Loss of membranous VEGFR1 expression is associated with an adverse phenotype and shortened survival in breast cancer

Angiogenesis is a key process in tumor growth and progression, which is controlled by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). In order to better understand the prevalence and prognostic value of VEGFR1 expression in breast cancer, a tissue microarray containing >2,100 breast cancer specimens, with clinical follow-up data, was analyzed by immunohistochemistry using an antibody directed against the membrane-bound full-length receptor protein. The results demonstrated that membranous VEGFR1 staining was detected in all (5 of 5) normal breast specimens. In carcinoma specimens, membranous staining was negative in 3.1%, weak in 6.3%, moderate in 10.9%, and strong in 79.7% of the 1,630 interpretable tissues. Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both P<0.0001). Cancers with moderate to strong (high) VEGFR1 expression were associated with significantly improved overall survival, as compared with tumors exhibiting negative or weak (low) expression (P=0.0015). This association was also detected in the subset of nodal-positive cancers (P=0.0018), and in the subset of 185 patients who had received tamoxifen as the sole therapy (P=0.001). In conclusion, these data indicated that membrane-bound VEGFR1 is frequently expressed in normal and cancerous breast epithelium. In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy

Transcriptome Analysis in Vulvar Squamous Cell Cancer

To date, therapeutic strategies in vulvar squamous cell carcinoma (VSCC) are lacking molecular pathological information and targeted therapy hasn’t been approved in the treatment of VSCC, yet. Two etiological pathways are widely accepted: HPV induced vs. HPV independent, associated with chronic skin disease, often harboring TP53 mutations (mut). The aim of this analysis was to analyze the RNA expression patterns for subtype stratification on VSCC samples that can be integrated into the previously performed whole exome sequencing data for the detection of prognostic markers and potential therapeutic targets. We performed multiplex gene expression analysis (NanoString) with 770 genes in 24 prior next generation sequenced samples. An integrative data analysis was performed. Here, 98 genes were differentially expressed in TP53mut vs. HPV+ VSCC, in the TP53mut cohort, where 56 genes were upregulated and 42 were downregulated in comparison to the HPV+ tumors. Aberrant expression was primarily observed in cell cycle regulation, especially in HPV+ disease. Within the TP53mut group, a distinct cluster was identified that was correlated to a significantly worse overall survival (p = 0.017). The RNA expression profiles showed distinct patterns with regard to the known VSCC subtypes and could potentially enable further subclassification in the TP53mut group

Thermophysical substantiation of renewable biomass pyrolytic processing due to heat decomposition

Актуальность исследования обусловлена необходимостью увеличения доли использования возобновляемых источников энергии в топливно-энергетическом балансе для снижения вредного воздействия на окружающую среду. Цель: оценка возможности пиролиза древесной биомассы и торфа за счет тепловыделения от разложения органической части сырья. Объекты: образцы торфа с двух месторождений Томской области, являющихся перспективными для разработки в энергетических целях, - Суховского и Аркадьевского, а также древесные отходы двух видов - щепа и опилки. Методы: физический эксперимент и дифференциально-термический анализ. Теплотехнические характеристики древесной биомассы определены с помощью методик ГОСТ Р 56881-2016, ГОСТ 33503-2015 и ГОСТ Р 55660-2013; теплотехнические характеристики торфа - с помощью ГОСТ 11306-2013, ГОСТ 11305-2013 и ГОСТ Р 55660-2013. Теплота сгорания сырья определена на бомбовом калориметре АБК-1 (РЭТ, Россия), элементный состав определен на анализаторе Vario Micro Cube (Elementar, Германия) с учетом содержания диоксида углерода карбонатов, устанавливаемого объѐмным методом согласно ГОСТ 13455-91. Результаты. Установлены оптимальные параметры пиролитической переработки различных видов биомассы - температура пиролиза и влажность исходного сырья. Оптимальной температурой для пиролиза древесных отходов, доведенных до воздушно-сухого состояния, является 400 °C, при которой суммарный тепловой эффект максимален и составляет 36,3 кДж/кг для опилок и 78,8 кДж/кг для щепы, для суховского торфа при 500 °C суммарный тепловой эффект равен 149,7 кДж/кг. Максимальные значения влажности, обеспечивающие покрытие тепловых затрат за счет теплоты экзотермических реакций, при данных температурах пиролиза составили 10 % для древесных отходов и 14 % для суховского торфа. Величина суммарного теплового эффекта пиролиза аркадьевского торфа даже в сухом состоянии имеет отрицательное значение.The relevance of the research is caused by the need of renewable energy sources share increase in the fuel and energy balance to reduce harmful impact on the environment. The main aim of the research is to evaluate the possibility of woody biomass and peat pyrolysis due to heat from the organic part decomposition of the raw material. Objects: peat samples from two deposits of the Tomsk region, promising for energy development, - Sukhovsky and Arkadievsky, as well as wood waste of two types - chips and sawdust. Methods: physical experiment and differential thermal analysis. Thermotechnical characteristics of woody biomass determined by the methods SS R 56881-2016, SS 33503-2015 and SS R 55660-2013; thermal characteristics of peat - using the SS 11306-2013, SS 113052013 and SS R 55660-2013. Calorific value of raw materials determined in the bomb calorimeter ABK-1 (RET, Russia), the elemental composition is determined by the analyser Vario Micro Cube (Elementar, Germany) taking into account the carbon dioxide content of the carbonates, established by volumetric method according to SS 13455-91. Results. The authors have established the optimal parameters of pyrolytic processing for various types of biomass, such as pyrolysis temperature and moisture of the raw material. The optimum temperature for pyrolysis of wood waste in the air-dry state is 400 °C, at which the total thermal effect is maximum and equal to 36,3 kJ/kg for sawdust and 78,8 kJ/kg for wood chips, for sukhovskoy peat at 500 °C total heat effect is equal to 149,7 kJ/kg. The maximum values of moisture, providing coverage of heat costs due to the heat of exothermic reactions, at these pyrolysis temperatures were 10 % for wood waste and 14 % for sukhovskoy peat. The value of the total thermal effect of arkadievsky peat pyrolysis even in the dry state has a negative value

