Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Pleomorphic mastocytoma associated with loss of chromosome 5, PDGFRA,and HRAS mutations: A case of cutaneous mastocytosis with severe atypia and indolent behavior

A 21‐year‐old female presented with a 5‐year history of an erythematous papule on her right breast. The biopsy showed a dense, dermal nodular infiltrate, extending focally into the subcutaneous tissue. The infiltrate was composed predominantly of pleomorphic cells with bi‐lobed, multi‐lobed, horseshoe, or ring‐shaped nuclei. There was a smaller subset of monomorphous cells characterized by a round, reniform, or elongated single‐lobed nucleus. Accompanying cells included few foamy histiocytes, lymphocytes, and numerous scattered eosinophils. No necrosis, vascular invasion, or ulceration was present. The pleomorphic and monomorphic granular cells were positive for Giemsa stain as well as for tryptase, CD117, CD68, CD2, and CD30 immunohistochemistry and negative for S100, CD1a, myeloperoxidase, lysozyme, and CD56. Clinical examination was negative for any additional similar lesions and serum tryptase was within normal limits. The bone marrow was not biopsied. In addition, fluorescent in situ hybridization revealed multiple clones with loss of number 5 chromosome and PDGFRA and HRAS mutations. The lesion did not recur or progress after a 6‐year clinical follow‐up. To our full knowledge, we report the first case of pleomorphic mastocytoma with loss of chromosome 5 and PDGFRA and HRAS mutations.     

双膦酸盐防治骨质疏松性骨折的研究进展

骨质疏松症(osteoporosis,OP)是一种全身高发骨骼疾病,其特点主要为骨密度下降、骨矿物质削减,破坏骨组织微细结构布局,进而致使骨机械强度下降、脆性增高,容易导致病理性骨折。骨质疏松性骨折(osteiporotic fracture,OPF)又称脆性骨折,是OP最严重的并发症之一,多发于老年人,发生率较高,因OP的特征故而导致OPF多呈粉碎性,愈合慢。且因骨强度低和骨脆性高而容易引起内固定松动和再骨折发生,故而残疾率和死亡率相对较高。就目前的研究现状来说,双膦酸盐(bisphosphonates,BPs)类药物成为临床防治OPF最常用的一线药物,其治疗目标是防止进一步的骨质流失,以减少初始或后续骨折的风险,故该类药物的应用显著降低OPF的发生,脊柱骨折发生率降低了40%～70%,髋部骨折发生率降低了40%～50%。然而,考虑到BPs类药物的主要作用机制,基于抑制破骨细胞活性和随后抑制骨形成,人们担心它们是否会延迟或损害骨折愈合的能力,甚至引起新发骨折形成,即非典型性骨折,这是一种罕见的无创伤性或极小创伤性股骨骨折。所以这个问题不禁引起了人们的思考:长期使用BPs类药物预防继发性骨折的疗效是否掩盖了与使用BPs类药物相关的骨折愈合障碍风险,最终引发非典型性骨折的出现?本文就BPs类药物对OPF防治的研究进展作一综述,为后续BPs类药物研究和临床用药提供一定的依据。     

Gail Model Underestimates Breast Cancer Risk in Thai Population

Background: The Gail model is the most widely used method for breast cancer risk estimation. This model hasbeen studied and verified for its validity in many groups but there has yet to be a study to validate the Gail model in aThai population. This study aims to evaluate whether the Gail model can accurately calculate the risk of breast canceramong Thai women. Methods: The subjects were recruited from the Division of Head, Neck, and Breast Surgery,Department of Surgery, Siriraj Hospital. The patients attending the division were asked to enroll in the study andcomplete questionnaires. Gail model scores were then calculated. Relationships between parameters were examinedusing the Pearson’s chi-square test, Fisher’s exact test, and independent-samples t-test. Results: There were 514women recruited. Age, parity, age at first-live birth, and history of atypical ductal hyperplasia (ADH) were significantrisk factors for breast cancer. The 5-year and lifetime risk score for breast cancer calculated by the Gail model werenot significantly different between the patient and the control subjects. The proportions of the subjects with lifetimerisk ≥20% were significantly higher in breast cancer patients (p=0.049). Conclusion: The Gail model underestimatedthe risk of breast cancer in Thai women. Calibration of the model is still required before adoption in Thai population.     

