Sex hormone receptors in gastric cancer

Gastric adenocarcinoma that originates from mucosal tissue invades submucosa, muscle, and serosa in different stages. The level of progesterone receptors (PgR), estrogen receptors (ER), and androgen receptors (AdR) in the superficial part of gastric cancer tissues (CAs) from 16 patients was determined and compared with that of the corresponding normal gastric mucosal tissues (NLm). There were PgR in all CAs (100%) with values that ranged from 20.5 to 548.4 fmol/mg protein. Eight CAs (50%) had ER values that ranged from 6.8 to 325.1 fmol/mg protein. AdR was found in two CAs with values of 14.7 and 16.4 fmol/mg protein. In NLm, 15 (93.8%) had PgR values that ranged from 7.3 to 473.2 fmol/mg protein and ten (62.5%) had ER values that ranged from 0.9 to 87.9 fmol/mg protein. AdR were present in two NLm with values of 1.5 and 73.5 fmol/mg protein. There was no statistical difference in levels of PgR and ER between CAs and NLm. There were PgR in all gastric cancers and in 93.8% of NLm. The results suggest that gastric mucosa may be the target tissues for progesterone action. Furthermore, the lack of correlation between the levels of ER and PgR in gastric cancer tissue suggests that the PgR in gastric cancers are probably estrogen independent.     

Sex hormone balance in prostate cancer]

In cancer of the prostatic gland of stage II--III in males, 50--60 years, a reduced gonadial endocrine function is observed, that is manifested in a considerably reduced excretion of testosterone and estrogen. Because of the different rate of reduction in the testosterone and estrogen excretion in patients 50--69 years of age, one may observe the state of relative and in 70--80 years old patients--absolute hyperandrogenization of the organism, which is likely to be an unfavorable factor, taking into account the property of testosterone metabolites (dihydrotestosterone in particular) to enhance proliferative processes in the prostatic gland.     

One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk

One-carbon metabolism biomarkers are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs. We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre) and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk. Furthermore, the relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case–control study of 613 CRC cases and 1,190 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5′-phosphate and riboflavin. Associations with CRC risk were estimated using conditional logistic regression. We found that the ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. In addition, associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high vs. low B-vitamin status). In conclusion, ratio-based B-vitamin markers were good predictors of total B-vitamin status and displayed similar associations as total B-vitamin status with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice.     

Sex hormone excretion in stomach cancer patients]

Study on the balance of sex hormones in 43 males and 45 females with gastric cancer indicated the presence of some deviations from normal level of androgens and estrogens excretion in gastric cancer patients. The character and intensity of the deviations observed were dependent on patients' sex and stage of the disease. In males the leading factor in sex hormones excretion disorders is a regular decrease both of 17-KS and estrogens, and only in stage UV hyperestrogenization phenomena are observed on account of active estrogens being predominant over androsterone. In females relative hyperestrogenization was observed already in stage III on acount of androsterone decrease, while in stage IV--due to reduction of total 17-KS in normal level of total enstrogens.     

Histochemical tumor markers for evaluation of hormone dependence in breast cancer

Lectin from the peanut (peanut agglutinin = PNA) possesses a high affinity for D-galactosyl-(1-3)-N-acetyl-D-galactosamine, used for histochemical investigations on formalin-fixed tissue sections of normal mammary gland as well as of benign and malignant breast diseases. Thereby, a lectin-binding pattern was found that partly exhibited secretory malfunction. Additional studies with a labeled antibody directed against a milk fat globule membrane glycoprotein, which was isolated by PNA affinity chromatography from human milk, confirmed the PNA receptor as a marker of a milk protein in breast carcinomas. The most important clinicopathological finding, however, was that in accordance with the secretory activity about 77% of PNA-positive tumors responded to endocrine treatment, whereas PNA-negative mammary carcinomas usually failed to show any response to hormonal therapy. These results also correlated with the hormone receptor content of tumor tissue.     

Sex steroid hormone receptors in cancer of the pancreas

Samples of tumor tissue from 11 patients with pancreatic carcinoma were studied for cytoplasmic receptors of androgens and estrogens. Androgen receptors were identified in most tumors suggesting hormone-dependent nature of pancreatic cancer. Application of antiandrogens for pancreatic cancer treatment is discussed.     

tRNA breakdown products as markers for cancer

Seven breakdown products of tRNA were quantitated by high pressure liquid chromatography in urine and were related to the creatinine content. In the urine of 26 of 27 patients with 13 different malignancies, there was an elevation of one or more of these "markers." The levels of excretion vary approximately with the stage of the disease.     