PSCA expression is associated with favorable tumor features and reduced PSA recurrence in operated prostate cancer

Abstract Background Prostate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear. Methods To clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry. Results PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001). Conclusions The absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests

6q deletion is frequent but unrelated to patient prognosis in breast cancer

Background!#!Deletions involving the long arm of chromosome 6 have been reported to occur in breast cancer, but little is known about the clinical relevance of this alteration.!##!Methods!#!We made use of a pre-existing tissue microarray with 2197 breast cancers and employed a 6q15/centromere 6 dual-labeling probe for fluorescence in situ (FISH) analysis RESULTS: Heterozygous 6q15 deletions were found in 202 (18%) of 1099 interpretable cancers, including 19% of 804 cancers of no special type (NST), 3% of 29 lobular cancers, 7% of 41 cribriform cancers, and 28% of 18 cancers with papillary features. Homozygous deletions were not detected. In the largest subset of NST tumors, 6q15 deletions were significantly linked to advanced tumor stage and high grade (p &amp;lt; 0.0001 each). 6q deletions were also associated with estrogen receptor negativity (p = 0.0182), high Ki67 proliferation index (p &amp;lt; 0.0001), amplifications of HER2 (p = 0.0159), CCND1 (p = 0.0069), and cMYC (p = 0.0411), as well as deletions of PTEN (p = 0.0003), 8p21 (p &amp;lt; 0.0001), and 9p21 (p = 0.0179). However, 6q15 deletion was unrelated to patient survival in all cancers, in NST cancers, or in subsets of cancers defined by the presence or absence of lymph-node metastases.!##!Conclusion!#!Our data demonstrate that 6q deletion is a frequent event in breast cancer that is statistically linked to unfavorable tumor phenotype and features of genomic instability. The absence of any prognostic impact argues against a clinical applicability of 6q15 deletion testing in breast cancer patients

Frequency of Androgen Receptor Positivity in Tumors: A Study Evaluating More Than 18,000 Tumors

Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3–100%) and neoplasms of the prostate (79.3–98.7%), breast (25.0–75.5%), other gynecological tumors (0.9–100%), kidney (5.0–44.1%), and urinary bladder (5.4–24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; p p p p p = 0.0024) in invasive breast carcinoma; high pT (p p p = 0.0055) as well as high grade (p < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy

Inhibin Alpha Expression in Human Tumors: A Tissue Microarray Study on 12,212 Tumors

