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Lymphoma is the most common hematological cancer in dogs. Canine diffuse large B cell lymphoma shows a relatively good response to treatment with multi-agent cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; however, the 2-year survival rate is as low as 20%. For human B cell type lymphoma, the anti-CD20 chimeric antibody, rituximab, was developed two decades ago. The combination of rituximab and CHOP chemotherapy was highly successful in improving patient prognosis. However, no anti-canine CD20 antibody is available for the treatment of canine lymphoma. During this study, a rat anti-canine CD20 monoclonal antibody was established. We also generated a rat-canine chimeric antibody against canine CD20 designed for clinical application. This chimeric antibody (4E1-7-B) showed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against the canine B cell lymphoma cell line CLBL-1. Moreover, to obtain stronger ADCC activity, a defucosylated 4E1-7-B antibody (4E1-7-B_f) was also generated, and it showed tenfold stronger ADCC activity compared with 4E1-7-B. 4E1-7-B_f as well as 4E1-7-B suppressed the growth of CLBL-1 tumors in an immunodeficient xenotransplant mouse model. Finally, a single administration of 4E1-7-B_f induced considerable peripheral B cell depletion in healthy beagles. Thus, 4E1-7-B_f is a good antibody drug candidate for canine B cell type lymphoma.

Background Schizophrenia places a great humanistic and financial burden to patients, families, and societies, and the burden is substantially impacted by comorbid conditions. This study aimed to estimate the lifetime prevalence of schizophrenia and to assess the health-related quality of life (HRQoL), work productivity, and indirect cost among schizophrenia patients with and without comorbidities (depressive symptoms, sleep disturbances, and anxiety problems). Methods This is a secondary analysis of existing data collected in 2019 from the Japan National Health and Wellness Survey. The schizophrenia patients were categorized based on their Patient Health Questionnaire-9 score, self-reported experience of sleep disturbances, and anxiety problems. The lifetime prevalence was estimated using the total number of diagnosed schizophrenia patients as the numerator and the total number of respondents as the denominator. The HRQoL was evaluated through the Short Form 12-Item (version 2) Health Survey and EuroQoL 5-dimensions scale. Work productivity and annual indirect costs were evaluated through the Work Productivity and Activity Impairment instrument and monthly wage rates. Multivariate analyses included the comparison of outcomes using generalized linear models. Results The study was conducted with 178 schizophrenia patients with an average age of 42.7 years old and an estimated lifetime prevalence of 0.59% (95% CI: 0.51%, 0.68%). Patients who experienced sleep disturbances, more severe depressive symptoms, and anxiety problems had lower HRQoL, higher levels of absenteeism, presenteeism, total work productivity and activity impairment, and almost twice more indirect costs, compared to those without these conditions. Conclusion Comorbid conditions among patients with schizophrenia impact significantly on their quality of life, work productivity as well as indirect costs.

Lymphoma is the most common neoplasm of lymphoid tissues in dogs. Exportin 1 (XPO1) is an important major nuclear receptor for exporting proteins and RNA species. The XPO1 upregulation can eliminate some tumor suppressor proteins (TSPs) function upon their nuclear–cytoplasmic export. The XPO1 inhibitor, KPT-335, blocks the translocation of TSPs and restores their function to induce cell cycle arrest, apoptosis, and cell proliferation. This in vitro study aimed to evaluate the XPO1 mRNA and protein expression in canine lymphoma cell lines and confirm the relevance with KPT-335. XPO1 mRNA and protein levels were quantified, and the effect of KPT-335 was assessed by a cell proliferation assay. The results indicated that XPO1 mRNA and protein were highly expressed in 17-71, CLBL-1, CLC, CLGL-90, and UL-1, and were moderately expressed in GL-1, Ema, and Nody-1. All canine lymphoma cell lines showed dose-dependent growth inhibition and decreased cell viability in response to KPT-335, with IC50 concentrations ranged from 89.8–418 nM. The expression levels of XPO1 mRNA and protein were related; however, no correlation was found between those expression levels and the efficacy of KPT-335. These findings suggest that XPO1 may represent a promising target for therapeutic intervention in canine lymphoma.

