Early administration of amatuximab,a chimeric high-affinity anti-mesothelin monoclonal antibody,suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model

Investigational New Drugs - Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the...     

Differential diagnosis of thymic epithelial neoplasms on computed tomography using the diameter of the thymic vein

Although differentiating benign and malignant thymic epithelial lesions is important to avoid unnecessary treatment and predict prognosis, it is challenging because of overlaps in the chest computed tomography (CT) findings. In this study, we investigated whether the diameter of the thymic vein and other CT findings could differentiate between benign (thymoma and thymic cysts) and malignant (thymic carcinoma, [TCa]) lesions.We conducted a retrospective study across two tertiary referral hospitals in Japan between November 2009 and June 2018. We included 12 patients with TCa, 34 patients with thymomas, and 17 patients with thymic cysts. We analyzed the receiver operating characteristic (ROC) curve to determine the best cut-off values and performed univariate and multivariate analyses of CT findings to distinguish TCa from other benign lesions. Post-hoc analysis was performed for the maximum short axis of the thymic vein using the Mann–Whitney U test, and the number of the maximum short axis of the thymic vein ≥ the cutoff was determined using the Fisher exact test with a family-wise error-correction using Bonferroni''s method.ROC analysis showed that a maximum short axis of the thymic vein ≥2 mm was considerably more frequent in TCa than in the other lesions (P < .001 for both), with 83% sensitivity and 86% specificity. Univariate and multivariate analyses revealed the association with TCa of the number of the maximum short axis of the thymic vein ≥2 mm (P = .005, multivariate generalized linear model analysis), ill-defined margin (P = .001), and mediastinal lymphadenopathy (P < .001). Thymic vein diameter was in descendimg order of TCa > thymoma > thymic cysts with statistically significant differences between the groups (Ps < .05).Thymic vein diameter was significantly longer in TCa than in thymoma and thymic cysts. Measurement of the maximum short axis of the thymic vein could be a powerful diagnostic tool to differentiate TCa from thymoma and thymic cysts.     

Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor, in rats

As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine oxidoreductase inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume. As a result, the dosing interval of citrate was found to be optimal at 4 hours, but not at 3 or 5 hours, because this treatment completely inhibited intrarenal xanthine deposition. The dose of citrate for the second treatment and the dosing volume were found to be sufficient at 1,500 mg/kg and 10 mL/kg, respectively. Subsequently, a 4-week study by simultaneous treatment at 3 mg/kg of FYX-051 and citrate (2,000 mg/kg) + citrate (1,500 mg/kg), under the improved conditions, revealed that renal lesions could be drastically inhibited. Thus, the present study demonstrated that the interval of two citrate treatments is pivotal and indicated that the improved model would be useful for the mechanistic study of FYX-051-induced urinary bladder carcinogenesis because of an easier treatment method than our previous model.     

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients.     

Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2

Purpose

To perform Preimplantation Genetic Diagnosis (PGD) on a paternal Brca2 unknown mutation carrier with early-onset breast cancer, whose paternal grandmother and mother had breast cancer at 60s.

Method

Elucidating the linkage via single sperm haplotyping on patient''s carrier brother, and identifying the genomic deletion via BLAST followed by PCR screening. PGD was subsequently conducted.

Result

The mutant allele was found by using 4 microsatellite and 2 intragenic SNP markers. Recombination was detected in 8 % of sperms. BLAST was utilized to locate putative hairpin structure(s), followed by PCR screening with seven sets of primers. A novel 2,596 bp deletion containing exon 15 ~ 16 was identified. Due to the severity of phenotype and the integrity of exon 11 encoding RAD51 binding domain, and the fact that the patient''s mother also had breast cancer at her 60s, we speculate a possible coexistence of maternal breast cancer risk allele(s). Embryo biopsy was performed on day 3. Unaffected morula and blastocyst were replaced on day 5, resulting in a singleton livebirth. A breast lump appeared in the patient after delivery without the presence of malignant cells.

Conclusion

Concerning the assisted reproductive option for breast cancer patients, the possibility of coexistence of multiple familial risk alleles and the significance of each mutation to the phenotype should be evaluated. To eliminate misdiagnosis resulting from recombination and/or allelic drop-out, both direct mutation detection and linkage analysis approaches may be necessary. BLAST is a very useful and cost-effective tool for identifying large genomic deletion.     

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

ABSTRACT: INTRODUCTION: This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account. METHOD: This was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded. RESULTS: At the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions. CONCLUSIONS: A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.     

010 中年男性广泛性缺血性心脏病的自然病程

从英国24家综合医疗机构随机抽取年龄为40～59岁的7 735例病人(均为男性),依据调查表和心电图结果分为以下7个病组：Ⅰ组：已确诊的心肌梗死病人;Ⅱ组：隐匿性心肌梗死病人;Ⅲ组：已确诊的心绞痛病人;Ⅳ组：有心绞痛症侯群的病人;V组：有可疑心肌梗死症侯群的病人;Ⅵ组：心电图示心肌缺血或可能心肌梗死的病人,Ⅶ组：无缺血性心脏病(IHD)证据的病人。对以上各组病人进行15年随访,将这期间调查对象发生的一系列致命及非致命的并发症分别与相应病组加以联系评估。