As a result of its expression in corresponding normal cell types, inhibin alpha (INHA) is used as an immunohistochemical marker for adrenocortical neoplasms and testicular or ovarian sex cord stromal tumors. However, other tumors can also express INHA. To comprehensively determine INHA expression in cancer, a tissue microarray containing 15,012 samples from 134 different tumor types and subtypes was analyzed by immunohistochemistry. INHA positivity was found in 72 of 134 tumor categories, including 26 categories with &ge;1 strongly positive case. A moderate to strong INHA positivity was found in 100% of 37 granulosa cell tumors of the ovary, 100% of 43 other sex cord stromal tumors of the ovary/testis, 100% of 31 granular cell tumors, 78.5% of 28 adenomas, 44% of 25 carcinomas of the adrenal cortex, and 46.7% of 15 pancreatic acinar cell carcinomas. At least a weak INHA positivity was seen in &lt;33% of cases of 46 additional tumor entities. In summary, these data support the use of INHA antibodies for detecting sex cord stromal tumors, granular cell tumors, and adrenocortical neoplasms. Since INHA can also be found in other tumor entities, INHA immunohistochemistry should only be considered as a part of any panel for the distinction of tumor entities

DOG1 overexpression is associated with mismatch repair deficiency and BRAF mutations but unrelated to cancer progression in colorectal cancer

Introduction. The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations. Methods. A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry. Results. DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p<0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes. Conclusion. Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity

High prevalence of p16 staining in malignant tumors.

p16 (CDKN2A) is a member of the INK4 class of cell cycle inhibitors, which is often dysregulated in cancer. However, the prevalence of p16 expression in different cancer types is controversial. 15,783 samples from 124 different tumor types and 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. p16 was detectable in 5,292 (45.0%) of 11,759 interpretable tumors. Except from adenohypophysis in islets of Langerhans, p16 staining was largely absent in normal tissues. In cancer, highest positivity rates were observed in uterine cervix squamous cell carcinomas (94.4%), non-invasive papillary urothelial carcinoma, pTaG2 (100%), Merkel cell carcinoma (97.7%), and small cell carcinomas of various sites of origin (54.5%-100%). All 124 tumor categories showed at least occasional p16 immunostaining. Comparison with clinico-pathological data in 128 vulvar, 149 endometrial, 295 serous ovarian, 396 pancreatic, 1365 colorectal, 284 gastric, and 1245 urinary bladder cancers, 910 breast carcinomas, 620 clear cell renal cell carcinomas, and 414 testicular germ cell tumors revealed only few statistically significant associations. Comparison of human papilloma virus (HPV) status and p16 in 497 squamous cell carcinomas of different organs revealed HPV in 80.4% of p16 positive and in 20.6% of p16 negative cancers (p<0.0001). It is concluded, that a positive and especially strong p16 immunostaining is a feature for malignancy which may be diagnostically useful in lipomatous, urothelial and possibly other tumors. The imperfect association between p16 immunostaining and HPV infection with high variability between different sites of origin challenges the use of p16 immunohistochemistry as a surrogate for HPV positivity, except in tumors of cervix uteri and the penis

Large-Scale Tissue Microarray Evaluation Corroborates High Specificity of High-Level Arginase-1 Immunostaining for Hepatocellular Carcinoma

Arginase-1 catalyzes the conversion of arginine to ornithine and urea. Because of its predominant expression in hepatocytes, it serves as a marker for hepatocellular carcinoma, although other tumor entities can also express arginase-1. To comprehensively determine arginase-1 expression in normal and neoplastic tissues, tissue microarrays containing 14,912 samples from 117 different tumor types and 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. In normal tissues, arginase-1 was expressed in the liver, the granular layer of the epidermis, and in granulocytes. Among tumors, a nuclear and cytoplasmic arginase-1 immunostaining was predominantly observed in hepatocellular carcinoma, where 96% of 49 cancers were at least moderately positive. Although 22 additional tumor categories showed occasional arginase immunostaining, strong staining was exceedingly rare in these entities. Staining of a few tumor cells was observed in squamous cell carcinomas of various sites. Staining typically involved maturing cells with the beginning of keratinization in these tumors and was significantly associated with a low grade in 635 squamous cell carcinomas of various sites (p = 0.003). Teratoma, urothelial carcinoma and pleomorphic adenomas sometimes also showed arginase expression in areas with squamous differentiation. In summary, arginase-1 immunohistochemistry is highly sensitive and specific for hepatocellular carcinoma if weak and focal staining is disregarded