Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer.

BACKGROUND: We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC). PATIENTS AND METHODS: Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression. RESULTS: Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status. CONCLUSIONS: CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.

Third Dentition Is the Main Cause of Premolar Supernumerary Tooth Formation.

While the prevalence of supernumerary teeth (ST) is high in permanent dentition, the etiology of ST in humans remains unclear. However, multiple murine models of ST have elaborated on dated mechanisms traditionally ascribed to ST etiology: one involves the rescue of rudimental teeth, and the second considers the contribution of odontogenic epithelial stem cells. It remains unclear whether these mechanisms of ST formation in mice are applicable to humans. The third dentition is usually regressed apoptotic-that is, the teeth do not completely form in humans. Recently, it was suggested that ST result from the rescue of regression of the third dentition in humans. The present investigation evaluates the proportion of collected general ST cases that evinced a third dentition based on the clinical definition of ST derived from the third dentition. We also investigated the contribution of SOX2-positive odontogenic epithelial stem cells to ST formation in humans. We collected 215 general ST cases from 15,008 patients. We confirmed that the general characteristics of the collected ST cases were similar to the results from previous reports. Of the 215 cases, we narrowed our analysis to the 78 patients who had received a computed tomography scan. The frequency of ST considered to have been derived from the third dentition was 26 out of 78 cases. Evidence of a third dentition was especially apparent in the premolar region, was more common in men, and was more likely among patients with ≥3 ST. SOX2-positive odontogenic epithelial stem cells within the surrounding epithelial cells of developing ST were observed in non-third dentition cases and not in third dentition cases. In conclusion, the third dentition is the main cause of ST in humans. The odontogenic epithelial stem cells may contribute to ST formation in cases not caused by a third dentition.

Diffuse Liver Metastasis of Small-Cell Lung Cancer Presenting as Acute Liver Failure and Diagnosed by Transjugular Liver Biopsy: A Rare Case in Whom Nodular Lesions Were Detected by Enhanced CT Examination.

Small-cell lung cancer (SCLC) is a subgroup of lung cancer with a high frequency of liver metastasis, which is a predictor of poor prognosis. Diffuse liver metastases of SCLC with no visible nodular lesions in the liver when examined using computed tomography (CT) are relatively rare; however, a few cases with rapid progression to acute liver failure that were diagnosed after death have been reported. In this paper, we report a 63-year-old man with diffuse liver metastases of SCLC that were histologically diagnosed using a transjugular liver biopsy while the patient was alive, even though no lesions were visible during a contrast-enhanced CT examination.

Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor.

BACKGROUND AND PURPOSE: Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration. EXPERIMENTAL APPROACH: Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine. KEY RESULTS: CAPE protected dopaminergic neurons in slice cultures from IFN-γ/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice. CONCLUSION AND IMPLICATIONS: CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.

Follow-up of a self-resolving renal pseudoaneurysm using contrast-enhanced power Doppler ultrasonography.

It has been standard practice to embolise a pseudoaneurysm caused by penetrating trauma whenever it is found, even in the absence of overt symptoms. This is a case report of a renal pseudoaneurysm (RPA) caused by a stab wound, which was safely monitored and followed using colour Doppler ultrasonography. On day 1, angiography showed a pseudoaneurysm of the renal artery in the parenchyma and ultrasonography showed blood flow into the pseudoaneurysm. Although abnormal blood flow into the kidney was seen, there appeared to be no leakage of blood from the pseudoaneurysm. The abnormal flow disappeared on day 12 and the area of the pseudoaneurysm became unclear from day 13. This report suggests the possibility that RPA caused by a stab wound could be an indication for conservative therapy under the following conditions: the RPA is detected initially; close monitoring using a colour Doppler ultrasound is possible; there is no leakage of blood from the right subclavian artery and there is a 2-week period of observation.

The role of edaravone on the impairment of endothelial barrier function induced by acute oxidative stress in cultured human umbilical vein endothelial cell monolayer.

BACKGROUND: The aim was to determine the effects of a novel free radical scavenger, edaravone, 3-methyl-1-phenyl-2-pyrazoline-5-one (ED), against endothelial barrier dysfunction induced by acute oxidative stress in cultured human umbilical vein endothelial cells (HUVECs). METHODS: To estimate the integrity of the HUVEC monolayer, transendothelial electrical resistance (TEER) was measured for 3 hours. We investigated the permeability change of the monolayer by measuring the concentration of fluorescence in isothiocyanate-labeled dextran (FITC-Dx), and estimated the degree of oxidative stress in terms of hydrogen peroxide (H2O2) in the apical chambers. RESULTS: The TEER changes in both xanthine oxidase (XO)+xanthine (X) and X/XO+ED group were significantly lower than the control group (p < 0.001). The amount of 4 FITC-Dx in the XO+X group was significantly higher than the control group at 3 hours (p < 0.001). In the XO+X group, the concentration of H2O2 was significantly higher than control and the X/XO+ED group (p < 0.001 each). Thus, edaravone improved the disturbed endothelial barrier function induced by acute oxidative stress. CONCLUSIONS: The permeability increase induced by acute oxidative stress was prevented by free radical scavenger edaravone significantly in vitro. This radical scavenger may have clinical applications to protect against endothelial barrier dysfunction.

IFN-alpha enhances TNF-alpha-induced apoptosis through down-regulation of c-Myc protein expression in HL-60 cells.

