Toripalimab plus lenalidomide for central nervous system recurrence in refractory CD5+ diffuse large B-cell lymphoma with MYD88 and CD79B comutation: a case report.

Background: CD5-positive (CD5+) non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL) is heterogeneous with a poor prognosis. For refractory DLBCL, the median overall survival was only 6.3 months. Therefore, there is a need for approaches to elongate the survival in this subgroup of relapsed DLBCL patients. Case Description: Here, we present a rare case of a 72-year-old patient with stage IV CD5+ non-GCB DLBCL with myeloid differentiation primary response 88 (MYD88) and cluster of differentiation 79B (CD79B) comutations. Zanubrutinib and rituximab therapy was initially administered until disease progression. Subsequently, zanubrutinib plus rituximab together with attenuated standard chemotherapy (miniCHOP) was applied and a notable response was observed. The patient tolerated the treatment well and exhibited a complete response in lung for about 5 months. Afterwards, the patients experienced relapse in the brain and started programmed death protein 1 (PD-1) regimens of toripalimab plus lenalidomide, which also exhibited a good response with decreased lesions in brain after half-year treatment. However, the patient experienced relapse again in the brain 3 months later and started chemotherapy with methotrexate plus rituximab. The patient had survived for over 2 years since the initial diagnosis of stage IV DLBCL and has continued to survive after experiencing a relapse in the brain for approximately 11 months till now. Conclusions: These findings suggest that toripalimab may be a new therapeutic option for central nervous system recurrence in refractory CD5+ DLBCL with MYD88 and CD79B comutation. Further clinical trials are warranted to confirm these results.

Molecular basis and targeted therapies for radioiodine refractory thyroid cancer.

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) are not amenable to novel 131 I therapy due to the reduced expression of sodium iodide symporter (Na+/I- symporter, NIS) and/or the impairment of NIS trafficking to the plasma membrane. RAIR-TC patients have a relatively poor prognosis with a mean life expectancy of 3-5 years, contributing to the majority of TC-associated mortality. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging for clinicians. In this review, we demonstrate the updated clinical scenarios or the so-called "definitions" of RAIR-TC suggested by several associations based on 131 I uptake ability and tumor response post-131 I therapy. We also discuss current knowledge of the molecular alterations involved in membrane-localized NIS loss, which provides a preclinical basis for the development of targeted therapies, in particular, tyrosine kinase inhibitors (TKIs), redifferentiation approaches, and immune checkpoint inhibitors.

The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing.

A thorough interrogation of the immune landscape is crucial for immunotherapy strategy selection and prediction of clinical responses in non-small-cell lung cancer (NSCLC) patients. Single-cell RNA sequencing (scRNA-seq) techniques have prompted the opportunity to dissect the distinct immune signatures between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of NSCLC. Here, we performed scRNA-seq on 72,475 immune cells from 40 samples of tumor and matched adjacent normal tissues spanning 19 NSCLC patients, and drew a systematic immune cell transcriptome atlas. Joint analyses of the distinct cellular compositions, differentially expressed genes (DEGs), cell-cell interactions, pseudotime trajectory, transcriptomic factors and prognostic factors based on The Cancer Genome Atlas (TCGA), revealed the central roles of cytotoxic and effector T and NK cells and the distinct functional macrophages (Mφ) subtypes in the immune microenvironment heterogeneity between LUAD and LUSC. The dominant subtype of Mφ was FABP4-Mφ in LUAD and SPP1-Mφ in LUSC. Importantly, we identified a novel lymphocyte-related Mφ cluster, which we named SELENOP-Mφ, and further established its antitumor role in both types, especially in LUAD. Our comprehensive depiction of the immune heterogeneity and definition of Mφ clusters could help design personalized treatment for lung cancer patients in clinical practice.

Conventional papillary thyroid carcinoma with intraglandular lymphatic dissemination shows more aggressive features.