Background Premature mortality, frequent relapse that easily leads to hospitalization, and discontinuous employment are key challenges for the treatment of schizophrenia. We evaluated risk factors for important clinical outcomes (death, hospitalization, resignation, and sick leave from work) in patients with schizophrenia in Japan. Methods A nested case–control study was conducted for patients with schizophrenia identified in a Japanese claims database. For each outcome, the case was matched with up to four controls of the same age, sex, index year, and enrollment status (employee or dependent family). Potential risk factors were defined by prescriptions or diagnoses within 3 months prior to or in the month of the event. The association among potential risk factors and each outcome was evaluated using multivariable conditional logistic regression analysis with stepwise variable selection. Results The number of cases and eligible patients for each outcome were 144 and 38,451 (death), 1,520 and 35,225 (hospitalization), 811 and 18,770 (resignation), and 4,590 and 18,770 (sick leave), respectively. Depression was a risk factor for death (odds ratio [OR]: 1.92; 95% confidence interval [CI]: 1.12, 3.29), hospitalization (OR: 1.22; 95% CI: 1.05, 1.42), and sick leave from work (OR: 1.46; 95% CI: 1.36, 1.57). Other risk factors for death were hospitalization history, Charlson Comorbidity Index (CCI) score, and prescription for laxatives. Prescriptions for hypnotics, laxatives, and anticholinergics were risk factors for hospitalization. Prescriptions for hypnotics and anticholinergics were risk factors for resignation. CCI score, prescription for hypnotics, laxatives, and antidiabetics were risk factors for sick leave from work. Conclusions Our findings suggest that depression and some physical symptoms, such as constipation and extrapyramidal symptoms, are risk factors for important clinical outcomes in patients with schizophrenia. Attention should be paid to both depression and physical symptoms for the treatment of schizophrenia.

The CheckMate 649 trial demonstrated the clinical benefit of nivolumab plus chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer. However, the background discrepancy between clinical practice and randomized controlled trials may impact the therapeutic strategy and prognosis of patients. This study aimed to assess the clinical significance of eligibility criteria determined by the CheckMate 649 trial and identify prognostic factors in clinical practice. A total of 160 patients with HER2-negative metastatic gastric cancer who underwent chemotherapy were retrospectively enrolled and classified into two groups based on eligibility criteria. Among the 160 patients, 76 (47.5%) and 84 (52.5%) were included in the eligible and ineligible groups, respectively. The ineligible group had a significantly lower induction of second- and third-line chemotherapy than the eligible group ( P  = 0.02 and P  = 0.02, respectively). The median overall survival in the eligible and ineligible groups was 22.9 and 10.5 months, respectively, with the ineligible group having a significantly poorer prognosis than the eligible group ( P  < 0.01). Responders to first-line chemotherapy had a better prognosis than non-responders in both groups ( P  = 0.01 and P  < 0.01, respectively). Multivariate analyses identified disease control as an independent prognostic factor in both groups ( P  < 0.01 and P  < 0.01, respectively). Patients with a poor general condition who fulfilled the ineligibility criteria as determined using randomized controlled trials are included in clinical practice, and these criteria are related to tumor response and prognosis.

Background Osteosarcopenia, characterized by muscle loss and osteoporosis, has emerged as a prognostic marker for various malignancies. However, its impact on the immune response in gastric cancer remains unclear. This study aimed to assess the clinical significance of osteosarcopenia and its relationship with the immune microenvironment in patients with advanced gastric cancer. Methods This study included 105 patients with pathological stage II/III gastric cancer who underwent gastrectomy between 2018 and 2022. Preoperative computed tomography was used to measure muscle mass and bone density, with sarcopenia and osteoporosis defined as values below the respective standard thresholds. Sarcopenia and osteoporosis were identified when both conditions were present. We explored the relationships between osteosarcopenia, clinicopathological factors, and prognoses. Additionally, immune marker expression was evaluated via immunohistochemistry. Results Among the 105 patients, 37 (35%) were diagnosed with osteosarcopenia. This condition significantly correlated with performance status, body mass index, and disease recurrence (all p  < 0.05). Overall survival and relapse-free survival were significantly lower in the osteosarcopenia group than those in the non-osteosarcopenia group (all p  < 0.05). Moreover, the osteosarcopenia group had significantly fewer CD8-positive, programmed cell death protein 1-positive, and programmed death-ligand 1-positive cells than that of the control group (all p  < 0.05). Conclusions Our findings suggest that osteosarcopenia is associated with the tumor microenvironment and might serve as a prognostic indicator in patients with advanced gastric cancer.

