Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia.

Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARγ, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH.

Correlation between aggression at the veterinary clinic and problem behaviors at home for cats in the USA.

OBJECTIVES: The aim of the study was to determine whether cats that exhibit aggression during veterinary visits are more likely to have behavior problems at home. METHODS: An online, anonymous, cross-sectional survey was developed and distributed to residents in the USA who were aged over 18 years and who were the primary owners of at least one cat. The survey collected information about cat and household factors, and utilized a validated questionnaire instrument for obtaining behavioral information of pet cats. RESULTS: Aggression at the veterinary clinic was reported in 42.6% of the cats. The frequency of aggression exhibited at the veterinary clinic was lower in cats that lived in multi-cat households. Most cats did not receive medications intended to reduce fear, anxiety and/or pain before veterinary visits. Aggression at the veterinary clinic was positively associated with behavior problems at home, including stranger-directed aggression, owner-directed aggression, resistance to restraint, familiar cat aggression, dog-directed aggression, house-soiling, separation-related behaviors and scratching claws on inappropriate surfaces indoors. CONCLUSIONS AND RELEVANCE: Cats that exhibit aggression at the veterinary clinic are more likely to exhibit aggression and anxiety-related behaviors at home. Veterinarians should screen cats that exhibit aggression at the veterinary clinic for behavior problems at home to institute prompt diagnosis and treatment.

TGF-ß and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma.

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Unveiling the genomic landscape of possible metastatic malignant transformation of teratoma secondary to cisplatin-chemotherapy: a Tempus gene analysis-based case report literature review.

In this case report, we describe a patient who developed metastatic liver cancer of unknown primary origin one year following the surgical removal of a retroperitoneal adenocarcinoma. The retroperitoneal adenocarcinoma is considered a malignant transformation of teratoma (MTT), given the patient's distant history of testicular tumor excised 25 years prior and treated with chemotherapy. Despite no primary tumor being identified, the leading primary hypothesis is that the liver metastasis stemmed from the resected retroperitoneal adenocarcinoma from one year prior. We theorize that the patient's cisplatin-based chemotherapy 25 years ago may have triggered the MTT, as documented in the existing literature. Using TEMPUS gene testing on both the retroperitoneal adenocarcinoma and the recently discovered liver metastasis, we identified several genes with variants of unknown significance (VUS) that could potentially be linked to cisplatin chemotherapy resistance. While we cannot conclude that this patient definitively underwent MTT, it remains the most plausible explanation. Future research should investigate both the validity of the genes we have uncovered with respect to cisplatin resistance, as well as other genes associated with cisplatin resistance to further understand the pathogenesis of cisplatin resistance for better prediction of treatment response. As the world of medicine shifts towards individualized therapies and precision medicine, reporting and analyzing genetic mutations derived from tumors remains imperative. Our case report aims to contribute to the growing database of defined mutations and underscores the immense potential of genetic analysis in directing personalized treatment options.

GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma.

BACKGROUND: Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. METHOD: In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. RESULTS: PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19-9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19-9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. CONCLUSION: Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

Highly differentiated follicular carcinoma of ovary: Use of imprint cytology at intraoperative consultation.

Highly differentiated follicular carcinoma of ovary (HDFCO) is a rare entity known to arise in struma ovarii. Clinical presentation and radiological features mimic other cystic ovarian neoplasm. Thus, intraoperative diagnosis of this entity can be challenging. We hereby report a HDFCO case of a 52-year-old woman, who presented with significant abdominal bloating for 3 months. Imaging showed a 11.7 cm left adnexal-mixed cystic and solid mass, adhering to the bowel with ascites. The mass was examined intraoperatively and showed multilocular cysts filled with straw or red brown-colored gelatinous fluid. Microscopically, the tumor consisted of small and large follicles with proteinous material and bland-looking cuboidal cells, suspicious for struma ovarii or granulosa cell tumor with extensive cystic changes, while imprint cytology slides showed watery colloid with cracking artifact favoring the former. However, the adherence to the bowel suggested HDFCO, and prompted surgical staging. The histology of the ovarian mass in the permanent section resembled goiterous thyroid tissue with invasion of endocervical stroma, uterine wall and colonic serosa, and presence of tumor nodules in omentum leading to the diagnosis of HDFCO. Due to striking resemblance of HDFCO to benign thyroid goiter, searching for invasive and metastatic foci is crucial for correct diagnosis. In addition, intraoperative imprint cytology revealing colloid with cracking artifact is helpful for differentiating struma ovarii and/or HDFCO from other ovarian lesions.

