Cervical intervertebral disc disease in 307 small-breed dogs (2000-2021): Breed-characteristic features and disc-associated vertebral instability.

OBJECTIVE: To evaluate the breed-characteristic features of cervical intervertebral disc disease (C-IVDD) and associated vertebral instability in small-breed dogs and to present the concept of intervertebral disc degeneration and associated instability stage, method of diagnosis, treatment and outcomes. ANIMALS: In total, 307 client-owned dogs with C-IVDD treated with spinal cord decompression with or without vertebral stabilization (2000-2021). METHODS: Information on age, sex, affected sites, stabilized sites, diagnostic methods for vertebral instability and outcomes were retrieved. The patient's age, affected sites (cranial vs caudal discs), and frequency of vertebral stabilization were compared in six CD and five NCD breed. Multivariable analyses of the chondrodystrophic (CD) vs non-CD (NCD) groups, and vertebral stabilization (dogs stabilized vs dogs not stabilized) were performed. RESULTS: In total, 222 (72.3%) and 77 (25.1%) were CD and NCD breeds, respectively. Vertebral instabilities were diagnosed based on the survey radiographs with computed tomography/magnetic resonance imaging (n = 2), dynamic myelography (n = 29), intraoperative spinal manipulation (n = 11) or second surgery in dogs with persistent postoperative paraspinal pain (n = 3). Of these dogs, 295 (96.1%) recovered (median follow-up: 8.5 [range, 1-119] months). Significant differences in age, affected sites and frequency of stabilization were noted among the breeds. Older age and frequent vertebral stabilization were the associated factors for the NCD breed dogs. Male dogs, caudal discs affected (C5-T1) and the NCD breed dogs were risk factors for the dogs with vertebral stabilization. CONCLUSION: Vertebral stabilization is indicated for small-breed dogs with cervical disc-associated vertebral instability.

Pulmonary abscess caused by Cladosporium cladosporioides after receiving outpatient chemotherapy.

Cladosporium cladosporioides is one of the most ubiquitous dematiaceous fungi that seldomly occur human infection. Here, we demonstrate a rare case of pulmonary phaeohyphomycosis with a distinctive pulmonary lesion during the nadir period of outpatient chemotherapy against endometrial cancer. In addition to severe neutropenia, excessive exposure to C. cladosporioides at patient's residence was considered as dominant causative factor. More caution is considered necessary for pulmonary phaeohyphomycosis in patients who receive outpatient chemotherapy and are homebound during neutropenic status.

Mucor pulmonary embolism in a patient with myelodysplastic syndrome.

Mucormycosis is a life-threatening infectious disease that occurs most commonly in immunocompromised patients such as those with hematological malignancies. Its clinical symptoms and associated radiological findings vary and specific biomarkers and culture characteristics have not been defined. An 85-year-old man who had been treated for myelodysplastic syndrome and tuberculosis for several months presented with subacute fever and worsening left-side chest pain. Contrast-enhanced computed tomography images depicted massive tumor-like consolidation without enhancement, expanding from the left lower lobe. Emboli that did not respond to anticoagulants were detected in the left descending pulmonary artery. Despite intensive treatment he developed multiple organ failure and died 47 days after hospitalization. Gross pathology of a lung autopsy specimen revealed left lower pulmonary arterial emboli and pulmonary infarction, which was concluded to be the direct cause of death. The emboli were histopathologically identified as invasive mycelia in vessels. Mucor sp. was detected via real-time polymerase chain reaction and immunohistopathological analyses revealed that the mold in the blood vessels of lung tissue was partially positive for the mucor antigen. In the present case of Mucor sp. pulmonary emboli in a patient with myelodysplastic syndrome, radiographic findings were hard to distinguish from those typical of a lung abscess.

Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for esophageal cancer: original questionnaire and EORTC QLQ-C30 survey.

Reflux following an esophagectomy with gastric conduit reconstruction in the posterior mediastinum is a clinically significant problem. In this study, we investigated the frequency and impact of reflux on the quality of life (QOL) among 158 patients who underwent an esophagectomy for esophageal cancer using an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). Reflux frequency was assessed using the original questionnaire. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Out of 35 patients (22.2%) reported no reflux symptoms. Patients were divided into two groups: those with reflux ≥ once/week (63 patients) and those with low frequency of symptoms (95 patients). Time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, the frequency plateaued after more than two years. QOL was assessed using the EORTC QLQ-C30. The ≥ once/week reflux group had a significantly lower global health status score than the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.007). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). Regarding symptoms, the ≥ once/week reflux group had significantly higher scores for fatigue, nausea, and vomiting, dyspnea and insomnia compared to the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4, P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Thus, reflux after an esophagectomy was associated with a lower QOL.

Effects of Subnormothermic Perfusion Before Transplantation for Liver Grafts from Donation After Cardiac Death: A Simplified Dripping Perfusion Method in Pigs.