OBJECTIVE: To investigate the invasive capability and other clinicopathological features of conventional papillary thyroid carcinoma (CVPTC) with intraglandular lymphatic dissemination. METHODS: Seventy-three conventional papillary thyroid carcinoma patients receiving total thyroidectomy were analyzed in this study. The expression of BRAF-V600E, D2-40 and CD31 in all thyroid samples was detected by immunohistochemical staining. The results were evaluated by two pathologists and were statistically analyzed. The rate of positive BRAF-V600E expression and the clinical invasiveness of CVPTC with intraglandular dissemination, multifocal non-intraglandular dissemination-CVPTC and single focus-CVPTC were evaluated. The correlation between BRAF-V600E expression, lymphatic vessel density, microvessel density and the clinicopathological characteristics of conventional papillary thyroid carcinoma were assessed. RESULTS: Twenty-five intraglandular dissemination-CVPTC, 17 multifocal non-intraglandular dissemination-CVPTC and 31 single focus-CVPTC cases were included in this study. The results showed that BRAF-V600E expression was independently correlated with intraglandular dissemination, age and pN staging (P < 0.05). The lymphatic vessel density in the intraglandular dissemination-CVPTC group was higher than that in the non-intraglandular dissemination-CVPTC group (P < 0.05). Compared with cases without intraglandular dissemination, intraglandular dissemination-CVPTC was associated with a younger age, higher lymph node metastasis rate, pN staging, the expression of BRAF-V600E and increased Capsule invasion and lymphovascular tumor thrombus (P < 0.05). During the follow-up of 30 months (median 15 months), two patients in the intraglandular dissemination-CVPTC group had cervical lymph node metastasis after the first operation. CONCLUSIONS: Intraglandular dissemination-CVPTC shows more aggressive features, and intraglandular lymphatic dissemination may be a potential biological indicator of poor prognosis.

Heat-induced antigen retrieval in fluorescence in situ hybridization: An effective approach enhancing signal intensity in poor-quality FFPE sections.

Fluorescence in situ hybridization (FISH) serves as an ancillary tool for assessing chromosomal abnormalities and is important in differential diagnoses and treatment decisions. In clinical practice, pathologists encounter unsatisfactory formalin-fixed paraffin-embedded (FFPE) sections exhibiting weak fluorescence signals, mostly due to inappropriate tissue processing or preservation, leading to interpretation difficulties. For the present study, FFPE samples for which conventional FISH failed were collected. Instead of a pretreatment step using a commercial kit, heat-induced antigen retrieval (HIAR) was introduced using either citrate buffer or Tris-EDTA buffer, while the subsequent experimental workflow remained unchanged. After HIAR-assisted FISH, the hybridization efficiency and signal intensity were markedly enhanced and no difference in signal adequacy was observed when comparing the effect of the two AR solutions. The present study demonstrated that HIAR is a reliable tool for FISH, particularly for poor-quality FFPE sections yielding weak or no fluorescence signals in the conventional analysis.

Prognostic Score-Based Stratification Analysis Reveals Universal Benefits of Radiotherapy on Lowering the Risk of Ipsilateral Breast Event for Ductal Carcinoma In Situ Patients with Different Risk Levels.

BACKGROUND: We aimed to analyze the effects of radiotherapy (RT) on the incidence rate of ipsilateral breast event (IBE) in ductal carcinoma in situ (DCIS) patients with lumpectomy after being stratified by prognostic score. METHODS: We identified DCIS patients who received lumpectomy, from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015. Cumulative incidence functions for competing risk were used to evaluate the effects of RT on IBE risk over time. Three multivariate regression models (weighted, non-weighted, and Fine-Gray) were applied to compare the IBE risk between the RT and non-RT groups after stratifying patients by prognostic score. RESULTS: Overall, 72,623 DCIS patients were identified from the SEER database and 49,206 (66.8%) patients received RT. During the follow-up period (ranging from 7 to 347 months), the cumulative probability of invasive and in situ IBE was significantly lower in the RT group than in the non-RT group (p < 0.001). After being stratified by prognostic score, the weighted IBE incidence rate increased as the risk level increased (p < 0.050). In multivariate regression models, RT lowered the IBE incidence rate by at least 30% in low-, moderate-, and high-risk DCIS (p < 0.010). In particular, the in situ and invasive IBE incidence rate decreased by over 50% in low-risk DCIS with RT (p < 0.001). CONCLUSIONS: RT is associated with a lowered IBE incidence rate in DCIS patients, regardless of the assigned risk levels for patients. The significant reduction in the IBE incidence rate in low-risk DCIS patients also indicates the potential benefits for recommending RT to such a patient population in clinical practice.