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer.

Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29-0.99) and 0.31 (95% confidence interval, 0.16-0.60), respectively (Ptrend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (Ptrend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (Ptrend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Night-Shift Work Duration and Risk of Colorectal Cancer According to IRS1 and IRS2 Expression.

BACKGROUND: We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status. METHODS: Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on IRS1 and IRS2, respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor IRS1 or IRS2 expression by immunohistochemistry (IHC). RESULTS: Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer (P trend = 0.06; multivariable HR = 1.20; 95% CI, 0.99-1.45). Longer duration of night-shift work was associated with a higher risk of IRS2-positive tumors (multivariable HR = 2.69; 95% CI, 1.48-4.89; P trend = 0.001, ≥15 years night shifts vs. never) but not with IRS2-negative tumors (multivariable HR = 0.90; 95% CI, 0.54-1.51; P trend = 0.72; P heterogeneity for IRS2 = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for IRS1-positive tumors (95% CI, 0.94-3.48; P trend = 0.06) and 1.13 for IRS1-negative tumors (95% CI, 0.71-1.80; P trend = 0.56; P heterogeneity for IRS1 = 0.02). CONCLUSIONS: Our molecular pathologic epidemiology data suggest a potential role of IRS in mediating carcinogenesis induced by night-shift work. IMPACT: Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.

The iron deficiency response in Arabidopsis thaliana requires the phosphorylated transcription factor URI.

Iron is an essential nutrient for plants, but excess iron is toxic due to its catalytic role in the formation of hydroxyl radicals. Thus, iron uptake is highly regulated and induced only under iron deficiency. The mechanisms of iron uptake in roots are well characterized, but less is known about how plants perceive iron deficiency. We show that a basic helix-loop-helix (bHLH) transcription factor Upstream Regulator of IRT1 (URI) acts as an essential part of the iron deficiency signaling pathway in Arabidopsis thaliana The uri mutant is defective in inducing Iron-Regulated Transporter1 (IRT1) and Ferric Reduction Oxidase2 (FRO2) and their transcriptional regulators FER-like iron deficiency-induced transcription factor (FIT) and bHLH38/39/100/101 in response to iron deficiency. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) reveals direct binding of URI to promoters of many iron-regulated genes, including bHLH38/39/100/101 but not FIT While URI transcript and protein are expressed regardless of iron status, a phosphorylated form of URI only accumulates under iron deficiency. Phosphorylated URI is subject to proteasome-dependent degradation during iron resupply, and turnover of phosphorylated URI is dependent on the E3 ligase BTS. The subgroup IVc bHLH transcription factors, which have previously been shown to regulate bHLH38/39/100/101, coimmunoprecipitate with URI mainly under Fe-deficient conditions, suggesting that it is the phosphorylated form of URI that is capable of forming heterodimers in vivo. We propose that the phosphorylated form of URI accumulates under Fe deficiency, forms heterodimers with subgroup IVc proteins, and induces transcription of bHLH38/39/100/101 These transcription factors in turn heterodimerize with FIT and drive the transcription of IRT1 and FRO2 to increase Fe uptake.

Non-linear Relationship Between Body Mass Index and Lower Urinary Tract Symptoms in Korean Males.