BACKGROUND: Liver transplantation from donors after cardiac death (DCD) provides a solution to the donor shortage. However, DCD liver grafts are associated with a high incidence of primary graft nonfunction. We investigated the effectiveness of subnormothermic porcine liver perfusion, before transplantation from DCD, on graft viability. METHODS: Landrace pigs (25-30 kg) were randomly allocated to 3 groups (5 per group): heart-beating (HB) graft, transplanted after a 4-hour period of cold storage (CS); DCD graft, retrieved 20 minutes after apnea-induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-hour period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs-Henseleit buffer (21-25°C, 10-15 cm H2O) for 30 minutes in a simplified dripping manner, without a machine perfusion system, after the 4-hour period of CS, and subsequently transplanted. RESULTS: Although all animals in the HB group survived for >7 days, all animals in the DCD group died within 12 hours after transplantation. In the SELP group, 2 recipients survived for >7 days and another 2 recipients were killed on day 5. The survival rate was significantly better for SELP than for DCD grafts (P = .0016). The values of tumor necrosis factor α were not significantly different between the SELP and HB groups. Preserved structure of the parenchyma was observed in the SELP group on histologic examination. CONCLUSIONS: A simplified subnormothermic perfusion before liver transplantation is expected to improve graft viability and survival.

A case of refractory lupus nephritis complicated by psoriasis vulgaris that was controlled with secukinumab.

It has been reported that T helper 17 cells are involved in the pathogenesis of systemic lupus erythematosus, but there is no report on interleukin-17-targeted therapy. We report a case of a 62-year-old female who presented with psoriasis vulgaris and refractory lupus nephritis. Because her conditions were resistant to conventional treatment, and flow cytometry confirmed the proliferation of activated T helper 17 cells in peripheral blood, and examination of a renal biopsy tissue sample confirmed infiltration of numerous interleukin-17-positive lymphocytes to the renal interstitium, administration of the anti-interleukin-17A antibody secukinumab was initiated. After starting secukinumab the clinical and biological features were improved.

Utility of initial induction chemotherapy with 5-fluorouracil, cisplatin, and docetaxel (DCF) for T4 esophageal cancer: a propensity score-matched analysis.

Although no consensus is available on the treatment of esophageal squamous cell carcinoma (ESCC) invading adjacent organs (T4), establishing effective induction treatments is crucial to altering an unresectable status and achieving curative resection. Here, we evaluated the efficacy of chemotherapy using 5-fluorouracil, cisplatin, and docetaxel (DCF) as the initial induction treatment for T4 ESCC. Fifty patients without distant metastasis who underwent initial induction chemotherapy using DCF for T4 ESCC were propensity score-matched with 50 patients who underwent radiotherapy concurrent with cisplatin and 5-fluorouracil (CRT). In the DCF group, 24 (48.0%) patients underwent surgery, achieving a 64% clinical response rate compared to 72.0% for induction CRT. CRT was also performed in another 24 (48.0%) patients in the DCF group in whom surgical resection was not indicated. The DCF group had significantly higher overall resectability than the CRT group (78.0% vs. 48.0%, P = 0.0017). The esophageal perforation rate during induction treatments was significantly lower in the DCF group than the CRT group (4.0% vs. 18.0%, P = 0.0205). Prognosis was significantly better in the DCF group than the CRT group (5-year cancer-specific survival 42.1% vs. 22.2%, P = 0.0146). Thus, induction DCF chemotherapy in patients with T4 ESCC reduced esophageal perforation and increased overall resectability, leading to better survival than CRT alone. Therefore, DCF chemotherapy may be an effective and safe option for initial induction treatment of T4 ESCC.

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

Comparison of short-term outcomes between 2- and 3-field lymph node dissection for esophageal cancer.

Although 3-field lymph node dissection (3-FLD) is often performed for thoracic esophageal squamous cell carcinoma (ESCC), the clinical effects of cervical lymph node dissection in addition to mediastinal and abdominal dissections on postoperative complications remain unclear. A total of 367 ESCC patients who underwent curative esophagectomy for thoracic esophageal cancer in our hospital from 2010 to 2015 were included in the study: 157 patients who underwent 2-field lymph node dissection (2-FLD) and 210 patients who underwent 3-FLD. Clinicopathological parameters and postoperative complications based on the Clavien-Dindo classification were compared between the two groups. We performed propensity score matching (PSM) analyses to compare the groups with well-balanced backgrounds. In terms of patient background, clinical T (p < 0.001), N (p < 0.001), and M (p = 0.002) stage of tumor was significantly more advanced; therefore, preoperative treatment was more frequently performed in the 3-FLD group than in the 2-FLD group (91.0% vs. 79.0%, P< 0.001). However, perioperative parameters including operation time, blood loss, and the number of dissected mediastinal and abdominal lymph nodes did not differ between the groups. In terms of postoperative complications, the occurrence rate of pneumonia increased significantly in patients with 3-FLD compared to 2-FLD (grade III or higher: 10.5% vs. 3.2%, P= 0.025). Although the duration of systemic inflammatory response syndrome (SIRS) was longer in the 3-FLD group than in the 2-FLD group (median 3 days vs. 2 days, P= 0.025), other postoperative parameters (including the highest level of postoperative serum C-reactive protein, intensive care unit stay, re-operation rate, and postoperative hospital stay) were similar between the groups. After PSM, the differences in the background between the groups disappeared. PSM analysis showed that there was no significant difference in each complication between the groups. The duration of SIRS tended to be longer in the 3-FLD group than in the 2-FLD group, but the difference was not significant. The field of lymphadenectomy negatively impacted the short-term outcome in ESCC patients in terms of pneumonia and inflammatory response. However, because the results of the PSM analyses indicate that the short-term outcome was similar between the two groups, 3-FLD could be as feasible as 2-FLD in ESCC patients.

