Glucose metabolic heterogeneity correlates with pathological features and improves survival stratification of resectable lung adenocarcinoma.

OBJECTIVE: We investigated whether glycolytic heterogeneity correlated with histopathology, and further stratified the survival outcomes pertaining to resectable lung adenocarcinoma. METHODS: We retrospectively analyzed the 18F-fluorodeoxyglucose positron emission tomography-derived entropy and histopathology from 128 patients who had undergone curative surgery for lung adenocarcinoma. Disease-free survival (DFS) and overall survival (OS) were analyzed using univariate and multivariate Cox regression models. Independent predictors were used to construct survival prediction models. RESULTS: Entropy significantly correlated with histopathology, including tumor grades, lympho-vascular invasion, and visceral pleural invasion. Furthermore, entropy was an independent predictor of unfavorable DFS (p = 0.031) and OS (p = 0.004), while pathological nodal metastasis independently predicted DFS (p = 0.009). Our entropy-based models outperformed the traditional staging system (c-index = 0.694 versus 0.636, p = 0.010 for DFS; c-index = 0.704 versus 0.630, p = 0.233 for OS). The models provided further survival stratification in subgroups comprising different tumor grades (DFS: HR = 2.065, 1.315, and 1.408 for grade 1-3, p = 0.004, 0.001, and 0.039, respectively; OS: HR = 25.557, 6.484, and 2.570, for grade 1-3, p = 0.006, < 0.001, and = 0.224, respectively). CONCLUSION: The glycolytic heterogeneity portrayed by entropy is associated with aggressive histopathological characteristics. The proposed entropy-based models may provide more sophisticated survival stratification in addition to histopathology and may enable personalized treatment strategies for resectable lung cancer.

Acute Orbital Apex Syndrome Caused by Idiopathic Sclerosing Orbital Inflammation.

Idiopathic sclerosing orbital inflammation (ISOI) is a distinct entity among other orbital diseases. It is characterized by marked fibrosis and inflammatory cell infiltration that can damage orbital structures. Clinical manifestations were variable, including ocular and periocular redness, proptosis, and pain. Ocular motor restrictions and optic nerve dysfunction might occur in severe cases. We herein report a patient of ISOI who presented with total ophthalmoplegia and acute vision loss. His symptoms were relieved mainly as his vision improved to 20/25 after receiving corticosteroid and immunosuppressant therapies. Therefore, ISOI should be one of the deferential diagnoses when we encounter cases with acute orbital apex syndrome. With prompt evaluation and in-time treatment, a favorable outcome is possible.

Apocrine Hidrocystoma with IgG4 Plasma Cell Infiltration Presenting as Recurrent Chalazion: A Case Report.

Apocrine hidrocystomas are benign cystic tumors resulting from apocrine sweat glands' proliferation. They typically present as solitary, slow-growing nodules at the head and neck, especially in the periorbital cutaneous region. We present a case of periorbital apocrine hidrocystoma in a 22-year-old woman that was treated as chalazion previously. Besides the hallmark histopathological findings of apocrine hidrocystoma, IgG4 plasma cell infiltration of the cystic wall was also found. The ratio of IgG4-to-IgG-positive plasma cells was high, whereas serum IgG4 was within the standard limit. This is, to date, the only probable IgG4-related ophthalmic disease associated with apocrine hidrocystoma.

Tumor glycolytic heterogeneity improves detection of regional nodal metastasis in patients with lung adenocarcinoma.

