Inflammatory pseudotumor of lymph node and spleen: An entity biologically distinct from inflammatory myofibroblastic tumor

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT.     

Towards a new WHO classification of renal cell tumor: what the clinician needs to know—a narrative review

In 1952, renal cell carcinomas had been divided into 2 categories—clear cell or granular cell—depending upon their cytoplasmic staining characteristics. In the following years, the inventory of renal epithelial tumors has expanded by the addition of tumors named by their architectural pattern (i.e., papillary RCC, tubulocystic RCC), anatomic location (i.e., collecting duct carcinoma, renal medullary carcinoma), associated diseases (i.e., acquired cystic disease-associated RCCs). With the extensive application of molecular diagnostic techniques, it becomes possible to detect genetic distinctions between various types of renal neoplasm and discover new entities, otherwise misdiagnosed or diagnosed as unclassified RCC. Some tumors such as ALK rearrangement-associated RCC, MiT family translocation renal carcinomas, SDH-deficient renal cancer or FH-deficient RCC, are defined by their molecular characteristics. The most recent World Health Organization (WHO) classification of renal neoplasms account for more than 50 entities and provisional entities. New entities might be included in the upcoming WHO classification. The aim of this review is to summarise and discuss the newly acquired data and evidence on the clinical, pathological, molecular features and on the prognosis of new RCC entities, which will hopefully increase the awareness and the acceptance of these entities among clinicians and improve prognostication for individual patients.     

ALK融合基因阳性肺腺癌患者耐药核心基因鉴定及药物靶点分析

目的 探讨ALK融合基因阳性肺腺癌患者原发灶及转移灶基因表达谱的差异,从而探索转移灶耐药机制及相应的药物靶点分析.方法 GEO数据库中选取GSE125864,根据肿瘤组织取材部位不同分为原发灶组和转移灶组.首先,比较两组患者之间显著差异基因的表达,并分析这些显著差异基因在生物学功能和富集信号通路等方面的不同;其次,对显...     

蛋白降解靶向嵌合体在非小细胞肺癌治疗中的研究进展

蛋白降解靶向嵌合体（proteolysis targeting chimeria, PROTAC）通过利用泛素蛋白酶体途径实现对靶蛋白降解，颠覆了传统小分子抑制剂的理念。在非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的突变靶点中，PROTAC技术在临床前研究中已经成功实现了鼠类肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene homolog, KRAS）、表皮生长因子受体（epidermal growth factor receptor, EGFR）和间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）等蛋白的有效降解。PROTAC药物以其事件驱动的独特优势，有望克服小分子抑制剂产生的获得性耐药的问题，并对难成药靶点展现出良好的治疗潜力，有望成为NSCLC治疗的新策略。     

非小细胞肺癌ALK基因重排检测

目的 通过荧光原位杂交(FISH)方法检测非小细胞肺癌(NSCLC)患者间变性淋巴瘤激酶(ALK)基因重排.方法 根据ALK断裂重排方式及特点,设计并制备红/绿双色荧光探针.以人外周血培养细胞为检测对象评价ALK融合基因检测探针的敏感性和特异性,以NSCLC石蜡组织样本为对象进行ALK基因重排检测以评价探针的性能.结果 本研究制备的荧光探针在EB病毒(EBV)转化的人淋巴细胞检测中的特异性和敏感性均可达到100％.在对2例NSCLC患者石蜡包埋组织样本检测中,检测阴性、阳性各1例,检测结果与免疫组织化学检测结果一致.结论 本研究中制备的双色荧光探针可用于NSCLC ALK基因重排的检测.     

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.     

Clinical characteristics of non‐small cell lung cancer patients with EGFR mutations and ALK&ROS1 fusions

ObjectiveTo study the relationship between clinical characteristics and anaplastic lymphoma kinase (ALK) fusions, c‐ros oncogene 1, receptor tyrosine kinase (ROS1) gene fusions, and epidermic growth factor receptor (EGFR) mutations in non‐small cell lung cancer (NSCLC) patients to distinguish these different types.MethodsBoth ALK, ROS1 gene rearrangements and EGFR mutations testing were performed. The clinical characteristics and associated pulmonary abnormalities were investigated.ResultsFour hundred fifty‐three NSCLC patients were included for analysis. One hundred seventy (37.5%), 32 (7.1%), and 9 cases (2.0%) with EGFR mutations, ALK gene fusions, and ROS1 gene fusions were identified, respectively. The EGFR‐positive and ALK&ROS1‐positive were more common in female (χ ² = 61.934, P < 0.001 and χ ² = 28.152, P < 0.001), non‐smoking (χ ² = 59.315, P < 0.001 and χ ² = 11.080, P = 0.001), and adenocarcinoma (χ ² = 44.864, P < 0.001 and χ ² = 12.318, P = 0.002) patients; proportion of patients with emphysema was lower (χ ² = 35.494, P < 0.001 and χ ² = 15.770, P < 0.001) than the wild‐type patients. The results of logistic regression analysis indicated that female (adjusted odds ratio [OR] 1.834, 95% confidence interval [CI] 1.069–3.144, P = 0.028), non‐smoking (adjusted OR 2.504, 95% CI 1.456–4.306, P = 0.001), lung adenocarcinoma (adjusted OR 4.512, 95% CI 2.465–8.260, P < 0.001), stage III–IV (adjusted OR 2.232, 95% CI 1.066–4.676, P = 0.033), and no symptoms of emphysema (adjusted OR 2.139, 95% CI 1.221–3.747, P = 0.008) were independent variables associated with EGFR mutations. Young (adjusted OR 3.947, 95% CI 1.873–8.314, P < 0.001) and lung adenocarcinoma (adjusted OR 2.950, 95% CI 0.998–8.719, P = 0.050) were associated with ALK/ROS1 fusions.Conclusions EGFR mutations were more likely to occur in non‐smoking, stage III–IV, and female patients with lung adenocarcinoma, whereas ALK&ROS1 gene fusions were more likely to occur in young patients with lung adenocarcinoma. Emphysema was less common in patients with EGFR mutations.     

The role of high-dose therapy and autologous stem cell transplantation for pediatric bone and soft tissue sarcomas

Crizotinib (XALKORI?, Pfizer) is a tyrosine kinase inhibitor targeting ALK, MET and ROS1, currently approved for the treatment of adults with ALK-rearranged non-small-cell lung cancer. Optimizing the management of frequent crizotinib-related adverse events is crucial to ensure its continuous administration and reproduce the response and survival rates reported in clinical trials. Here, we propose some practical measures, which are mostly derived from the recommendations given to the investigators of the PROFILE 1001, 1005, 1007 and 1014 trials and are based on experience and scientific findings regarding the management of these disorders. While visual disturbances or bradycardia are frequent but benign, the severity of the cardiac and hepatic adverse events requires special attention potential to QT interval prolongations and to the monitoring of electrolyte levels and liver function, taking into account potential drug–drug interactions.     

BRAF V600E mutation as a novel mechanism of acquired resistance to ALK inhibition in ALK-rearranged lung adenocarcinoma: A case report

Rationale:Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance.Patient concerns:A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again.Diagnosis:The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma.Interventions:Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again.Outcomes:Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient''s resistance to lorlatinib.Lessons:We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.