Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.     

Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.Subject terms: Acute myeloid leukaemia, Cancer immunotherapy     

Morvan Syndrome Converted from Isaacs' Syndrome after Thymectomy with Positivity for Both Anti-LGI1 and Anti-CASPR2 Antibodies

Anti-voltage-gated potassium channel complex antibodies-mediated disorder includes Isaacs'' syndrome, which is characterized by neuromyotonia, and Morvan syndrome, which is characterized by neuromyotonia, encephalopathy and autonomic dysfunction. We herein report a patient with Morvan syndrome that converted from Isaacs'' syndrome after thymectomy. The patient first presented with myospasm in all extremities and positivity for both anti-leucine-rich glioma inactivated 1 (LGI1) and anti-contactin-associated protein like 2 (CASPR2) antibodies and subsequently developed encephalopathy after thymectomy, which was successfully improved by immunotherapy. This is the first case of Morvan syndrome wherein thymectomy worsened Isaacs'' syndrome, suggesting that immunotherapy should be considered for Isaacs'' syndrome accompanied by positivity for both anti-LGI1 and anti-CASPR2 antibodies to prevent worsening to Morvan syndrome.     

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

Aims: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. Methods: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using¹⁸fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day,n=16) for 12weeks.¹⁸F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%).¹⁸F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of¹⁸F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.     

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi‐institutional study

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease‐specific survival (DSS) and disease‐free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5‐year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5‐year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high‐grade chondrosarcoma, particularly for those with DDCS.     

Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index

Aims/IntroductionMany East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in ''super‐aged'' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups.Materials and MethodsData were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m²). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed.ResultsIn this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups.ConclusionsIn this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile.     

Late recurrence after resection of mass-forming intrahepatic cholangiocarcinoma: report of a case

The outcome after surgical resection for intrahepatic cholangiocarcinoma has not been satisfactorily evaluated due to its malignant behavior. Surgical resection, however, has the potential to improve the prognosis and may allow surgeons to experience rare cases with long survival. This report presents the case of a patient who developed recurrence 9?years after resection of intrahepatic cholangiocarcinoma. A 76-year-old female was diagnosed to have intrahepatic cholangiocarcinoma and underwent an extended right posterior subsegmentectomy. The gross appearance showed a mass-forming type tumor. The histopathological examination revealed well to moderately differentiated adenocarcinoma associated with portal vein invasion. Subcutaneous metastasis in the head as the first sign of relapse was diagnosed 9?years after hepatectomy. The histopathological findings of the subcutaneous tumor were similar to those of the intrahepatic cholangiocarcinoma, thus suggesting metastasis from intrahepatic cholangiocarcinoma. Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose was useful for detecting multiple metastases. Long-term follow-up for more than 5?years is recommended because the present case shows that late recurrence of intrahepatic cholangiocarcinoma occurs even 5?years after resection.     

15-Deoxy-Delta12,14-prostaglandin J2 inhibits IL-1beta-induced cyclooxygenase-2 expression in mesangial cells

BACKGROUND: Cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins, is induced in mesangial cells in response to proinflammatory cytokines. Recently, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), one of the natural ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), has been reported to have an anti-inflammatory effect. Therefore, we examined the effect of 15d-PGJ2 on COX-2 expression in cultured rat mesangial cells.METHODS: Mesangial cells were incubated with 15d-PGJ2 for 30 minutes and then exposed to interleukin-1beta (IL-1beta). The expression of COX-2 mRNA and proteins was determined by Northern blot and immunoblot analyses, respectively. Accumulation of prostaglandin E2 (PGE2) was measured by an enzyme-linked immunosorbent assay (ELISA). Activities of mitogen-activated protein kinases (MAPKs) were evaluated by an immunoblot analysis. DNA binding activities of activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) were examined by an electrophoretic mobility shift assay (EMSA). The activities of PPAR responsive elements (PPRE) and COX-2 promoter were measured by a luciferase reporter assay.RESULTS: 15D-PGJ2 significantly suppressed IL-1beta-induced COX-2 expression and PGE2 production, but thiazolidinediones, synthetic PPARgamma ligands, did not affect COX-2 expression. Moreover, the cells transfected with a PPRE luciferase reporter did not respond to 15d-PGJ2. IL-1beta rapidly activated extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), which were involved in the up-regulation of COX-2 induction, but 15d-PGJ2 inhibited the activation of these kinases. 15d-PGJ2 inhibited the IL-1beta-induced increase in binding activities of nuclear proteins to consensus AP-1 site and AP-1-like site of COX-2 promoter but not of NF-kappaB. IL-1beta was unable to activate the COX-2 promoter when the AP-1-like site was mutated.CONCLUSIONS: These data suggest that 15d-PGJ2 inhibits IL-1beta-induced COX-2 expression, independent of PPARgamma activation, by suppression of ERK and JNK pathways and AP-1 activation in mesangial cells. Thus, 15d-PGJ2 may play an important role in the negative feedback mechanism of COX-2 expression in renal inflammation and may be useful as an anti-inflammatory agent.     

Carpal tunnel syndrome grading system in rheumatoid arthritis

The grading system of Hashizume and Hirooka for carpal tunnel syndrome (CTS) was modified to refine the system for surgical treatment selection for specific subsets of CTS in patients with rheumatoid arthritis (RA). The grading system uses clinical signs and symptoms of CTS, including pain indications, to identify surgical subsets of patients to facilitate treatment selection. Retrospective analysis of the system included radiographic and electromyographic findings. Twenty-nine hands of 21 adult patients with CTS in RA were graded in the current study. Eight hands with mild synovitis received conservative treatment only. Endoscopic carpal tunnel release (ECTR), using Okutsu's universal subcutaneous endoscopic system with a clear cannula, was performed in 11 hands with moderate synovitis. Open carpal tunnel release (OCTR) combined with flexor tenosynovectomy was performed in 9 hands with severe synovitis. One more hand required OCTR after ECTR when malignant RA was diagnosed. Clinical results, evaluated using Kelly's criteria, were: excellent in 19 hands, good in 5, fair in 4, and poor in the 1 patient with malignant RA. Clinical symptoms of CTS improved in all but the latter patient. Although the sample size in the current study is small, the results appear to warrant further study to determine the clinical utility of the grading system. Received: April 2, 2001 / Accepted: November 1, 2001