Molecular characterization of two novel atypical porcine pestivirus (APPV) strains from piglets with congenital tremor in China

As one of emerging porcine viruses, atypical porcine pestivirus (APPV) was found in three continents since it emerged in 2015. It is now thought as the causative agent for congenital tremor type A‐II in piglets. At the end of 2017, two APPV strains were identified from piglets with congenital tremor in Guangxi and Yunnan, China. The genome of APPV GX04/2017 strain was so far determined to be 11,534 nucleotides (nt) in length and contains a single open reading frame (ORF) encoding a polyprotein comprising 3,635 amino acids. Comparative analysis of ORF, N^pro, E2, and NS3 gene sequences revealed that the APPV GX04/2017 strain shares nucleotide sequence identities of 82.8%–92.8% with other APPV strains, while YN01/2017 strain is 79.4%–97.4% homology to the others. Phylogenetic analysis showed that the APPV GX04/2017 and YN01/2017 are two novel APPV strains with the highest homology to each other, and relative high similarity to the APPV 000515 and JX‐JM01 strains in genome sequence. The current findings provide updated information about APPV epidemiology and divergence in China, which would certainly help to establish reliable diagnosis and surveillance programs for APPV.     

The co-expression characteristics of LAG3 and PD-1 on the T cells of patients with breast cancer reveal a new therapeutic strategy

Many studies have shown a special interaction between LAG3 and PD-1 in T cell inhibition, while the co-expression and effect of LAG3 and PD-1 on T cells in breast cancer patients are still not very clear. Here, with strict exclusion criteria, 88 patients with breast cancer and 18 healthy controls were enrolled. The percentages of LAG3⁺PD-1⁺ T cells in their peripheral blood (PBL) and tumor infiltrating T cells (TIL) were analyzed by flow cytometry, which showed an increase in TILs but no difference in PBLs and presented differences in TILs in different molecular subtypes (P < 0.05). In triple-negative breast cancer (TNBC), the highest percentages were observed, while in ER+/PR+ breast cancer, the lowest percentages were observed; however, these percentages were not different in different clinical stages (P > 0.05). Immunohistochemical staining showed that the expression of their ligands, PD-L1, MHC class II molecular and FGL1, was inconsistent in different molecular subtypes and clinical stages. Analysis of the functions of T cells with different phenotypes showed that the proliferation and secretion capacity of LAG3⁺PD-1⁺ T cells was obviously exhausted, with more than a two-fold of decrease compared with the groups of single positive LAG3 or PD-1 (P < 0.05). Finally, in a mouse model of TNBC, the dual blockade of LAG3 and PD-1 was indicated to achieve a better anti-tumour effect than either one alone (P < 0.05), which may provide a new strategy for the immunoregulatory treatment of patients with TNBC in the future.     

抗PD-(L)1、抗CTLA-4免疫治疗标志物研究进展

免疫检查点抑制剂已经改变了包括肺癌、黑色素瘤等许多肿瘤的治疗情况，并且在一些难治性肿瘤中表现出持久的应答率，然而在部分接受治疗的患者中表现出无反应及严重免疫相关副作用。为了优化免疫疗法的使用，可能需要多种临床应答的预测性标志物。本研究回顾了几种潜在有效生物标志物的可用数据，通过免疫组化检测肿瘤细胞和免疫细胞中PD-L1的表达，提示其是一种临床疗效的良好预测标志物;且PD-L1表达阴性者经免疫治疗后仍可获益。PD-L1表达在肿瘤内是动态和异质性的:在原发性灶和转移灶之间或在穿刺标本和大体标本之间表达不一致。肿瘤突变负荷与新抗原的高比率可获得持久获益。外周血标志物也可作为潜在标志物，增加的绝对淋巴细胞计数（ALC）与疾病控制和生存显著相关。在这篇综述中，我们旨在讨论抗PD-（L）1与抗CTLA-4 免疫治疗相关标志物研究现状，为临床运用提供指导，以便能够准确筛选出从这些治疗中获益更多的患者。