性激素及其受体与食管癌的关系

研究表明食管癌组织上存在性激素受体,但食管癌内分泌治疗的研究尚存在许多不一致的结果.现就性激素(雌雄激素)、性激素受体(ER、AR)与食管癌的关系作一综述,以分析食管癌内分泌治疗的可行性及存在的问题.     

Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR −/−) participating in a breast cancer case–control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER−/PR− breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER−/PR− breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER−/PR− breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.     

Usefulness of lymphocyte-to-monocyte,neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy

Background

Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT.

Methods

A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS).

Results

Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress.

Conclusion

High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.

     

血清性激素水平和体重指数与绝经后女性乳腺癌发病的相关性研究

目的 探讨绝经后女性乳腺癌的发病与血清性激素水平和体重指数的关系。方法 选择2013年3月—12月在哈尔滨医科大学附属肿瘤医院乳腺外科接受手术治疗的初诊绝经后乳腺癌118例作为病例组以及60例绝经后乳腺良性病变者作为对照组,并收集所有受试对象的身高、体重等基本资料。应用酶联免疫吸附实验(ELISA)方法检测受试对象的血清雌二醇(Estradiol,E2)、雌酮(Estrone,E1)、睾酮(Testesterone,TSTO)以及雄烯二酮(Androstenedione,AED)水平,并对结果进行分析。结果 病例组血清E2、E1、AED水平显著高于对照组(P＜0.05),病例组的血清TSTO平均水平稍高于对照组,但差异无统计学意义(P＞0.05);病例组体重指数(BMI)与对照组无明显差异(P＞0.05);病例组血清E1以及总研究对象的血清E1、TSTO、AED在超重组内的水平明显高于非超重组(P＜0.05),未发现其余各组的激素水平与BMI指数具有相关性(P＞0.05)。结论 绝经后女性乳腺癌患者的血清性激素水平升高,血清E2、E1、AED水平升高可能是与绝经后女性乳腺癌的发病相关,BMI高的绝经后女性的血清性激素水平较高。     

New pre-treatment eosinophil-related ratios as prognostic biomarkers for survival outcomes in endometrial cancer

Background

Systemic inflammation has long been related with adverse survival outcomes in cancer patients, and its biomarkers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), are recognized as poor prognostic indicators. However, the role of eosinophils in this field has been largely overlooked. Here, we describe two new pre-treatment biomarkers, expressed as Eosinophil-to-Lymphocytes Ratio (ELR) and Eosinophil*Neutrophil-to-Lymphocytes ratio (ENLR), and we analyse their impact on prognosis of endometrial cancer (EC) patients.

Methods

A total of 163 consecutive patients diagnosed with EC and treated with postoperative radiotherapy +/? chemotherapy in our institution from January 2011 to December 2015 were evaluated. The cohort was divided in two groups applying the cut-off value of 0.1 and 0.5 according to ROC curve for pre-treatment ELR and ENLR, respectively. After patients’ stratification according to the ESMO-ESGO-ESTRO modified risk assessment, subgroup analyses were conducted.

Results

Higher values of ELR and ENLR were associated with worse OS (p?=?0.004 and p?=?0.010, respectively). On univariate analysis, the factors associated with shorter OS were ELR?≥?0.1 (HR?=?2.9, p?=?0.017), ENLR ≥ 0.5 (HR?=?3.0, p?=?0.015), advanced FIGO stage (HR?=?3.4, p?=?0.007), endometrioid histology (HR?=?0.26, p?=?0.003) and ESMO-ESGO-ESTRO high-risk (HR?=?10.2, p?=?0.023). On multivariate Cox regression, higher ELR and ENLR were independently associated with a worse outcome adjusted for the standardly applied prognostic factors.

Conclusions

Increased values of ELR and ENLR portend worse OS in EC, especially in patients classified by the ESMO-ESGO-ESTRO guidelines as a high-risk group. To our best knowledge, this is the first report describing eosinophils-related ratios as prognostic biomarkers in malignant tumours.

     

Age-dependent changes in breast cancer hormone receptors and oxidant stress markers