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia.

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT.

A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

Cricoid pressure impedes tracheal intubation with the Pentax-AWS Airwayscope®: a prospective randomized trial.

BACKGROUND: It is unclear how cricoid pressure affects tracheal intubation with the Pentax-AWS Airwayscope(®) (AWS). We conducted a prospective randomized clinical trial in anaesthetized patients. METHODS: Sixty patients were allocated to either the cricoid pressure (CP) group (n=30) or the sham group (n=30). We compared the two groups with regard to intubation time, number of attempts required for insertion of the Intlock blade (disposable blade of the AWS) and tracheal intubation, percentage of glottic opening (POGO) score, and subjective difficulty of both laryngoscopy and passage of a tube through the glottis. RESULTS: Intubation time was significantly longer in the CP group (median 45[IQR40-59] s) than in the sham group (32[28-45] s) (P=0.003, 95% CI for median difference 5-24 s). The number required for insertion of the Intlock blade did not differ between the groups (P=0.08), but the number for tracheal intubation was significantly higher in the CP group (1 attempt in 14 patients, 2 in 7, 3 in 9) than in the sham group (1 attempt in 24 patients, 2 in 6; P=0.002). POGO score did not differ significantly between the groups (P=0.60), nor did the subjective difficulty of laryngoscopy (P=0.06). The visual analogue scale score for passage of a tube through the glottis was significantly higher in the CP group than in the sham group (P<0.001). CONCLUSIONS: Cricoid pressure impedes tracheal intubation using the AWS, and is associated with longer intubation time, which can be attributed to increased difficulty in the passage of a tube through the glottis. CLINICAL TRIAL REGISTRY NUMBER: UMIN000018209.

Impact of number of [(18)F]fluorodeoxyglucose-PET-positive lymph nodes on survival of patients receiving neoadjuvant chemotherapy and surgery for oesophageal cancer.

BACKGROUND: [(18) F]fluorodeoxyglucose (FDG)-PET has been used to evaluate the response of primary tumours to neoadjuvant therapy for oesophageal cancer. The clinical significance of the number of PET-positive nodes before and after therapy has not been investigated previously. METHODS: [(18) F]FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy to identify the number of PET-positive nodes, and these numbers were assessed in relation to metabolic changes in the primary tumour. RESULTS: Of 302 patients in total, 90 had no PET-positive nodes, 83 had one, 59 had two and 70 patients had three or more positive nodes before therapy. After treatment, the numbers were: none in 207 patients, one in 59, two in 20 and three or more in 16 patients. The number of PET-positive nodes after treatment was influenced by both the number of PET-positive nodes before therapy and the response to preoperative therapy, and correlated with the number of metastatic lymph nodes. Overall survival was longer in patients who had no PET-positive nodes after treatment than in those who had one or more. Multivariable analysis identified the numbers of PET-positive nodes before and after chemotherapy as independent prognostic factors, together with clinical response, tumour depth and lymph node involvement. CONCLUSION: The number of PET-positive nodes after treatment correlated with survival in patients with oesophageal cancer who underwent neoadjuvant chemotherapy.

Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer.

To develop gene-modified T-cell-based antileukemia adoptive immunotherapy, concomitant administration of CD4(+) and CD8(+) T cells that have been gene modified using identical HLA class I-restricted leukemia antigen-specific T-cell receptor (TCR) gene transfer has not yet been fully investigated. Here, using CD4(+) and CD8(+) T cells that had been gene modified with a retroviral vector expressing HLA-A*24:02-restricted and Wilms' tumor 1 (WT1)-specific TCR-α/ß genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells), we examined the utility of this strategy. WT1-siTCR/CD4(+) T cells sufficiently recognized leukemia cells in an HLA class I-restricted manner and provided target-specific Th1 help for WT1-siTCR/CD8(+) T cells. By using a xenografted mouse model, we found that WT1-siTCR/CD4(+) T cells migrated to leukemia sites and subsequently attracted WT1-siTCR/CD8(+) T cells via chemotaxis. Therapy-oriented experiments revealed effective enhancement of leukemia suppression mediated by concomitant administration of WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells. Importantly, this augmented efficacy in the presence of WT1-siTCR/CD4(+) T cells was correlated with longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8(+) T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia.

Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

Determination of HLA-A, -C, -B, -DRB1 allele and haplotype frequency in Japanese population based on family study.

The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies.

Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM).

A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS.