Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes

l ‐Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti‐LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody‐dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side‐effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney‐derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and K_A values were increased by anti‐CD98hc mAb, suggesting anti‐LAT1 mAbs detect an epitope on LAT1‐CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.     

Impact of imbalanced graft‐to‐spleen volume ratio on outcomes following living donor liver transplantation in an era when simultaneous splenectomy is not typically indicated

The impact of an imbalanced graft‐to‐spleen volume ratio (GSVR) on posttransplant outcomes other than postreperfusion portal hypertension remains unknown. The importance of GSVR might vary according to whether simultaneous splenectomy (SPX) is performed. This retrospective study divided 349 living donor liver transplantation (LDLT) recipients from 2006 to 2017 into 2 groups: low GSVR (≤0.70 g/mL) and normal GSVR (>0.70 g/mL). The cutoff value of GSVR was set based on the first quartile of the distributed data. Graft survival and associations with various clinical factors were investigated between the groups according to whether SPX was performed. Low GSVR did not affect outcomes when SPX was performed. In contrast, it was associated with an increased incidence of early graft loss (EGL) and poor graft survival by presenting posttransplant thrombocytopenia, cholestasis, coagulopathy, and massive ascites when the spleen was preserved. Among patients with a preserved spleen, the multivariable analysis results revealed that older donor age and low GSVR were independent risk factors for graft loss. In conclusion, low GSVR was an independent predictor of graft loss after LDLT when the spleen was preserved. Preserved spleen with extremely low GSVR may be related to persistent hypersplenism, impaired graft function, and consequent EGL.     

Stride length of elderly patients with lumbar spinal stenosis: Multi-center study using the Two-Step test

BackgroundShort stride length is one of clinical symptoms associated with lumbar spinal stenosis (LSS). Short stride is a risk factor for falls; therefore, identification of factors associated with short stride is critical for fall prevention in LSS patients. Although the Two-Step test can conveniently assess maximal stride length, it has not become widely used; therefore, its data are limited. We identified the potential factors associated with short stride of elderly LSS patients using Two-Step test.MethodsClinical data of patients aged >65 years who planned to undergo surgery for LSS were prospectively collected at multiple institutions. Patients were assessed with the Two-Step test and Timed Up-and-Go Test prior to surgery; 357 consecutive patients were enrolled. We determined the cut-off value of the Two-Step test score for short stride, referring to the Timed Up-and-Go Test score of 13.5 s, used to indicate high risk of falls in elderly individuals. Logistic regression model was constructed to identify factors associated with short stride.ResultsThe Two-Step test score showed moderate-to-strong inverse correlation with that of Timed Up-and-Go Test (r = ?0.65, p < 0.001). Using the tentative Two-Step test cut-off value (0.93) for short stride, multivariable analysis showed that age ≥80 years (OR = 2.3, 95% CI:1.1–4.8), a score of <60 for lumbar function in Japanese Orthopedic Association Back Pain Evaluation Questionnaire (OR = 2.7, 95% CI:1.5–4.7), motor deficit (OR = 2.7, 95% CI:1.2–6.1), and sagittal vertical axis ≥50 mm (OR = 2.1, 95% CI:1.2–3.5) were factors significantly associated with short stride in elderly patients with LSS.ConclusionsUsing the Two-Step test, we found that 80 years old and over, lumbar dysfunction, motor deficit of the lower extremities, and forward-bent posture were associated with short stride in LSS patients. Therefore, elderly LSS patients with these conditions may have a higher risk for falls.     

Development of a patient-oriented disease specific outcome measure of health-related quality of life (HRQOL) for musculoskeletal oncology patients

BackgroundAccording to improved functional outcome and life expectancy in orthopaedic oncology patients, there has been a growing interest in not only oncologic and functional outcomes but also health-related quality of life (HRQOL), including body image, mental status, or social activities, after surgery. However, there has been a lack of disease-specific measures focusing on the ability of orthopaedic oncology patients to evaluate their HRQOL comprehensively. Therefore, our aims in the present study were 1) to develop a patient-oriented disease-specific outcome measure of HRQOL for musculoskeletal oncology patients (COMMON-LE), and 2) to examine the practical applicability, reliability and validity of the COMMON-LE for patients with musculoskeletal tumors in the lower extremity.MethodsThe COMMON-LE was developed by expert committee of orthopaedic oncology and rehabilitation. A total of 101 patients were surveyed using the COMMON-LE, as well as the TESS, the MSTS score, and the SF-36, to assess their psychometric characteristics, including reliability, validity, and responsiveness.ResultsThe COMMON-LE showed no marked floor and ceiling effects. Test-retest reliability and internal consistency determined using the intraclass correlation coefficient (0.928) and Cronbach's alpha (0.948–0.968), respectively, were excellent. Each domain of the COMMON-LE (pain, ADL, socioemotional condition and general health) was well correlated with the scores of the standard measures (SF-36, TESS, MSTS score). Factor analysis and the AIC network showed the questionnaire items of the COMMON-LE were clearly separable into three clusters according to their content, corresponding to each domain of the questionnaire.ConclusionsWe have successfully developed and validated a disease-specific measure, the COMMON-LE, to evaluate not only physical function, but also various aspects of HRQOL in patients with musculoskeletal tumors. The COMMON-LE has sufficient reliability and internal consistency, and good validity, and appears to be practically applicable to this group of patients.     