Acute kidney injury (AKI) due to vitamin D therapy for osteoporosis is encountered in clinical practice, but epidemiological studies are scarce. We aimed to determine the association between AKI and vitamin D therapy and to identify risk factors for AKI using the Japanese Adverse Drug Event Report database. We used reporting odds ratios (RORs) to detect signals and evaluate risk factors using multiple logistic regression analysis. Among 298,891 reports from April 2004 to September 2023, 1071 implicated active vitamin D 3 analogs as suspect drugs for adverse events. There was a significant association between AKI and active vitamin D 3 analogs (ROR [95% confidence interval {CI}], eldecalcitol: 16.75 [14.23–19.72], P  < 0.001; alfacalcidol: 5.29 [4.07–6.87], P  < 0.001; calcitriol: 4.46 [1.88–10.59], P  < 0.001). The median duration of administration before AKI onset was 15.4 weeks. Multiple logistic regression analysis showed a significant association between AKI and age ≥ 70 years (odds ratio [95% CI], 1.47 [1.04–2.07]; P  = 0.028), weight < 50 kg (1.55 [1.12–2.13]; P  = 0.007), hypertension (1.90 [1.42–2.54]; P  < 0.001), and concomitant use of nonsteroidal anti-inflammatory drugs (1.58 [1.10–2.25], P  = 0.012) and magnesium oxide (1.96 [1.38–2.78]; P  < 0.001). Our results suggest that active vitamin D 3 analogs are associated with AKI development. Physicians prescribing these medications to patients with risk factors should consider the possibility of AKI, especially during the first 6 months.

The clinical significance of laparoscopic subtotal gastrectomy (LsTG) with a small remnant stomach remains unclear in patients with gastric cancer, including at an advanced stage. The present study assessed postoperative quality of life (QOL) and survival after LsTG compared with laparoscopic total gastrectomy (LTG). We retrospectively analyzed consecutive patients with gastric cancer who underwent LsTG (n=26) or LTG (n=26). Surgical outcome, postoperative nutritional status, QOL, and prognosis were compared between the LsTG and LTG groups. The Postgastrectomy Syndrome Assessment Scale was used to evaluate postoperative QOL. Operating time was significantly shorter (p<0.01) and postoperative morbidity was significantly lower (p=0.04) in the LsTG than in the LTG group. The reduction in body weight after surgery was significantly greater in the LTG than in the LsTG group (p<0.01). The Postgastrectomy Syndrome Assessment Scale revealed that, compared with LTG, LsTG significantly improved postoperative QOL (p<0.05). There was no significant difference in relapse-free survival and cancer-specific survival between the two groups. Three patients in the LTG group died of pneumonia and overall survival was significantly longer in the LsTG group (p=0.01). This study demonstrated the efficacy of LsTG with a small remnant stomach to prevent a decline in postoperative QOL and non-cancer-related death.

Tumor-associated macrophage (TAM) infiltration is associated with poor prognosis in human patients with melanoma. However, the mechanism by which TAMs infiltrate tumor tissues in dogs remains unclear. Therefore, the present study aimed to identify macrophage chemotactic factors involved in macrophage migration in canine oral malignant melanoma (OMM). We first analyzed RNA-seq data of canine OMM, then performed immunohistochemistry of OMM tissue, and finally performed a macrophage migration assay using factors secreted from a canine melanoma cell line. The RNA-seq and immunohistochemistry revealed high TAM infiltration in canine oral malignant melanoma. Migration assays were performed using macrophage cell lines and culture supernatants from seven canine melanoma cell lines to identify macrophage chemotactic factors. The analysis of chemokine expression in canine melanoma cell lines revealed a positive correlation between CXCL8 expression and macrophage migration. Furthermore, macrophage migration was significantly reduced by CXCL8 gene knockout and anti-CXCL8-neutralizing monoclonal antibody. Additionally, the addition of recombinant CXCL8 protein rescued the reduction in migratory macrophage cells caused by CXCL8 knockout. These findings indicate that CXCL8 plays a crucial role in macrophage migration and that targeting CXCL8 may be a novel therapeutic approach for canine melanoma.

INTRODUCTION: Surgical repair of severe perineal tears is required immediately postpartum. Owing to their low prevalence, the post-treatment course of severe tears is not well known. Herein, we report a rare case of a young woman who underwent robot-assisted curative resection with anal preservation for a rectal neuroendocrine tumor (NET) incidentally discovered following a severe perineal tear.CASE PRESENTATION: A 29-year-old woman experienced a severe perineal tear during the first vaginal delivery, which led to the incidental discovery of a 20-mm rectal NET. Four months after the perineal tear, the gynecology and digestive surgery teams ensured that the tear wound had completely healed and anal function was preserved. The patient underwent robot-assisted ultra-low anterior resection with lymph node dissection. The procedure was successfully completed, preserving anal function, and histopathology confirmed an NET (G2, pT2N2aM0, pStage IIIB). The patient recovered smoothly and was discharged on the seventh postoperative day.CONCLUSIONS: Rectal surgery after severe perineal tears may be associated with scarring and fibrosis around the rectum, and precautions should be taken at the time of rectal dissection. Depending on the tumor condition, it may be advisable to perform rectal surgery several months after the tear rather than immediately after treatment for the tear.