PD-L1-positive circulating endothelial progenitor cells associated with immune response to PD-1 blockade in patients with head and neck squamous cell carcinoma.

A number of the inhibitors against programmed death protein 1 (PD-1) have been approved to treat recurrent or metastatic squamous cell carcinoma of head and neck (HNSCC). The interaction between PD-1 and its ligand (PD-L1) serves as an immune checkpoint that governs cytotoxic immune effectors against tumors. Numerous clinical trials of PD-1/PD-L1 inhibitors have so far been discordant about having sufficient PD-L1 expression in the tumor as a prerequisite for a successful anti-PD-1 treatment. On the other hand, vascular endothelial cells modulate immune activities through PD-L1 expression, and thus it is possible that the expressions of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CPCs) could affect antitumor immunity as well as neoangiogenesis. Here we investigated the potential involvement of PD-L1+ CECs and PD-L1+ CPCs in PD-1 blockade treatments for HNSCC patients. We measured CD8+ T cells, CECs, and CPCs in the peripheral blood of the HNSCC patients treated by anti-PD-1 therapies. We found that their PD-L1+ CPC expression before anti-PD1 therapies was strongly correlated with treatment responses and overall survival. Moreover, if the first infusion of PD-1 inhibitors reduced ≥ 50% PD-L1+ CPCs, a significantly better outcome could be predicted. In these patients as well as in an animal model of oral cancer, Pd-l1+ CPC expression was associated with limited CD8+ T-cell infiltration into the tumors, and anti-PD-1 treatments also targeted Pd-l1+ CPCs and increased CD8+ T-cell infiltration. Our results highlight PD-L1+ CPC as a potential regulator in the anti-PD-1 treatments for HNSCC.

Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-ß stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

Invasiveness and surgical timing evaluation by clinical features of ground-glass opacity nodules in lung cancers.

BACKGROUND: The early stages of lung cancer with ground-glass opacity (GGO) pattern are detectable. However, it remains a challenge for physicians how best to treat GGO nodules as invasive tumors are occasionally found, even in pure GGO nodules. This study identified the invasiveness by the clinical features of the GGO nodules. METHODS: A retrospective review of patients with resected GGO nodules from August 2015 to February 2019 was performed. A total of 92 patients were enrolled and gender, age, tumor location, operation times, tumor size, histopathologic and radiological findings were analyzed. RESULTS: In this study, the sequential of GGO nodules invasiveness was significantly related to the tumor size and solid component. After regrouping the population into preinvasive and invasive groups, the invasiveness was significantly related to tumor size, solid component, tumor volume and maximal computed tomography (CT) value. CONCLUSIONS: The invasiveness is difficult to evaluate according to the CT features only when the GGO nodules are less than 2 cm and consolidation/tumor ratio (C/T ratio) are less than 0.25. Tumor size and solid component are significant factors for predicting invasiveness. Part-solid GGO nodules with a diameter greater than 1 cm require surgical consideration due to their high risk of invasiveness.

The Impact of the Epigenetic Cancer Drug Azacitidine on Host Immunity: The Role of Myelosuppression, Iron Overload and tp53 Mutations in a Zebrafish Model.

The unsatisfactory real-world efficacy of the hypomethylating agent azacitidine in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) has prompted us to investigate the hematological adverse events and host variables that may compromise the use of this epigenetic drug. Using the zebrafish, we found that azacitidine destroyed their myeloid precursors and impaired myeloid function by inhibiting antigen processing, allogeneic response and phagocytic activity, resulting in increased susceptibility to infection even by the normal flora E. coli. In addition, iron overload, a MDS-associated condition following repeated transfusions, exacerbated bacterial infection especially by V. vulnificus with known iron dependence. Furthermore, we show that the tp53M214K mutant zebrafish survived longer than the wild-type (WT) when challenged with bacteria following azacitidine treatment. This was attributed to the mutant's hematopoietic cells rather than its general genetic background, since the WT animals reconstituted with the tp53M214K mutant kidney marrow became more resistant to bacterial infection following treatment with azacitidine. The clinical relevance of our findings was indicated by a MDS case with severe azacitidine-induced bone marrow suppression and by the association of hyperferritinemia with bacteremia in azacitidine-treated patients, while tp53M214K-mediated resistance to azacitidine-induced myelosuppression may explain the survival advantage of malignant MDS and AML clones over their normal counterparts under azacitidine treatment. Together, we propose that myelosuppression, iron overload and TP53 mutations may represent the host variables that compromise the azacitidine efficacy.