OBJECTIVES: The purpose of this study was to evaluate the association between body mass index (BMI) and severe lower urinary tract symptoms (LUTS) in Korean males. METHODS: This study was conducted on males aged ≥50 years who participated in the 2011 Korean Community Health Survey. LUTS severity was assessed using the Korean version of the International Prostate Symptom Score (IPSS) questionnaire, and was dichotomized as severe (IPSS >19) and non-severe (IPSS ≤19). BMI was divided into 6 categories: <18.5, 18.5-22.9, 23.0-24.9, 25.0-27.4, 27.5-29.9, and ≥30.0 kg/m2. To evaluate the relationship between BMI and LUTS, a survey-weighted multivariate Poisson regression analysis was performed to estimate prevalence rate ratios (PRRs). Age, smoking status, alcohol intake, physical activity, educational level, household income, and comorbidities were adjusted for in the multivariate model. RESULTS: A U-shaped relationship was detected between BMI and severe LUTS. Compared with a BMI of 23.0-24.9 kg/m2, the PRR for a BMI <18.5 kg/m2 was 1.65 (95% confidence interval [CI], 1.35 to 2.02), that for a BMI of 18.5-22.9 kg/m2 was 1.25 (95% CI, 1.09 to 1.44), that for a BMI of 25.0-27.4 kg/m2 was 1.20 (95% CI, 1.00 to 1.45), that for a BMI of 27.5-29.9 kg/m2 was 1.11 (95% CI, 0.83 to 1.47), and that for a BMI ≥30.0 kg/m2 was 1.85 (95% CI, 1.18 to 2.88). CONCLUSIONS: This study showed that both high and low BMI were associated with severe LUTS.

Characterization of the hepatosplenic and portal venous findings in patients with Proteus syndrome.

Proteus syndrome (PS) is a rare disorder caused by a mosaic AKT1 variant that comprises patchy overgrowth of tissues derived from all three germinal layers affecting multiple viscera. We sought to delineate the extent of hepatoportal manifestations in patients with PS. We identified patients with PS who had abdominal imaging from 1989 to 2015 in a natural history study. Imaging was characterized for evidence of focal findings in the liver, spleen, and portal vasculature and for organomegaly. Relevant clinical and laboratory data were compared among those with or without organomegaly. Abdominal imaging was available on 38 patients including 20 who had serial studies. Nine patients had focal hepatic lesions including vascular malformations (VMs). Focal splenic abnormalities were noted in seven patients. Patients without cutaneous VMs did not have visceral VMs. Nine patients had splenomegaly, 12 had portal vein dilation, and 4 had hepatomegaly. There was a weak correlation of portal vein dilation to spleen height ratio (r2 = 0.18, p < .05). On laboratory evaluation, hepatic function was normal but there was thrombocytopenia in those with splenomegaly; platelet counts were 179 ± 87K/µL compared to those with normal spleen size at 253 ± 57K/µL (p < .05). Overall, focal hepatosplenic abnormalities occurred in 11 of 38 (29%) patients with PS. Splenomegaly and portal venous dilation were both found in 8 of 38 (21%) patients; however, other than relative thrombocytopenia, there was no evidence of portal hypertension. Although the AKT1-E17K somatic variant is a suspected oncogene, there were no malignant lesions identified in this study.

Association of Coffee and Tea with Ferritin: Data from the Korean National Health and Nutrition Examination Survey (IV and V).

There have been few studies that have evaluated the association between coffee intake and iron in Korean population. Data from the Korean National Health and Nutrition Examination Survey (IV and V; 2007-2012) was used to investigate the association between coffee and green tea intake and serum ferritin levels in Korean adults. Beverage intake was assessed using a food frequency questionnaire. Multivariate linear regression was performed to evaluate the relationship between coffee and tea intake and serum ferritin levels, after adjusting for age, body mass index, education level, smoking status, alcohol consumption, physical activity, hypertension, diabetes mellitus, and daily iron intake. Coffee intake was negatively related to serum ferritin levels in both sexes. The multivariate-adjusted geometric mean of serum ferritin level was 100.7 ng/mL (95% confidence interval [CI]: 98.2-103.4) in men drinking <1 coffee/day, and 92.2 ng/mL (95% CI: 89.7-94.8) in those drinking ≥3 coffees/day. In women, the equivalent serum ferritin levels were 35.6 ng/mL (95% CI: 34.8-36.4) and 28.9 ng/mL (95% CI: 27.8-30.1). However, green tea intake was not related to serum ferritin levels. In conclusion, coffee consumption was associated with lower serum ferritin levels in Korean adults.

Association between Smoking and Unintentional Injuries among Korean Adults.

