Objective Neuroendocrine neoplasms (NENs) are rare and indolent diseases, but the efficacy of treatment without surgical resection is temporary and limited. Targeted immunotherapy is an important ...treatment strategy in several cancers. However, the tumor and host immune reactions in the NEN microenvironment are poorly understood. Therefore, we investigated the immune checkpoint system and host immune response in pathological NEN specimens. Methods The expression of the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1 was immunohistochemically detected in archival tissue samples obtained from 20 patients with gastroenteropancreatic NENs. We additionally assessed the expression of programmed death (PD)-1, PD-L1, and the tumor-infiltrating lymphocyte (TIL) markers CD8 and family of transcription factor P3 (FOXP3). Results All 20 NENs expressed the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1. The PD-L1 and/or PD-1 expression in the tumor cells and/or TILs was confirmed in 75% of the cases. PD-1-, CD8-, and FOXP3-positive TILs were more frequently associated with PD-L1-positive tumors than with PD-L1 negative tumors (PD-1: 19.5 vs. 7.3, CD8: 18.1 vs. 7.1, FOXP3: 13.2 vs. 3.2, p=0.438, p=0.419, P=0.603, respectively). The number of cells positive for PD-1 tended to gradually increase in increasing grade of NENs but did not reach significance (Grade 1: 5.8, Grade 2: 10.2, NEC: 18.1, p=0.903). Conclusion NENs consistently express mismatch repair proteins but have a high expression of PD-L1 and/or PD-1 in the tumor microenvironment. NEC and PD-L1-positive NENs may be immunologically "hot" tumors, so an immunological approach may be an appropriate treatment strategy for these tumors.
Although the moderate thermal stimulation of articular cartilage exerts chondroprotective effects, it is difficult to effectively heat deep articular cartilage with conventional methods. ...Photosensitizers increase the ambient temperature using near-infrared (NIR) radiation, which has high tissue permeability. We hypothesized that the intra-articular administration of photosensitizers and NIR irradiation would exert a greater heating effect on articular cartilage. We aimed to evaluate the heating effect of this method on cultured chondrocytes and rat knee cartilage. In vitro, we irradiated a photosensitizer-containing medium with NIR and measured changes in the medium temperature, cytotoxicity, and gene expression of heat shock protein (HSP) 70 and aggrecan (ACAN). In vivo, the knee joints of rats treated with photosensitizers were irradiated with NIR, and changes in intra-articular temperature and gene expression were measured, alongside histological analysis. The results showed that the medium and intra-articular temperature were raised to approximately 40 °C with no apparent disruption to articular cartilage or the immunohistochemically enhanced staining of HSP70 in chondrocytes. The gene expression of HSP70 and ACAN was increased in both cultured and articular cartilage. In summary, this method can safely heat joints and enhance cartilage metabolism by inducing HSP70 expression in articular cartilage. It presents a new hyperthermia therapy with effective cartilage protection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the rehabilitation ward, many elderly patients require continuous use of medication after a stroke or bone fracture, even after discharge. They are encouraged to self-manage their medications from ...the time of admission. Medication errors, such as a missed dose or incorrect administered medication can worsen conditions, resulting in recurrent strokes, fractures, or adverse effects. The study was aimed to identify risk factors, such as medication and prescription, contributing to errors in self-management of medication.
This study was conducted on patients who self-managed their medication in the rehabilitation ward of Higashinagoya National Hospital from April 2018 to March 2020. The patient background including age and sex were investigated. The medication factors examined include the number of medications and administrations per day, dosing frequency on indicated days, prescription and start date are the same, medications from multiple prescriptions, and one package or one tablet at each dosage. The group of medication error cases were defined as the medication error group and that of control cases as the no-medication error group. A logistic regression analysis was performed for factors related to medication errors.
A total of 348 patients were included in the study, of which 154 patients made medication errors, with 374 total medication error cases. The median number of medications in the medication error group was six, and that in the no-medication error group was five. Statistically significant factors correlated with errors made during self-management of medication were the number of medications, number of administrations per day, dosing frequency on indicated days, and medication from multiple prescriptions.
When a patient is self-managing their medications, errors are likely to occur due to a high number of medicines they are taking and the complexity of the dosage regimen. Therefore, to prevent medication errors, reviewing the prescribed medications and devise ways to simplify the dosage regimens is crucial.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship ...between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment.
ClinicalTrials.gov identifier: NCT00680953.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is an innovative treatment for advanced somatostatin‐positive neuroendocrine tumors (NETs). PRRT cannot ...be performed in Japan because there is no approval or insurance cover so far.
Methods
We relied on foreign institutions to perform PRRT for Japanese patients with NETs. We retrospectively evaluated the safety and efficacy of PRRT. The inclusion criteria were pathologically confirmed well‐differentiated NET and visible tumor uptake on pre‐therapeutic somatostatin receptor scintigraphy. 177Lu‐DOTA‐TOC was used as the standard treatment, and patients received three infusions every 8 weeks. Until the end of 2017, combination treatment with 90Y and 177Lu‐DOTA‐TOC was performed using the same protocol.
Results
Thirty‐five patients were evaluated, and the primary lesions were pancreas, rectum, small intestine, stomach, and other locations. The partial response rate was 42.9%. Progression‐free survival (PFS) was 12.8 months and overall survival was 42.8 months. There was no significant difference in PFS between front‐line and late‐line PRRT (11.0 months vs 28.0 months; P = .383). Severe adverse events included lymphocytopenia (20.0%) and thrombocytopenia (5.7%). Myelodysplastic syndrome occurred in one case.