Mediator complex subunit 16 is down-regulated in papillary thyroid cancer, leading to increased transforming growth factor-ß signaling and radioiodine resistance.

Mediator complex subunit 16 (MED16) is a component of the mediator complex and functions as a coactivator in transcriptional events at almost all RNA polymerase II-dependent genes. In this study, we report that the expression of MED16 is markedly decreased in papillary thyroid cancer (PTC) tumors compared with normal thyroid tissues. In vitro, MED16 overexpression in PTC cells significantly inhibited cell migration, enhanced sodium/iodide symporter expression and iodine uptake, and decreased resistance to radioactive 131I (RAI). Conversely, PTC cells in which MED16 had been further knocked down (MED16KD) exhibited enhanced cell migration, epithelial-mesenchymal transition, and RAI resistance, accompanied by decreased sodium/iodide symporter levels. Moreover, cell signaling through transforming growth factor ß (TGF-ß) was highly activated after the MED16 knockdown. Similar results were obtained in MED12KD PTC cells, and a co-immunoprecipitation experiment verified interactions between MED16 and MED12 and between MED16 and TGF-ßR2. Of note, the application of LY2157299, a potent inhibitor of TGF-ß signaling, significantly attenuated MED16KD-induced RAI resistance both in vitro and in vivo In conclusion, our findings indicate that MED16 reduction in PTC contributes to tumor progression and RAI resistance via the activation of the TGF-ß pathway.

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and also an important metabolic disorder associated with insulin resistance (IR). Hyperandrogenism is a key feature of PCOS. However, whether hyperandrogenism can cause IR in PCOS remains largely unknown. The mammalian target of rapamycin complex 1 (mTORC1) and its regulated autophagy are closely associated with IR. In the present study, we investigated the role of mTORC1-autophagy pathway in skeletal muscle IR in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. DHEA-treated mice exhibited whole-body and skeletal muscle IR, along with the activated mTORC1, repressed autophagy, impaired mitochondria, and reduced plasma membrane glucose transporter 4 (GLUT4) expression in skeletal muscle of the mice. In cultured C2C12 myotubes, treatment with high dose testosterone activated mTORC1, reduced autophagy, impaired mitochondria, decreased insulin-stimulated glucose uptake, and induced IR. Inhibition of mTORC1 or induction of autophagy restored mitochondrial function, up-regulated insulin-stimulated glucose uptake, and increased insulin sensitivity. On the contrary, inhibition of autophagy exacerbated testosterone-induced impairment. Our findings suggest that the mTORC1-autophagy pathway might contribute to androgen excess-induced skeletal muscle IR in prepubertal female mice by impairing mitochondrial function and reducing insulin-stimulated glucose uptake. These data would help understanding the role of hyperandrogenism and the underlying mechanism in the pathogenesis of skeletal muscle IR in PCOS.

Depression-Like Behavior in a Dehydroepiandrosterone-Induced Mouse Model of Polycystic Ovary Syndrome.