OBJECTIVE: The diagnostic performance of 18F-FDG PET for detecting regional lymph node metastasis in resectable lung cancer is variable, and its sensitivity for adenocarcinoma is even lower. We aimed to evaluate the value of 18F-FDG PET-derived features in predicting pathological lymph node metastasis in patients with lung adenocarcinoma. METHODS: We retrospectively analyzed pretreatment 18F-FDG PET-derived features of 126 lung adenocarcinoma patients who underwent curative surgery. A logistic regression model was used to analyze the association between study variables and pathological regional lymph node status obtained from the curative surgery. Furthermore, Cox regression analysis was used to test the effect of the study variables on survival outcomes, including disease-free survival (DFS) and overall survival (OS). RESULTS: The primary tumor entropy (OR = 1.7, p = 0.014) and visual interpretation of regional nodes via 18F-FDG PET (OR = 2.5, p = 0.026) independently predicted pathological regional lymph node metastasis. The areas under the receiver-operating-characteristic curves were 0.631, 0.671, and 0.711 for visual interpretation, primary tumor entropy, and their combination, respectively. Based on visual interpretation, a primary tumor entropy ≥ 3.0 improved the positive predictive value of positive visual interpretation from 51.2% to 63.0%, whereas an entropy < 3.0 improved the negative predictive value of negative visual interpretation from 75.3% to 82.6%. In cases with positive visual interpretation and low entropy, or negative visual interpretation and high entropy, the nodal metastasis rates were approximately 30%. In the survival analyses, the primary tumor entropy was also independently associated with DFS (HR = 2.7, p = 0.001) and OS (HR = 4.8, p = 0.001). CONCLUSIONS: Our preliminary results show that the primary tumor entropy may improve 18F-FDG PET visual interpretation in predicting pathological nodal metastasis in lung adenocarcinoma, and may also show a survival prognostic value. This versatile biomarker may facilitate tailored therapeutic strategies for patients with resectable lung adenocarcinoma.

Combined methyl aminolevulinate-based photodynamic therapy and imiquimod in a patient with perianal extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare form of intraepithelial adenocarcinoma. Complete surgical removal of localized disease is the standard treatment for EMPD but carries anaesthesia-related risks and possible postoperative functional deficits. Herein, we present a case of perianal EMPD successfully treated with topical methyl aminolevulinate-based photodynamic therapy (MAL-PDT), followed by topical imiquimod. Immunohistochemical analysis after PDT revealed high expression of Toll-like receptor 7 on keratinocytes, Paget's cells, and dermal inflammatory cells, as well as increased expression of intraepidermal Langerhans cells, dermal macrophages, and T cells. We propose that MAL-PDT may prime the enhancing effects of topical imiquimod. Combined local treatment with PDT and imiquimod may provide an alternative and non-invasive strategy for perianal EMPD.

Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition.

Annually, 48,000 people die from pancreatic ductal adenocarcinoma (PDAC), ranking it the fourth among cancer-related deaths in the United States. Currently, anti-cancer drugs are not effective against PDAC, and only extends survival by 3 months. Aberrant DNA methylation has been shown to play an important role during carcinogenesis in PDAC, with approximately 80% of tumor overexpressing the DNA methyltransferase 1 (DNMT1) protein. In the present study, we used DNMTs as a screening platform to find a new DNMT inhibitor, n-butylidenephthalide (n-BP), which is identified from a Chinese herbal drug. n-BP could inhibit DNMT1 expression in both dose-dependent and time-dependent manner. It also displays an effect in suppressing growth of PDAC cells and inducing cell cycle arrest at G0/G1 phase leading apoptosis. Growth suppression can be restored by the overexpression of DNMT1 in PDAC cells. Furthermore, we found n-BP-mediated DNMT1 suppression influenced the protein stability rather than changing the RNA expression. Through microarray studies, we found that the patched domain contained 4 (PTCHD4) is the potential downstream gene of DNMT1. Following silencing of PTCHD4 expression by siRNA, n-BP decreased tumor growth inhibition. Finally, in vivo, two animal models were used to evaluate the efficacy and survival after n-BP treatment by interstitial control release polymer delivery. The results show that n-BP could effectively inhibit PDAC tumor volume growth and extend animal survival. In summary, n-BP may inhibit the growth of human PDAC cells though reducing DNMT1 and increasing the expression of PTCHD4 both in vitro and in vivo.

Expression of Estrogen and Progesterone Receptor in Tumor Stroma Predicts Favorable Prognosis of Cervical Squamous Cell Carcinoma.