Conclusion
PRRT was effective and safe for Japanese patients with advanced NETs. PRRT was equally effective as front‐line and late‐line treatment.
Highlight
Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is an innovative treatment for advanced somatostatin‐positive neuroendocrine tumors. This retrospective study by Kobayashi and colleagues, which constitutes the first report of peptide receptor radionuclide therapy for Japanese patients with advanced neuroendocrine tumors, demonstrated good efficacy and safety in the Japanese patient cohort.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction: When compared to transforaminal lumbar interbody fusion (TLIF) with a single boomerang cage (DB technique) enhances intervertebral stability. TLIF for lumbar degenerative disease can ...achieve clinical results comparable to PLIF; however, there are no reports of the superiority of TLIF over PLIF in terms of radiological results, and corrective loss in TLIF is an issue.Objective: To clarify the intervertebral stability of DB and posterior lumbar interbody fusion (PLIF), including cage subsidence and intervertebral bone fusion.Methods: The patients underwent DB (group D) or PLIF (group P) for lumbar degenerative disease. The primary outcome was the incidence of cage subsidence (>2 mm on computed tomography) 1 year postoperatively, and the secondary outcome was the incidence of intervertebral non-union. Logistic regression was used to calculate the risk ratio for cage subsidence.Results: Cage subsidence occurred more frequently in the P group, 15 (17%) cases in the D group, and 26 (41%) cases in the P group (P=0.002); the adjusted risk ratio for cage subsidence in the D group was 0.56 (95% CI: 0.33-0.97), halving the incidence of cage subsidence in the D group compared with the P group. The percentage of non-union between the vertebral bodies was 33 (38%) cases in group D and 29 (45%) in group (P=0.4).Conclusions: The DB technique may improve intervertebral stability with less cage subsidence than PLIF.
Purpose
Peptide receptor radionuclide therapy (PRRT) with
177
Lu-DOTA
0
-Tyr
3
-octreotate (
177
Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine ...tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.
Methods
Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of
177
Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.
Results
Six Japanese patients (three men and three women; mean age 61.5 years; range 50–70 years) with SRS-positive unresectable NETs were recruited.
177
Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%–69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of
177
Lu-DOTATATE was 16.8 Gy (range 12.0–21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2–21.5 Gy). Administration of
177
Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.
Conclusion
PRRT with
177
Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy,
177
Lu-DOTA
0
-Tyr
3
-octreotate .
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and ...articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Peptide receptor activation therapy (PRRT) is a promising treatment option for metastatic neuroendocrine tumors (NETs). However, predicting tumor shrinkage before treatment is challenging. We ...analyzed the shrinkage rate of each metastatic tumor lesion to identify predictive factors related to shrinkage. Patients with metastatic NET who underwent PRRT were included in this retrospective study. For each patient, between one to five metastatic lesions were selected in descending order of size, and the change in the maximum tumor diameter after treatment was defined as the shrinkage rate per lesion (L-SR). We analyzed the relationship between pretreatment clinicopathological factors and L-SR. The median L-SR of all 75 lesions in 20 patients was 20% (95% CI: 4.8−26.1%). While previous treatment with cytotoxic agents (34.4%, p < 0.05) and primary tumor of the pancreas (27.8%, p < 0.05) were significantly favorable factors, a primary tumor of the rectum was significantly more resistant to shrinkage (−20.5%, p < 0.001). Therefore, lesion-based analysis of PRRT for NETs showed that pancreatic NET and previous treatment with cytotoxic agents were favorable factors for tumor shrinkage; however, rectal NET was a factor associated with resistance to shrinkage.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
In Kyoto Prefecture, Japan, the number of hip fractures increased during 2013–2017 compared to 2008–2012. However, the estimated overall incidence rate increased only in femoral neck ...fractures in men aged ≥75 and women aged ≥85.
Purpose
The incidence rate of hip fractures in Japan has plateaued or decreased. We investigated the annual hip fracture occurrences in Kyoto Prefecture, Japan, from 2008 to 2017.
Methods
Patients aged 65 years and above who sustained hip fractures between 2008 and 2017 and were treated at one of the participating 11 hospitals were included. The total number of beds in these institutions was 3701, accounting for 21.5% of the 17,242 acute-care beds in Kyoto Prefecture. The change in incidence rate was estimated utilizing the population according to the national census conducted in 2010 and 2015.
Results
The total number of hip fractures was 10,060, with 47.5% femoral neck fractures and 52.5% trochanteric fractures. A decrease in number was seen only in trochanteric fractures in the group of 75- to 84-year-old women. The population-adjusted numbers of femoral neck fractures showed a significant increase in all age groups in men, whereas in women, there was an increase in femoral neck fractures in the ≥85 group and trochanteric fractures in the age group 65–74, and a decrease in trochanteric fractures in the age group 75–84. The estimated change in incidence rate showed an increase in femoral neck fractures in men aged ≥75 and women aged ≥85.
Conclusion
In Kyoto Prefecture, the number of hip fractures increased in the second half of the study period (2013–2017) compared to the first half (2008–2012). However, the incidence rate had not increased, except in femoral neck fractures in men aged ≥75 and women aged ≥85.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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