Patients with polycystic ovary syndrome (PCOS) can suffer from psychological disorders, among which depression is the most commonly diagnosed. However, the pathogenesis is still unclear. The aims of the present study were to investigate the behaviors of dehydroepiandrosterone (DHEA)-induced PCOS mice, the effects of high-fat diet (HFD) on mouse behaviors, and the underlying mechanism. Prepubertal C57BL/6 mice (25 days of age) were divided into four groups and injected daily with the vehicle sesame oil or DHEA on the normal chow or a 60% HFD for 20 consecutive days. Depression-like behavior of the mice was examined using a forced swim test, tail suspension test, and open field test. Thereafter, the animals were killed and four brain regions were collected. The brain levels of monoamines and their metabolites, including norepinephrine, serotonin, 5-hydroxy-3-indolacetic acid, dopamine, and 3,4-hydroxyphenylacetic acid, were analyzed by HPLC. Our data show that DHEA-treated mice exhibited depression-like behavior according to the results from behavioral assessment. The brain contents of monoamines and/or their metabolites decreased in DHEA-treated mice compared with controls. HFD did not seem to markedly affect the behavioral responses, the brain monoamines, or their metabolites in the mice. These findings suggest that DHEA treatment induced depression-like behavior in PCOS mice, possibly through down-regulation of brain monoamines and/or their metabolites, which implies the contribution of hyperandrogenism to the psychological symptoms of women with PCOS.

Black Cohosh Ameliorates Metabolic Disorders in Female Ovariectomized Rats.

Estrogen deficiency is associated with metabolic derangements in menopausal women. Black cohosh has been widely used as an alternative therapy in the treatment of menopausal syndrome. However, its role in metabolism needs to be defined. The aim of the present study was to investigate the long-term effect of black cohosh on glucose and lipid metabolism in a rat model of post-menopause. Adult female Sprague-Dawley rats were sham operated (SHAM), ovariectomized (OVX), OVX with the treatment of estradiol valerate (OVX + E), or OVX with the treatment of isopropanolic black cohosh extract (OVX + iCR). Body weight, body composition, and blood glucose levels of the animals were monitored. The rats were then sacrificed after 3 months of the treatments. At the end of the experiment, OVX + iCR and OVX + E rats exhibited a significant decrease in body weight gain, body and abdominal fat mass, serum triglycerides levels, hepatic fat accumulation, and adipocyte hypertrophy compared with OVX rats. In addition, insulin resistance and glucose intolerance were improved in OVX + iCR but not in OVX + E rats. No hepatotoxicity was detected in OVX + iCR animals. Furthermore, western blot analysis suggested the increased lipolysis in adipose tissue of OVX + iCR and OVX + E rats. Data from in vitro experiments using cultured primary rat adipocytes also showed that black cohosh could affect lipolysis of adipocytes. In conclusion, the long-term treatment of black cohosh at a proper dosage ameliorated metabolic derangements in OVX rats. Thus, this drug is promising for the treatment of metabolic disorders in menopausal and post-menopausal women.

High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy associated with both reproductive and metabolic disorders. Dehydroepiandrosterone (DHEA) is currently used to induce a PCOS mouse model. High-fat diet (HFD) has been shown to cause obesity and infertility in female mice. The possible effect of an HFD on the phenotype of DHEA-induced PCOS mice is unknown. The aim of the present study was to investigate both reproductive and metabolic features of DHEA-induced PCOS mice fed a normal chow or a 60% HFD. Prepubertal C57BL/6 mice (age 25 days) on the normal chow or an HFD were injected (s.c.) daily with the vehicle sesame oil or DHEA for 20 consecutive days. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that an HFD did not affect the reproductive phenotype of DHEA-treated mice. The treatment of HFD, however, caused significant metabolic alterations in DHEA-treated mice, including obesity, glucose intolerance, dyslipidemia, and pronounced liver steatosis. These findings suggest that HFD induces distinct metabolic features in DHEA-induced PCOS mice. The combined DHEA and HFD treatment may thus serve as a means of studying the mechanisms involved in metabolic derangements of this syndrome, particularly in the high prevalence of hepatic steatosis in women with PCOS.