OBJECTIVES: The aim of this study was to investigate the expression of estrogen receptor α (ERα) and progesterone receptor B (PRB) in the stroma and carcinoma tissues of cervical cancer and their relationship to clinical characteristics and the status of human papillomavirus (HPV) infection. METHODS: Expressional levels of ERα and PRB in tissue blocks of 95 cervical carcinomas were independently scored by 2 pathologists. Human papillomavirus DNA, viral load, and genotypes were determined by polymerase chain reaction. Clinical characteristics were reviewed from chart and cancer registry. RESULTS: Estrogen receptor α and PRB were mainly expressed in the stroma but not in the carcinoma tissues of the cervical cancer, and their expressions were highly correlated. More stromal ERαs were found in early-stage tumors than in advanced-stage tumors. Greater stromal expressions of ERα and PRB were associated with a more favorable prognosis (P = 0.018 and P = 0.004, respectively). The expressions were not related to the differentiation of cancer, the status of HPV infection, the HPV load, or the genotype. In multivariate analysis, stromal ERα and PRB expressions were independently associated with a lower risk of mortality. The adjusted hazard ratios of mortality for low and high expressions of ERα were 0.19 (95% confidential interval [95% CI], 0.04-0.87) and 0.15 (95% CI, 0.03-0.81), respectively, whereas for low and high expressions of PRB hazard ratios were 0.46 (95% CI, 0.19-1.16) and 0.24 (95% CI, 0.06-0.96), respectively. CONCLUSIONS: This study showed that stromal ERα and PRB expressions are independent prognostic indicators of cervical squamous cell carcinoma.

Human pituitary tumor-transforming gene 1 overexpression reinforces oncogene-induced senescence through CXCR2/p21 signaling in breast cancer cells.

INTRODUCTION: hPTTG1 (human pituitary tumor-transforming gene 1) is an oncogene overexpressed in breast cancer and several other types of cancer. Increased hPTTG1 expression has been shown to be associated with poor patient outcomes in breast cancer. Although hPTTG1 overexpression plays important roles in promoting the proliferation, invasion, and metastasis of cancer cells, it also has been suggested to induce cellular senescence. Deciphering the mechanism by which hPTTG1 overexpression induces these contradictory actions in breast cancer cells is critical to our understanding of the role of hPTTG1 in breast cancer development. METHODS: MCF-10A and MCF-7 cells were used to identify the mechanism of hPTTG1-induced senescence. The interplay between hPTTG1 overexpression and chemokine C-X-C motif receptor 2 (CXCR2)/p21-dependent senescence in tumor growth and metastasis of MCF-7 cells was investigated by orthotopic transplantation of severe combined immunodeficiency (SCID) mice. Additionally, human invasive ductal carcinoma (IDC) tissue arrays were used to confirm the hPTTG1/CXCR2/p21 axis established in vitro. RESULTS: In this study, we investigated the mechanism of hPTTG1-induced senescence as well as its role in breast cancer progression and metastasis. Herein, we showed that hPTTG1 overexpression reinforced senescence through the CXCR2/p21 signaling. Furthermore, hPTTG1 overexpression activated NF-κB signaling to transactivate the expression of interleukin (IL)-8 and growth-regulated oncogene alpha (GROα) to execute CXCR2 signaling in MCF-7 cells. When CXCR2 expression was knocked down in hPTTG1-overexpressing MCF-7 cells, hPTTG1-induced senescence was abrogated by alleviating CXCR2-induced p21 expression. In a mouse model, CXCR2-mediated senescence limited hPTTG1-induced tumor growth and metastasis. Moreover, CXCR2 knockdown in hPTTG1-overexpressing MCF-7 tumors dramatically accelerated tumor growth and metastasis. Our in vitro and in vivo results demonstrated that hPTTG1 overexpression reinforces senescence through CXCR2 signaling, and the evasion of CXCR2/p21-dependent senescence was critical to hPTTG1 exerting its oncogenic potential. Interestingly, although CXCR2-dependent senescence restrained hPTTG1-induced tumor progression, when MCF-7 cells and hPTTG1-overexpressing MCF-7 cells were co-transplanted into the mammary fat pads of SCID mice, hPTTG1-overexpressing senescent cells created a metastasis-promoting microenvironment that promoted lung metastasis of the MCF-7 cells. Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis. CONCLUSIONS: Our findings provide novel molecular insights into hPTTG1-induced senescence and identify a novel mechanism by which hPTTG1 promotes metastasis by regulating the senescence-associated microenvironment.