High Titer of ADAMTS13 Inhibitor Associated with Thrombotic Microangiopathy of the Gut and Skeletal Muscle after Allogeneic Hematopoietic Stem Cell Transplantation

Transplantation-associated thrombotic microangiopathy (TMA) is one of the main complications after hematopoietic stem cell transplantation (HSCT). At the time of onset of gut TMA, a patient developed a high titer of an inhibitor of the non-immunoglobulin G type to ADAMTS13, which physiologically hydrolyzes von Willebrand factor to control spontaneous intravascular thrombus formation. The patient developed symptoms of myositis, a disorder that has occasionally been reported to manifest after HSCT and to resemble some idiopathic autoimmune diseases. However, a muscle biopsy specimen presented pathologic findings of TMA, including microvascular platelet thrombus formation, without inflammatory lymphocyte infiltration. ADAMTS13 activities returned to normal after steroid treatment, and the improvement of TMA symptoms followed. This patient appears to represent a rare case of post-HSCT TMA associated with the development of an ADAMTS13 inhibitor.     

Minimum leakage rate (0.5%) of stapled esophagojejunostomy with sacrifice of a small part of the jejunum after total gastrectomy in 390 consecutive patients

BACKGROUND: The development of new surgical instruments and devices has facilitated the performance of esophagojejunostomy after total gastrectomy. However, total prevention of dehiscence of anastomoses remains difficult. We introduced a new procedure for esophagojejunostomy using a circular stapler, requiring sacrifice of only a small part of the jejunum. METHODS: The study group comprised 390 consecutive patients who underwent reconstruction by Roux-en-Y esophagojejunostomy, performed with a circular stapler, sacrificing a small part of the jejunum after total gastrectomy. We assessed anastomotic leakage and anastomotic stenosis after surgery. RESULTS: Only 2 patients (0.5%) had leakage and 4 (1.0%) had anastomotic stenosis after reconstruction. All the patients were cured by conservative therapy. CONCLUSIONS: Esophagojejunostomy performed with a circular stapler after total gastrectomy, with sacrifice of only a small part of the jejunum, is a useful and easy procedure, with a leakage rate of 0.5%.     

Inflammatory paradental cyst (IPC) in the mandibular premolar region in children

OBJECTIVES: We investigated the occurrence of inflammatory paradental cysts (IPC) in the mandibular premolar, and demonstrated the points of difference with regard to diagnostic features between IPC and dentigerous cysts (DC). MATERIAL AND METHODS: We analyzed the radiographs and histology of 60 cases with a cystic lesion associated with inflammation in the mandibular premolar region based on diagnostic criteria as IPC. RESULTS: In 4 out of 60 cases, we diagnosed the 4 cysts as IPCs in the mandibular premolar region, and recognized that one form of IPC was similar to a mandibular infected buccal cyst. The other 56 non-IPC cases were diagnosed as DC. On the IPCs, the permanent tooth normally erupted in all 4 cases after treatment, but in one case, the IPC recurred. CONCLUSIONS: The present investigation suggested that we might have misdiagnosed IPCs in the mandibular premolar region as DC to date. It is important to consider the differences between IPC and DC with regard to the causes of recurrence during treatment of IPC.     

Multiplex genomic profiling of non–small cell lung cancers from the LETS phase III trial of first-line S-1/carboplatin versus paclitaxel/carboplatin: results of a West Japan Oncology Group study

Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first-line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non–squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue.     

Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma

Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor–A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor–2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.     

Feasibility of extended-field irradiation and intracavitary brachytherapy combined with weekly cisplatin chemosensitization for IB2–IIIB cervical cancer with positive paraaortic or high common iliac lymph nodes: a retrospective review

Background

The aim of this retrospective study was to investigate the feasibility of primary treatment with extended-field irradiation and weekly cisplatin (extended-field concurrent chemoradiotherapy, EFCCRT) as initial therapy in patients with International Federation of Gynecology and Obstetrics IB1 to IIIB cervical cancer with paraaortic or high common iliac lymph node metastases.

Methods

Participants comprised patients with confirmed cervical cancer, showing paraaortic or high common iliac lymph node metastases on diagnostic imaging, treated with EFCCRT. Total external radiation doses were 50.4 Gy to the whole pelvis and 45.0 Gy to the lumbar paraaortic region. High-dose-rate intracavitary brachytherapy was performed to deliver a total dose of 18–24 Gy in 6-Gy fractions prescribed at point A. Weekly cisplatin (30–40 mg/m²) was given concurrently with radiotherapy.

Results

Twenty-four patients were treated. Median follow-up interval was 34 months. The dose of cisplatin was 30 mg/m² in 2 cases, 35 mg/m² in 8 cases, and 40 mg/m² in 14 cases. Twenty-two cases (92 %) received more than 160 mg/m² cisplatin. Ten cases (42 %) experienced acute grade 3/4 hematological toxicity, and 9 cases (38 %) experienced acute grade 3 nonhematological toxicity. No case presented late grade 3/4 toxicity. Three-year progression-free and overall survival rates were 54 % and 72 %, respectively. Eleven cases recurred during follow-up. Sites of recurrence were within the irradiation field in 4 cases, outside the field in 6 cases, and in both fields in 1 case.

Conclusion

EFCCRT and high-dose-rate intracavitary brachytherapy for patients with paraaortic or high common iliac lymph node metastases from cervical cancer is feasible.     

Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis

The effects of galectin-9 on a mouse collagen-induced arthritis (CIA) model were assessed to clarify whether galectin-9 suppresses CIA by regulating T cell immune responses. Galectin-9 suppressed CIA in a dose-dependent manner, and such suppression was observed even when treatment was started on 7 days after the booster, indicating its preventive and therapeutic effects. Galectin-9 induced the decreased levels of pro-inflammatory cytokines, IL-17, IL-12, and IFNgamma in the joint. Galectin-9 induced the decreased number of CD4(+) TIM-3(+) T cells in peripheral blood. Galectin-9-deficient mice became susceptible to CIA may be by increased number of CD4(+) TIM-3(+) T cells and decreased number of Treg cells. We further found that galectin-9 induces differentiation of naive T cells to Treg cells, and it suppresses differentiation to Th17 cells in vitro. The present results suggested that galectin-9 ameliorates CIA by suppressing the generation of Th17, promoting the induction of regulatory T cells.     

Baseline saliva level of 3-methoxy-4-hydroxyphenylglycole (MHPG) associates with a consequent cognitive decline in non-demented elderly subjects: three-years follow-up study

The aim of the study was to explore the relation between saliva level of 3-methoxy-4-hydroxy-phenylglycol (MHPG) and a later cognitive decline in non-demented elderly subjects. We have reported that sMHPG in 214 elderly subjects living in the community (age 74.5±5.9years) was associated with scores on the Mini-Mental State Examination (MMSE) and the Frontal Assessment Battery (FAB) in 2004 to 2006 (Time A). The same cohort underwent these cognitive tests again from 2007 to 2009 (Time B). The cognitive function of the 147 of 214 subjects could be reassessed by the same cognitive tests. The score on the FAB, but not the MMSE, was significantly reduced at Time B (14.6±2.6) compared with that of Time A (15.2±1.9). There was a significant negative correlation between the baseline sMHPG and the changes in the FAB score subtracted from Time B to Time A or the scores on the FAB at Time B in men, but not at Time A. These correlations were not found in women. These data indicate that high sMHPG might be associated with subsequent cognitive decline assessed by the FAB in non-demented elderly men living in the community.