total of 12 male Sumo wrestlers were affiliated with a local Sumo club (average age = 15 ± 1 years). The total energy expenditure (TEE) was measured using DLW, whereas body composition was evaluated using BIA. Daily physical activity was quantified using a tri-accelerometer (Active style Pro HJA-750C). Results The TEE was 4,194 ± 734 kcal/day, while daily physical activity without training was 786 ± 50 minutes. Within six months, the body weight increased by 2.0 ± 3.2 kg, fat-free mass (FFM) was augmented by 2.1 kg, while fat mass did not change significantly. The surplus energy accumulated was 5.6 ± 213 kcal/day. Conclusions The excess energy of junior Sumo wrestlers predominantly increases their FFM. To increase their physical prowess, wrestlers adhere to a lifestyle characterized by high-intensity training and attenuated daily physical activity.

Dynamic Cerebral Autoregulation during Repeated Handgrip Exercise: Comparisons with Spontaneous Rest and Sit-Stand Maneuvers.

Induced arterial pressure oscillation may improve the assessment of dynamic cerebral autoregulation (dCA) based on transfer function analysis (TFA). This study investigated dCA during repeated handgrip exercise (RHE) and compared it to spontaneous rest and sit-stand maneuvers (SSMs) which are often used for dCA assessment. After a 5-minute rest, 20 healthy young adults (10 women) underwent 5 minutes of RHE and SSMs at 0.05 Hz and 0.10 Hz in random order. Power spectral densities (PSDs) and TFA gain, phase, and coherence of mean arterial pressure (MAP) and blood velocity in the middle cerebral artery (MCAvmean) were compared in very low (VLF: 0.02-0.07 Hz) and low (LF: 0.07-0.20 Hz) frequencies. End-tidal CO2 (EtCO2) was recorded throughout the study. Compared with rest, RHE increased PSDs of MAP and MCAvmean in VLF (444% and 273% respectively) and LF (1571% and 1765% respectively), with significant elevations in TFA coherence (VLF: 131%, LF: 128%), while SSMs exhibited the highest PSD and coherence values (all P < 0.05). TFA gains and phases were similar between RHE and rest, but VLF gain was higher while VLF and LF phases were lower during SSMs than RHE (all P < 0.05). EtCO2 was higher during SSMs than rest and RHE (both P < 0.05), with the individual changes positively correlated with VLF gain changes (R2 = 0.289, P < 0.001). These results suggest that RHE significantly increases arterial pressure oscillation and TFA coherence and may improve the dCA assessment in individuals not capable of performing repeated postural changes.

Glycated hemoglobin (HbA1c) is independently associated with the bioelectrical impedance phase angle in junior sumo wrestlers: A pilot study.

The study explores the relationship between phase angle (PhA), an indicator of cellular health, and metabolic health parameters among junior sumo wrestlers in Japan. Given the demanding lifestyle and high-energy diets of sumo wrestlers that predispose them to metabolic syndrome post-retirement, this study focuses on a younger cohort. The primary aim is to evaluate if PhA could serve as an early indicator of metabolic health issues within this unique demographic. A total of 14 sumo wrestlers aged 9-17 years were assessed to determine the relationship between PhA and various metabolic markers, including glycated hemoglobin (HbA1c), using a TANITA MC-780A-N body composition analyzer and standard blood tests. Bivariate regression analysis and Pearson's correlation revealed a negative relationship between PhA and HbA1c even after adjusting for age and weight (ß = -0.496, r2 = 0.776, r = -0.756, p = 0.004). The results indicate a significant negative relationship between PhA and HbA1c levels, suggesting that lower PhA values, which indicate poorer cellular integrity, are associated with higher HbA1c levels, signifying impaired glycemic control. These findings underscore the potential of PhA as a valuable biomarker for monitoring metabolic health in young sumo wrestlers, with implications for early intervention and management strategies.

Periarterial or perivenous invasion is an independent indicator of lymph node metastasis in invasive breast carcinoma of no special type.

Pathological diagnosis of breast cancer often includes cases of lymph node metastases without lymphatic or lymphovascular invasion by the primary tumor. In this study, to resolve this discrepancy, we designed a sensitive method to detect lymphatic invasion and correlate it with lymph node metastasis. Elastica van Gieson (EVG) staining and D2-40 immunohistochemistry revealed the abundant distribution of lymphatic vessels around blood vessels in the mammary tissue in close proximity to the elastic fibers around the arteries and veins. Based on the histological location of the blood and lymphatic vessels, we hypothesized that, in breast cancer, perivascular invasion is similar to lymphatic invasion and correlates with the presence of lymph node metastasis. Using EVG staining, perivascular invasion was histologically classified into periarterial invasion (periA), perivenous invasion (periV), and periarterial or perivenous invasion (periA/V). We tested our method and compared it to other methods commonly used for identifying lymphatic invasion in 105 patients with invasive breast carcinoma of no special type (IBC-NST) who received minimal preoperative therapy. The correlation between perivascular invasion and lymph node metastasis in these patients was statistically analyzed, including findings related to lymphatic invasion, such as retractile artifacts and perineural invasion. PeriA, periV, and periA/V showed significant correlations with lymph node metastasis. PeriA/V had high sensitivity and negative predictive value. The odds ratio (OR) for periV was significantly high in the univariate analysis, while the ORs for periA/V, retraction artifacts, and perineural invasion were significantly high in both the univariate and multivariate analyses. In particular, periA/V revealed a strong correlation with lymph node metastasis (OR: 61.8). These findings indicate that the IBC-NST periA/V ratio is a sensitive pointer of lymphatic invasion and could be an independent and reliable indicator of lymph node metastasis.

Fatal hemophagocytic lymphohistiocytosis with intravascular large B-cell lymphoma following coronavirus disease 2019 vaccination in a patient with systemic lupus erythematosus: an intertwined case.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

Disability is the major negative predictor for achievement of Boolean-based remission in patients with rheumatoid arthritis treated with tocilizumab.

OBJECTIVE: To analyze the efficacy of tocilizumab (TCZ) and the factors that influence achievement of Boolean-based remission in patients with rheumatoid arthritis (RA) treated with TCZ in daily clinical practice. METHODS: The efficacy of TCZ at 24 weeks after initiation of TCZ in 80 patients with RA was analyzed by comparing achievement of "DAS28 remission" with that of "Boolean-based remission". The predictive factors that influence achievement of Boolean-based remission were determined using multiple logistic regression analysis using a step-wise method. RESULTS: DAS28 remission and Boolean-based remission were achieved in 50.0 and 12.5% of patients, respectively. Significant differences in achieving Boolean-based remission were observed when patients were stratified by disease duration in tertiles (p < 0.05) and by physical function in tertiles (p < 0.05); no such differences were observed for achieving DAS28 remission. The least achievable component among the Boolean-based remission criteria was patient's global assessment. The predictive factor for not achieving Boolean-based remission at 24 weeks was having a worse baseline physical function (odds ratio, 3.66; 95 % confidence interval, 1.17-14.48). CONCLUSIONS: This study suggests that baseline disability predicts a lack of achievement of Boolean-based remission. Thus, better responses to TCZ may be obtained when TCZ is initiated in RA patients before disability develops.