Incidental pharyngoesophageal diverticulum mistaken for a thyroid nodule: Report of two cases.

Pharyngeal or Zenker's diverticulum is an infrequent disorder that results from an outpouching of pharyngeal mucosa through a weakened area in the posterior pharyngeal wall. As it may mimic a thyroid nodule on ultrasonography (US), accurate diagnosis is important to ensure appropriate treatment. Fine-needle aspiration (FNA) is recommended for the initial evaluation of thyroid nodules. We report the FNA diagnosis of two cases of Zenker's diverticulum that were suspected to be thyroid nodules on US. Pap stained aspirate smears showed findings characteristic of Zenker's diverticulum: benign squamous cells, bacteria, and vegetable debris and the absence of colloid and/or thyroid epithelial cells. US and CT findings were consistent with the diagnosis.

Intestinal microbial dysbiosis aggravates the progression of Alzheimer's disease in Drosophila.

Neuroinflammation caused by local deposits of Aß42 in the brain is key for the pathogenesis and progression of Alzheimer's disease. However, inflammation in the brain is not always a response to local primary insults. Gut microbiota dysbiosis, which is recently emerging as a risk factor for psychiatric disorders, can also initiate a brain inflammatory response. It still remains unclear however, whether enteric dysbiosis also contributes to Alzheimer's disease. Here we show that in a Drosophila Alzheimer's disease model, enterobacteria infection exacerbated progression of Alzheimer's disease by promoting immune hemocyte recruitment to the brain, thereby provoking TNF-JNK mediated neurodegeneration. Genetic depletion of hemocytes attenuates neuroinflammation and alleviated neurodegeneration. We further found that enteric infection increases the motility of the hemocytes, making them more readily attracted to the brain with an elevated oxidative stress status. This work highlights the importance of gut-brain crosstalk as a fundamental regulatory system in modulating Alzheimer's disease neurodegeneration.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.

PI3K inhibitor enhances the cytotoxic response to etoposide and cisplatin in a newly established neuroendocrine cervical carcinoma cell line.

BACKGROUND: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC. RESULTS: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin. HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin synergistically inhibited HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Taken together, the data implied the combination of etoposide and cisplatin with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis. MATERIALS AND METHODS: A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 were analyzed to establish its characteristic profile. Next, HM-1 was treated with PI3K inhibitors, BKM120 and/or BEZ235, in combination with two well-known genotoxic drugs, etoposide and/or cisplatin, to evaluate which combination could serve as a more effective treatment approach. Their inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression. CONCLUSIONS: The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a potential new treatment strategy against NECC.

Adenocarcinoma of the rete testis with prominent papillary structure and clear neoplastic cells: morphologic and immunohistochemical findings and differential diagnosis.

Adenocarcinoma of the rete testis is rare, and its etiology is unknown. The definite diagnosis merely depends on the exclusion of other tumors and histological features. We first describe a 38-year-old man with a carcinoma arising in the rete testis. The tumor was characterized by clear neoplastic cells and branching papillary growth. Focal stromal invasion and transition of normal rete epithelium to neoplastic cells were seen. The neoplastic cells were positive for epithelial membrane antigen, Ber-Ep4, vimentin, renal cell carcinoma marker, and CD10, while negative for Wilms' tumor 1, thyroid transcription factor-1, estrogen receptor, prostate specific antigen, placental alkaline phosphate, CD117, and alpha-1-fetoprotein. According to the above features, we diagnosed this tumor as adenocarcinoma of the rete testis. To our best knowledge, this is the first reported case of adenocarcinoma of the rete testis with prominently papillary structure and clear neoplastic cells. The rarity of adenocarcinoma of the rete testis and the unique features in our case cause diagnostic pitfalls. A complete clinicopathological study and thorough differential diagnosis are crucial for the correct result.

Solitary metastasis to the breast after complete resection of encapsulated type AB thymoma: a case report.

INTRODUCTION: Type AB thymoma is generally considered a benign tumor with excellent prognosis. Rare case reports of type A and AB thymomas with recurrence and metastasis have been documented, although extrathoracic metastases are extremely rare. To the best of our knowledge, this is the first reported case of type AB thymoma with solitary metastasis to the breast. CASE PRESENTATION: We describe an 83-year-old Taiwanese woman with a metastatic thymoma to the breast 10 years after complete resection of noninvasive and encapsulated primary tumor, and analyze the possible factors to explain the recurrence and metastasis of the stage I thymomas. CONCLUSIONS: Even a clinically benign tumor such as type AB thymoma still has a possibility of metastasizing to an unusual site. When any uncommon tumor presents in any site, a suspicion of secondary neoplasm and thorough clinical history are required.