Outcome of hypovascular hepatic nodules with positive uptake of gadoxetic acid in patients with cirrhosis

Objectives

To evaluate the longitudinal risk to patients with cirrhosis of hypervascular hepatocellular carcinoma (HCC) developing from hypovascular hepatic nodules that show positive uptake of gadoxetic acid (hyperintensity) on hepatocyte phase images.

Methods

In 69 patients, we evaluated findings from serial follow-up examinations of 633 hepatic nodules that appeared hypovascular and hyperintense on initial gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) until the nodules demonstrated hypervascularity and were diagnosed as hypervascular HCC. Cox analyses were performed to identify risk factors for the development of hypervascular HCCs from the nodules.

Results

The median follow-up was 663 days (range, 110 to 1215 days). Hypervascular HCCs developed in six of the 633 nodules (0.9 %) in five of the 69 patients. The only independent risk factor, the nodule’s initial maximum diameter of 10 mm or larger, demonstrated a hazard ratio of 1.25. The one-year risk of hypervascular HCC developing from a nodule was 0.44 %. The risk was significantly higher for nodules of larger diameter (1.31 %) than those smaller than 10 mm (0.10 %, p?<?0.01).

Conclusions

Hypervascular HCC rarely develops from hypovascular, hyperintense hepatic nodules. We observed low risk even for nodules of 10 mm and larger diameter at initial examination.

Key Points

? Hypervascularization was rare on follow-up examination of hypovascular, hyperintense nodules ? The risk of hypervascularization in a nodule increased with large size ? Hypovascular, hyperintense nodules require neither treatment nor more intense follow-up

     

Evaluation of beam modeling for small fields using a flattening filter-free beam

The characteristics of a flattening filter-free (FFF) beam are different from those of a beam with a flattening filter. For small-field dosimetry, the beam data needed by the radiation treatment planning system (RTPS) includes the percent depth dose (PDD), off-center ratio (OCR), and output factor (OPF) for field sizes down to 3 × 3 cm² to calculate the beam model. The purpose of this study was to evaluate the accuracy of calculations for the FFF beam by the Eclipse^? treatment planning system for field sizes smaller than 3 × 3 cm² (2 × 2 and 1 × 1 cm²). We used 6X and 10X FFF beams by the Varian TrueBeam^? to produce. The AAA and AXB algorithms of the Eclipse were used to compare the Monte Carlo (MC) calculation and the measurements from three dosimeters, a diode detector, a PinPoint dosimeter, and EBT3 film. The PDD curves and the penumbra width in the OCR calculated by the Eclipse, measured data, and those from the MC calculations were in good agreement to within ±2.8 % and ±0.6 mm, respectively. However, the difference in the OPF values between AAA and AXB for a field size of 1 × 1 cm² was 5.3 % for the 6X FFF beam and 7.6 % for the 10X FFF beam. Therefore, we have to confirm the small field data that is included for the RTPS commission procedures.     

Diagnosis and treatment of eosinophilic esophagitis in clinical practice

Eosinophilic esophagitis (EoE) is a chronic and abnormal Th2 type immunological response characterized by intense eosinophilic inflammation localized within the esophagus. This leads to esophageal dysfunction and remodeling accompanied by subepithelial fibrosis. Recently, EoE has been recognized as one of the major causes of dysphagia or food impaction in adults. The prevalence of EoE has been increasing over the past several decades, particularly in Western countries. EoE should be differentiated from secondary esophageal eosinophilia (EE) in gastroesophageal reflux disease (GERD) and eosinophilic gastroenteritis, involving the entire gastrointestinal tract. EoE is an uncommon condition in Asia compared with Western countries. With the growing interest and awareness of this condition during the past decade, reports of this disease are increasingly emerging in Asian countries including Japan. Typical EoE does not respond to proton pump inhibitor (PPI) therapy according to the current Western diagnostic guidelines. However, some cases of EE exhibit symptomatic relief and histological improvement in response to PPI [i.e., PPI-responsive esophageal eosinophilia (PPI-REE)]. The understanding of the clinical manifestations and unique endoscopic images of EoE, differences and similarities between GERD, PPI-REE, and EoE will all serve as the differential diagnosis. Further knowledge of the indications and efficacy of PPI therapy and topical steroid therapy will also aid in the management of these diseases. In this article, we will review the current diagnosis and treatment of EoE in clinical practice.     

Mesenchymal chondrosarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study on 57 patients

Background

This study aimed to elucidate the clinical features and prognostic factors of mesenchymal chondrosarcoma (MCS) and investigate optimal treatment strategies.

Methods

Data from 57 patients with MCS were collected from a Japanese Musculoskeletal Oncology Group (JMOG) and retrospectively analyzed.

Results

Data from 29 males and 28 females were collected. Primary tumor sites were the head and neck (7 patients), trunk (35 patients), and extremities (15 patients). The tumors originating in the trunk were significantly associated with a worse OS compared with those originating at the other sites in all patients and those with localized disease (P = 0.020 and P = 0.019, respectively). In patients with localized disease, the tumors originating in the head and neck were significantly associated with better OS and MFS compared with those originating in the trunk (P = 0.024 and P = 0.014, respectively). Positive surgical margin was significantly correlated with the worse LRFS (P = 0.018). Adjuvant chemotherapy exhibited a clear trend toward improved OS when MCS was localized in the trunk or extremities (P = 0.057).

Conclusions

Adequate surgery is considered to be the mainstay of treatment for localized MCS. Prognosis was different depending on the site of tumor origin.