Comparison of trait and state mind wandering among schizotypal, subclinically depressed, and control individuals.

BACKGROUND: Mind wandering is a common phenomenon in daily life. However, the manifestations and cognitive correlates of mind wandering in different subclinical populations remain unclear. In this study, these aspects were examined in individuals with schizotypal traits and individuals with depressive symptoms, i.e., subclinical populations of patients with schizophrenia and depression. METHODS: Forty-two individuals with schizotypal traits, 42 individuals with subclinical depression, and 42 controls were recruited to complete a mind wandering thought sampling task (state level) and a mind wandering questionnaire (trait level). Measures of rumination and cognitive functions (attention, inhibition, and working memory) were also completed by participants. RESULTS: Both subclinical groups exhibited more state and trait mind wandering than did the control group. Furthermore, individuals with schizotypal traits demonstrated more trait mind wandering than individuals with subclinical depression. Rumination, sustained attention, and working memory were associated with mind wandering. In addition, mind wandering in individuals with subclinical depression can be accounted for by rumination or attention, while mind wandering in individuals with high schizotypal traits cannot be accounted for by rumination, attention, or working memory. CONCLUSIONS: The results suggest that individuals with high schizotypal traits and subclinical depression have different patterns of mind wandering and mechanisms. These findings have implications for understanding the unique profile of mind wandering in subclinical individuals.

Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer.

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models.

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3ß1, αvß3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype.

BACKGROUND: Germline heterozygous gain-of-function (GOF) mutations in the PIK3CD gene lead to a rare primary immunodeficiency disease known as activated phosphoinositide 3-kinase (PI3K) δ syndrome type 1(APDS1). Affected patients present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation, increased levels of serum immunoglobulin (Ig) M, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia. Due to highly heterogeneous phenotypes of APDS1, it is very likely that suspected cases may be misdiagnosed. METHODS: Herein we reported three patients with different clinical presentations but harboring pathogenic variants in PIK3CD gene detected by trio whole-exome sequencing (trio-WES) and confirmed by subsequent Sanger sequencing. RESULTS: Two heterozygous mutations (c.3061G > A, p.E1021K and c.1574 A > G, p.E525G) in PIK3CD (NM_005026.3) were identified by whole exome sequencing (WES) in the three patients. One of two patients with the mutation (c.3061G > A) presented with abdominal pain and diarrhea as the first symptoms, which was due to intussusception caused by multiple polyps of colon. The patient with mutation (c.1574 A > G) had an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-like clinical manifestations, including multisystemic inflammation, acute nephritic syndrome, and positive perinuclear ANCA (p-ANCA), thus the diagnosis of ANCA-AAV was considered. CONCLUSIONS: Our study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia. TRIAL REGISTRATION: Retrospectively registered.

Targeting HER2 genomic alterations in non-small cell lung cancer.

Oncogenic mutations and amplifications in the erythroblastic oncogene B (ERBB2), or human epidermal growth factor receptor 2 (HER2), have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer (NSCLC). Each genomic alteration occurs in 2-4% of NSCLC by next generation sequencing and is associated with constitutive HER2 activation. The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular domain. Unlike in breast and gastric cancer, HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted agents. High HER2 protein overexpression by immunohistochemistry (3+) only occurs in 2-4% of NSCLC. Until now HER2-targeted agents (such as afatinib and ado-trastuzumab emtansine) only demonstrate modest clinical activity in patients with HER2-mutant NSCLC. Retrospective studies show concern for inferior clinical benefit of immune checkpoint inhibitors in HER2-mutated NSCLC. Therefore, platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this patient population. In May 2020 trastuzumab deruxtecan (T-DXd) received the U.S. Food and Drug Administration breakthrough therapy designation for HER2-mutant metastatic NSCLC, and was added as an option for HER2-mutant NSCLC to the NCCN guidelines V1.2021. A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring HER2 exon 20 mutations was just opened for enrollment in September 2020. In this review, we highlight the current knowledge and perspectives on targeting-HER2 genomic alterations in NSCLC.

Durable clinical response to the multidisciplinary management of neurosurgery, radiation and chemoimmunotherapy in a patient with PD-L1/PD-L2/JAK2 (PDJ)-amplified, refractory triple-negative breast cancer.

Patients with refractory metastatic triple-negative breast cancer (mTNBC) and symptomatic brain metastases have poor prognosis and are challenging to treat. The addition of an programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitor (pembrolizumab or atezolizumab) to first line chemotherapy has prolonged survivals in mTNBC patients with PD-L1-positive tumor and/or tumor-infiltrating immune cells. The clinical efficacy of the chemoimmunotherapy combination in patients with refractory mTNBC, especially brain metastasis, is unknown. Co-amplification of PD-L1, PD-L2, and Janus kinase 2 (PD-L1/PD-L2/JAK2) genes (PDJ amplification) is associated with high PD-L1 protein expression and a 65-87% response rate to PD-1/PD-L1 inhibitors in patients with lymphomas. But the utility of PDJ amplification as a biomarker predictive of response to PD-1/PD-L1 inhibitors is unknown for mTNBC patients. Here, we report a 46-year-old woman who had rapid tumor progression in the brain and lung within 3 months after chemotherapy, neurosurgery, and gamma knife stereotactic radiosurgery for brain metastasis. Next-generation sequencing of her brain metastasis specimen revealed 9 copies of PDJ amplification and a tumor mutational burden of 5 mutations per megabase. Although high PDJ mRNA expression levels were detected, PD-L1 protein expression was negative on tumor cells and 10% on tumor-associated immune cells. After the debulking brain tumor resection, she received pembrolizumab monotherapy, whole brain radiation, and then atezolizumab and nab-paclitaxel with good intracranial and extracranial responses for >16 months. To the best of our knowledge, this is the first report that PDJ amplification is associated with durable clinical response to the PD-1/PD-L1 inhibitor-containing, multidisciplinary management in a patient with refractory, PD-L1 protein-negative, PDJ-amplified mTNBC. Further study is warranted to understand the underlying mechanism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.