Tumor-to-Tumor Metastasis: Lung Carcinoma Metastasizing to Thyroid Neoplasms.

Tumor-to-tumor metastasis is extremely rare in the thyroid glands, and only seven cases of lung carcinoma metastasizing to thyroid tumors have been reported in the literature. We report another two cases of lung carcinoma metastasizing to thyroid neoplasms and review of the literature. The first case was a 64-year-old man presenting with neck mass, hoarseness, and easy choking for 2 months. Image studies showed several nodular lesions within bilateral thyroid glands. A histological examination after radical thyroidectomy revealed lung small cell carcinoma metastasizing to a thyroid follicular adenoma. The second case was a 71-year-old woman with a history of lung adenosquamous carcinoma. The PET/CT scan showed left lower lung cancer and a hypermetabolic area in the right thyroid lobe, highly suspicious for malignancy. Radical thyroidectomy and left lung lobectomy were performed, and the thyroid gland revealed lung adenosquamous carcinoma metastasizing to a papillary thyroid carcinoma.

Schimmelpenning syndrome: a case report and literature review.

We report a case of a male newborn with Schimmelpenning syndrome, which presented as diffuse sebaceous nevi covering the left side of the body, from the lower chin midface to the lower leg; cardiac-ocular comorbidities were also present. We present photographs of this patient's sebaceous nevi, which may assist physicians in the early diagnosis of this condition and prevent unnecessary examinations and inadequate therapies.

Serine protease PRSS23 is upregulated by estrogen receptor α and associated with proliferation of breast cancer cells.

Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor α (ERα), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ERα is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins.In the present study, we aimed to clarify the correlation between and functional implication of ERα and PRSS23 in breast cancer. Analysis of published breast cancer microarray datasets revealed that the gene expression correlation between ERα and PRSS23 is highly significant among all ERα-associated proteases in breast cancer. We then assessed PRSS23 expression in 56 primary breast cancer biopsies and 8 cancer cell lines. The results further confirmed the coexpression of PRSS23 and ERα and provided clinicopathological significance. In vitro assays in MCF-7 breast cancer cells demonstrated that PRSS23 expression is induced by 17ß-estradiol-activated ERα through an interaction with an upstream promoter region of PRSS23 gene. In addition, PRSS23 knockdown may suppress estrogen-driven cell proliferation of MCF-7 cells.Our findings imply that PRSS23 might be a critical component of estrogen-mediated cell proliferation of ERα-positive breast cancer cells. In conclusion, the present study highlights the potential for PRSS23 to be a novel therapeutic target in breast cancer research.

Primary prostatic Wilms' tumor: a case report.

BACKGROUND: Extrarenal Wilms' tumors (EWTs) are very rare, and a single case of prostatic EWT has been reported in the English-language literature. CASE: A 46-year-old man presenting with lower urinary tract symptoms was diagnosed with a prostatic tumor histologically proven to be a EWT. CONCLUSION: During the evaluation of a patient with a prostatic tumor, more common prostatic neoplasms such as adenocarcinoma, transitional cell carcinoma and carcinosarcoma must first be considered. However, the presence of a primary prostatic Wilms' tumor must also be taken into consideration.

Angioimmunoblastic T-cell lymphoma of cytotoxic T-cell phenotype containing a large B-cell proliferation with an undersized B-cell clonal product.

Angioimmunoblastic T-cell lymphoma is a nodal peripheral T-cell lymphoma considered to be derived from CD4 follicular helper T cells. It is characterized by the proliferation of arborizing vessels, hyperplastic follicular dendritic cells, and a polymorphous lymphoid infiltrate including large B immunoblasts, which could be polyclonal, oligoclonal, or monoclonal. The polymerase chain reaction-based clonality study of lymphoproliferations is increasingly popular in the diagnostic workup. With the commercially available Biomed-2 protocols, lymphoproliferations with amplicons in the expected size ranges are considered clonal, whereas clonal products outside the expected ranges are extremely rare. We presented the case of a 60-year-old male patient with angioimmunoblastic T-cell lymphoma, in which the neoplastic T cells expressed CD8, bcl-6, and programmed death-1. Furthermore, there was a proliferation of large B cells in this tumor. The results of T-cell receptor gene rearrangement study using the Biomed-2 protocols showed clonal rearrangement with amplicons falling within the expected size ranges. Interestingly, the size of the amplicons detected by the Biomed-2 immunoglobulin heavy chain gene (IgH) rearrangement using FR2/JH primers was around 240 bp, slightly smaller than the expected size ranges. Through cloning, sequencing, and BLAST searches, we confirmed that the FR2/JH amplicon was derived from the IgH rearrangement with a deletion of a short segment. Our case illustrates that polymerase chain reaction amplicons outside the expected size ranges may still be clonal products.