Using a cross-sectional representative national survey, we evaluated the relationship between cigarette smoking and unintentional injuries among Korean adults. We used data from the 2009 Korean Community Health Survey. Smoking status was defined as never smokers, ex-smokers, and current smokers. Current smokers were categorized into light daily smokers (1-10 cigarettes/day), moderate daily smokers (11-20 cigarettes/day), or heavy daily smokers (≥21 cigarettes/day). We used the Poisson regression model with a robust variance estimation to estimate prevalence rate ratios (PRR) and corresponding 95% confidence interval (95% CI). After adjusting for demographic characteristics, socioeconomic variables, lifestyle variables, and health status variables, former smokers (PRR, 1.19, 95% CI 1.11-1.28), light daily smokers (PRR 1.22, 95% CI 1.13-1.32), moderate daily smokers (PRR 1.33, 95% CI 1.24-1.42), and heavy daily smokers (PRR 1.40, 95% CI 1.25-1.57) had an increased risk for unintentional injuries compared with non-smokers. In conclusion, cigarette smoking is associated with unintentional injuries in a dose-response manner in Korean adults. The findings suggest that community smoking cessation programs may reduce morbidity and mortality from unintentional injuries.

Increased number of arginase 1-positive cells in the stroma of carcinomas compared to precursor lesions and nonneoplastic tissues.

Arginase 1 (Arg1) is involved in dampening the response of antitumor T lymphocytes. Arg1 expression has been reported in a variety of cancer cell lines and tumor-associated myeloid-derived cells. However, its examination in situ in tumor microenvironment is poorly investigated. We examined the Arg1-positive cells in tumor microenvironment of gastric carcinomas (GCs), colorectal carcinomas (CRCs) and prostate carcinomas (PCs), and analyzed their clinicopathological significance. Immunohistochemical staining for Arg1 was done in 60 GCs, 38 gastric adenomas, 40 CRCs, 10 colonic adenomas, 36 PCs, and 15 benign prostatic hyperplasia (BPH). Arg1 expression was predominantly localized in tumor microenvironment and the stroma of nonneoplastic tissues. Cells with Arg1 expression were mostly leukocytes, morphologically resembling polymorphonuclear neutrophils, and showed CD15 expression. Arg1 expression was focally expressed in cancer cells of 6 PCs, but not in those of GCs and CRCs. Arg1-positive cells were significantly more infiltrated in tumors than adenomas and nonneoplastic tissues, such as BPH, intestinal metaplasia and adjacent tissues. There were no significant findings between them and clinicopathological parameters, except for the relationship to gender and tumor differentiation in CRCs. These findings suggest that Arg1-positive cells in tumor microenvironment is involved in the occurrence of GCs, CRCs, and PCs. More expansive studies are necessary to better elucidate their clinicopathological significance in carcinomas.

Parathyroid Hormone Levels Are Independently Associated with eGFR and Albuminuria: The Dong-gu Study.

Increased parathyroid hormone (PTH) was associated with cardiovascular mortality and morbidity in CKD patients. Our aim was to investigate the associations among estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR) and PTH independent of 25-hydroxyvitamin D (25(OH)D). This study included 9,162 individuals who completed the baseline survey of the Dong-gu Study, which was conducted in Korea from 2007 to 2010. The eGFR, ACR, PTH and 25(OH)D were measured in participants who met the detailed inclusion criteria. After being adjusting for covariates (sex, age, waist circumference, smoking, alcohol intake, physical activity, hypertension medications, diabetes medication, total cholesterol, triglyceride, HDL cholesterol) and log-ACR, the PTH value stratified by 25(OH)D level significantly decreased with increasing eGFR levels in each 25(OH)D stratum. Moreover, after adjustment for the same covariates and log-eGFR, the PTH value stratified by 25(OH)D level significantly increased with increasing ACR levels in each 25(OH)D stratum. In conclusion, the PTH values significantly decreased with increasing eGFR levels and increased with increasing ACR levels independently of 25(OH)D in an adult Korean population ≥50 y of age.

Combined use of CEMIP and CA 19-9 enhances diagnostic accuracy for pancreatic cancer.

Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5 U/ml (40.8-3342.5) and 0.67 ng/ml (0.40-1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806-0.888) and 0.760 (95% CI: 0.689-0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P < 0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.

Physical Activity and Colorectal Cancer Prognosis According to Tumor-Infiltrating T Cells.

BACKGROUND: Evidence suggests that high-level physical activity may potentially reduce cancer mortality through its immune enhancement effect. We therefore hypothesized that survival benefits associated with physical activity might be stronger in colorectal carcinomas with lower immune reaction at diagnosis. METHODS: Using molecular pathological epidemiology databases of 470 colon and rectal carcinoma cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis physical activity in strata of densities of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in tumor tissue. Cox proportional hazards regression model was used to adjust for potential confounders, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, KRAS, BRAF, and PIK3CA mutations, and expression of CTNNB1 (beta-catenin), PTGS2 (cyclooxygenase-2), and IRS1. RESULTS: The association of postdiagnosis physical activity with colorectal cancer-specific mortality differed by CD3+ cell density (P interaction < .001). Multivariable-adjusted colorectal cancer-specific mortality hazard ratios for a quartile-unit increase in physical activity were 0.56 (95% confidence interval = 0.38 to 0.83) among cases with the lowest quartile of CD3+ cell density compared with 1.14 (95% confidence interval = 0.79 to 1.65) in cases with the highest quartile. We observed no differential survival association of physical activity by densities of CD8+ cells, CD45RO+ cells, or FOXP3+ cells. CONCLUSIONS: The association between postdiagnosis physical activity and colorectal cancer survival appeared stronger for carcinomas with lower T cell infiltrates, suggesting an interactive effect of exercise and immunity on colorectal cancer progression.

Thymic epithelial tumors and metastasis to the brain: a case series and systematic review.

BACKGROUND: Thymic epithelial tumors (TETs) rarely metastasize to the brain. Clinico-pathologic features of TET patients with brain metastasis are not well described. METHODS: TET patients referred for consultation or screening for clinical trials are included. Imaging to evaluate for brain metastases was performed when clinically indicated or if required for screening. Tumor tissue from brain metastases was obtained for analysis, when available. Clinical characteristics and survival was evaluated and a systematic review of the literature on brain metastases associated with TETs was performed. RESULTS: Fourteen TET patients with brain metastasis were identified. Median age at TET diagnosis was 53 years (range: 31-71 years). Twelve patients had thymic carcinoma and two patients had World Health Organization B3 thymoma. Median time from TET diagnosis to discovery of brain metastases was 2.5 years (range: 9 months-8.3 years). Eleven patients had extracranial, extrathoracic metastases during presentation with brain metastases. Three patients underwent surgery and radiation therapy, eight patients received radiation therapy alone, and one patient had surgery alone. One patient with thymoma died 11 months after diagnosis of brain metastases and another patient died but with unknown date of diagnosis of brain metastases. Among 12 patients with thymic carcinoma, 11 of whom had a known date of brain metastases diagnosis, the median potential follow-up is 35.8 months, and median overall survival (OS) from diagnosis of brain metastases is 13.1 months. CONCLUSIONS: Although uncommon, patients with advanced thymic carcinoma can develop brain metastases. Appropriate imaging and aggressive treatment should be considered for these patients.

Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells.

Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44+CD24+ESA+ pancreatic CSCs. PAUF knockdown (shPAUF) CFPAC-1 diminished the number of spheres and decreased stemness genes and CSC surface markers (CD133, c-MET and ALDH1). In addition, siPAUF CFPAC-1 decreased the mRNA expression of multidrug resistant protein 5 (MRP5) and ribonucleotide reductase M2 (RRM2) and were more vulnerable to gemcitabine and 5-FU than negative control (p<0.05). In conclusion, PAUF was increased in pancreatic CSCs and the suppression of PAUF enhances chemotherapeutic response to gemcitabine and 5FU by decreasing MRP5 and RRM2 in pancreatic cancer cells.

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer.

Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3+ cell density (ptrend = 0.006), but not with CD3+, CD8+, or CD45RO+ cell density (with the adjusted α level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3+ cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3+ cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.