We examined the effect of interferon-alpha (IFN-alpha) in combination with tumor necrosis factor-a (TNF-alpha) on growth, differentiation and apoptosis in HL-60 human myeloid leukemia cells. IFN-alpha inhibited cell growth and induced apoptosis, but not differentiation, in HL-60 cells. IFN-alpha enhanced TNF-alpha-induced apoptosis. We also investigated the expression of c-Myc and Bcl-2 oncoproteins, which are implicated in the survival or death of a cell. The levels of c-Myc protein expression were not changed by IFN-alpha alone at 24hrs of treatment, but were down-regulated at 72 hrs, accompanied by the appearance of apoptotic cells. While, IFN-alpha did not affect the level of Bcl-2 protein expression during this cultivation time. Interestingly, a combination treatment of IFN-alpha with TNF-alpha showed a greater decrease of c-Myc expression than TNF-a alone at 24hrs. Whereas, IFN-alpha did not significantly modulate Bcl-2 expression levels which were down-regulated by TNF-alpha. Therefore, the enhancement of TNF-alpha-induced apoptosis by IFN-a might be closely associated with the greater down-regulation of c-Myc protein, rather than Bcl-2. In contrast, with rapid down-regulation of c-Myc expression caused by TNF-alpha, IFN-alpha down-regulated c-Myc rather late (at 72 hrs), suggesting that both cytokines have a distinct pathway regulating c-Myc protein expression. However, the enhancement of apoptosis in the combination treatment would suggest the presence of a common signaling pathway for induction of apoptosis at down-stream of c-Myc.

Efficacy of endoscopic hemoclipping for GI bleeding in relation to severity of shock.

BACKGROUND/AIMS: To examine the efficacy of prospectively performing endoscopic hemoclipping in patients with severe gastrointestinal bleeding by assessing in relation to the severity of the case. METHODOLOGY: Endoscopic hemoclipping was performed in 44 patients in shock caused by severe gastrointestinal bleeding. The level of severity was categorized using two factors. One factor was the presence or absence of severe shock, and the other was the presence or absence of active bleeding at endoscopy. Age, blood transfusion volume, APACHE III score, coagulopathy, initial hemostatic, rebleeding and mortality rate were recorded in relation to those four subsets. If rebleeding occurred, the systolic blood pressure, heart rate and serum hemoglobin concentration were compared between the initial time of bleeding and rebleeding. RESULTS: Initial hemostasis was successfully achieved in all cases. The severe shock group required significantly more blood transfusions. The most severe subset had the highest APACHE III score, and coagulopathy. Rebleeding occurred in seven cases in the severe shock group only. In the rebleeding group, the systolic body pressure was lower, heart rate was higher, and serum hemoglobin concentration was lower than the non-rebleeding group. Four patients, all in subset 1, died, but no patient died due to gastrointestinal bleeding. CONCLUSIONS: The endoscopic hemoclipping method is very effective for severe gastrointestinal bleeding in shock. The severity of shock was a more important risk factor than the presence of active bleeding. Our category of severity is simple, it reflects the patients' clinical condition accurately, and is very useful for patients with gastrointestinal bleeding.

Analysis of cartilage-derived retinoic-acid-sensitive protein (CD-RAP) in synovial fluid from patients with osteoarthritis and rheumatoid arthritis.

We have measured the concentration of cartilage-derived retinoic-acid-sensitive protein (CD-RAP) in synovial fluid (SF) from the knees of 49 patients with osteoarthritis (OA) and 79 with rheumatoid arthritis (RA) in order to investigate the correlation between the type of joint disease and level of CD-RAP. The mean concentration of CD-RAP in synovial fluid was significantly higher in OA than in RA. The level of CD-RAP in the group of patients with mild OA was significantly higher than in the moderate or severe groups and that in the group with mild RA was also significantly higher than in the other RA groups and decreased with progression of the disease. Immunohistochemical studies showed expression of CD-RAP in the cytoplasm of chondrocytes in newly-formed fibrocartilage. Since CD-RAP is mainly produced in young and proliferating chondrocytes, our results suggest that the level of CD-RAP in synovial fluid reflects remodelling of articular cartilage and may be used as a marker to estimate objectively the restorative reaction of chondrocytes.

[Collective health: a challenge for nursing]. / Saúde Coletiva: um desafio para a enfermagem.

This study takes public health as the point of departure to discuss both the concept of collective health and its object and field of action, emphasizing the concepts of man, collective and individual spheres, and health-disease, through a discussion of the interdisciplinary construction of the collective health field. The authors then place nursing within this field, emphasizing what appears to be the greatest challenge, i.e., to approach nursing as a practice of relationships.

[International health: various current concepts]. / Saúde internacional: alguns aspectos conceituais contemporâneos.

This study is a theoretical approach on international health with the purpose to point out some aspects which can enhance the understanding of the International Health field and its operational and conceptual elements in the socio-economic process of integration of neighboring countries.

Spontaneous rupture of the pancreaticoduodenal artery possibly related to prior occlusion of the common hepatic artery: report of a case.

We report herein a case of spontaneous rupture of the pancreaticoduodenal artery (PDA) associated with obstruction of the common hepatic artery. A 68-year-old man was admitted to our hospital following the sudden onset of severe upper abdominal pain. Computed tomography revealed a large mass formation in the peritoneal cavity. Hemorrhagic shock rapidly developed during the initial evaluation, necessitating an exploratory laparotomy to be performed in the emergency room. This revealed a large hematoma in the retroperitoneal space, and a ruptured PDA was sutured. Postoperative angiography showed obstruction of the common hepatic artery and also suggested that the source of the bleeding was the PDA. Thus, a diagnosis of spontaneous rupture of a PDA aneurysm associated with occlusion of the common hepatic artery was made. Following this case report, we discuss the development of true aneurysms of the PDA and the treatment of ruptured true PDA aneurysms resulting in shock.