Platonin improves survival of skin allografts.

BACKGROUND: Platonin is an immunomodulator with NF-κB inhibitory activity. It not only inhibits interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α production in sepsis, but also attenuates heatstroke reactions. In addition, platonin redirects differentiation of dendritic cells toward an intermediate stage of maturation. The study was designed to examine whether platonin can reduce acute graft rejection. MATERIALS AND METHODS: A C57BL/6 to BALB/c mice skin transplantation model was used. Platonin was given intraperitoneally to transplant recipients at various doses. Skin grafts were submitted to histologic analysis. NF-κB DNA binding activity and inducible nitric oxide synthase (iNOS) expression were determined in harvested draining lymph nodes. Leukocyte count, hepatic and renal functions were serially assessed. An array of serum cytokines was evaluated on d 1, 3, 5, and 7 after skin transplantation. RESULTS: Platonin resulted in significantly prolonged skin allograft survival in a dose- and time-dependent manner. Histologic changes in the skin allografts paralleled the gross appearance of rejection. Serum cytokine analysis shows that platonin significantly suppressed the production of the proinflammatory cytokines IL-6 and TNF-α. However, no significant changes occurred in the serum levels of Th1-type and Th2-type cytokines. NF-κB activity and iNOS expression were remarkably suppressed in draining lymph nodes. In terms of toxicity, there were no significant differences in body weight, leukocyte count, plasma alanine aminotransferase, or creatinine between the platonin-treated and control groups. CONCLUSION: Platonin effectively prolongs skin allograft survival without major toxicity.

Bilateral parotitis caused by Mycobacterium chelonae in an immunocompetent child.

This report is of a healthy 3-year-old boy with bilateral parotitis caused by Mycobacterium chelonae. He was treated with antibiotics, but the symptoms did not improve. The biopsy pathology report revealed chronic caseating granulomatous inflammation. After 2 weeks, Mycobacterium chelonae was identified from the biopsy specimen culture. The antibiotics were changed to amikacin and clarithromycin, according to the susceptibility test. Two weeks later, he underwent debridement surgery. Only partial excision of the infected tissue was performed because of the possibility of facial nerve injury. After another 2 weeks of treatment with amikacin and clarithromycin, parotidectomy was performed. The patient then received a 6-month course of oral clarithromycin. At the 1-year follow up, he was well and without residual mass. His immunologic examinations were all within normal limits. This is the first report of bilateral parotitis caused by Mycobacterium chelonae in an immunocompetent boy in the English-language literature.

Potentiation of the immunotherapeutic effect of autologous dendritic cells by pretreating hepatocellular carcinoma with low-dose radiation.

PURPOSE: To determine whether exposing hepatocellular carcinoma (HCC) to low dose radiation increases the efficacy of dendritic cell-mediated immunotherapy for HCC. METHODS: Tumour specimens collected from 20 recruited patients with HCC were cultured in primary culture (half successfully) and then exposed to low-dose radiation (0.5 Gy). Immature DCs derived from peripheral blood monocytes of patients were pulsed with autologous HCC cell lysates and matured with a cytokine cocktail. Autologous tumour lysate-pulsed DCs (TLP-DCs) were used to stimulate mixed lymphocytes, which were then tested for inhibitory effect on the growth of HCC cells. Surface markers of immunogenicity on primary HCC cells, MHC, and Fas were investigated before and after low-dose irradiation. RESULTS: Exposing HCC cells to low-dose (0.5 Gy) radiation enhanced the immunotherapeutic effect of TLP-DC-stimulated lymphocytes. Growth inhibition increased from 50.6+/-7.5% without irradiation to 74.3+/-4.3% with radiation. The expression of MHC class ll and Fas was upregulated after irradiating HCC cells. CONCLUSION: Exposing tumour cells to a low dose of radiation can enhance the immunotherapeutic effect of the autologous tumor lysate-pulsed DC vaccine.