Breast cancer incidence increases with age but this relationship has not been fully explored with regard to expression of estrogen receptor (ER) and ER-inducible genes (PR, pS2, Bcl2, cathepsin D), or the age-dependence of oxidant stress markers that also affect ER-inducible gene expression. In this three-part study, we first correlated age at diagnosis with expression of breast cancer markers ER, PR, pS2, Bcl2, and cathepsin D, quantitated by enzyme immunoassays from a European collective of 3000 cryobanked primary breast cancers and 300 adjacent non-malignant breast tissues. Results were then compared with ER and PR data reported to the SEER registry for 83,541 US cancers diagnosed during 1992–1997. Lastly, a homogeneous subset of 70 ER-positive tumors preselected from the European collective was blindly analyzed for age-specific changes in the DNA-binding content of redox-sensitive transcriprtion factors, AP1 and Sp1, and the oxidant stress-activated protein kinase, phosphorylated(P)-Erk5. Increases in breast tumor ER from patients aged <30 to >80 years mirrored 10-fold lower increases in non-malignant breast tissue ER content up to age 60, rising faster thereafter and reaching a near 25-fold differential between malignant and non-malignant breast tissue by age 80. ER-inducible markers PR, pS2, Bcl2, and cathepsin D were overexpressed in tumors relative to non-malignant breast tissue but, unlike ER, did not increase with patient age. While SEER data demonstrated that the increase in US breast cancer incidence rates after age 50 is confined to ER-positive tumors in patients of all ethnic subsets, these patients also showed a striking increase in the proportion of higher-risk ER-positive/PR-negative breast cancers arising after age 50. Mechanistically essential for ER-inducible PR expression, Sp1 DNA-binding function (but not Sp1 content) was lost with age in ER-positive tumors; and this functional defect correlated with increased tumor content of the oxidant stress marker, P-Erk5. Altogether these findings support two hypotheses: (i) dysregulated ER expression underlies the age-specific increase in breast cancer incidence after age 50; and (ii) oxidative stress and loss of Sp1 DNA-binding may contribute to an increasing incidence in higher-risk ER-positive/PR-negative breast cancers with aging.     

Circulating microRNAs in plasma as early detection markers for breast cancer

In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time‐point of diagnosis) and healthy control individuals using TaqMan low‐density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT‐qPCR. Four miRNAs (miR‐148b, miR‐376c, miR‐409‐3p and miR‐801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR‐148b, miR‐409‐3p and miR‐801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood‐based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests.     

Intermediate markers as surrogate endpoints in cancer research

Because studies with surrogate cancer endpoints can be smaller, faster, and substantially less expensive than those with frank cancer outcomes, the use of surrogate endpoints is undeniably attractive. This attractiveness is likely to grow in coming years as the rapidly advancing discoveries in cell and molecular biology generate new therapies requiring testing and new markers that could plausibly serve as surrogates for cancer. Surrogate endpoint studies can certainly be suggestive. They continue to play a legitimate role in phase II studies, and they may give the right answers about intervention effects on or exposure associations with cancer. The problem is the uncertainty attached to most potential surrogates. Except for those few surrogates that are both necessary for and developmentally relatively close to cancer, the existence of plausible alternative pathways makes inferences about cancer from many surrogates problematic. Merely being on the causal pathway to cancer does not in itself constitute surrogate validity. It is the totality of causal connections that is critical. There is, unfortunately, a fairly extensive history of quite plausible surrogate markers giving the wrong answer about various chronic disease therapies. There is no reason to believe that cancer surrogacy is immune to such inferential difficulties. This article is, in part, an invitation, even a plea, for researchers to carry out the investigations necessary to evaluate potential surrogates, particularly surrogate-cancer studies and intervention or exposure-surrogate-cancer mediation analyses. Such studies are needed to generalize from surrogate endpoint findings to cancer. There is, however, an implicit and perhaps unavoidable irony here: the large, long, expensive studies required to evaluate potential surrogates fully are precisely the studies that surrogates were designed to replace. The exposure dependence alluded to earlier complicates matters further: establishing validity for a given surrogate for one intervention or exposure vis-à-vis cancer does not necessarily translate into validity for another intervention or exposure. One can enhance the inferential strength of surrogacy by using further "downstream" markers. Results of trials with CIN3 as an endpoint are arguably more persuasive than those from intervention studies with HPV infection endpoints. Similarly, one could consider only the advanced adenoma (> or = 1 cm, villous elements, or high-grade dysplasia) as the primary endpoint in adenoma recurrence trials. The inferential gain, however, comes with substantial costs: studies with CIN3 endpoints must be much larger than those with HPV infection endpoints; adenoma recurrence trials with sufficient rates of recurrence of advanced adenomas must be five or six times larger than trials with any recurrent adenomas as endpoints. A law emerges here: in using surrogate endpoints, inferential certainty is directly associated with study cost. In other words, one gets what one pays for. The problems inherent in using surrogate endpoints need not be regarded as a cause for pessimism in cancer research. If anything, the limitations of surrogacy are reminders of the complexity of cancer causation and affirm the continued importance of large clinical trials and observational epidemiologic studies with explicit cancer endpoints.     

Molecular markers as therapeutic targets in lung cancer

Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women.Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment,advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens.As conventional treatments for lung cancer reach their limitations,researchers have attempted to discover novel drug therapies aimed at specific targets contributing to the progression of tumorigenesis.Recent advances in systems biology have enabled the molecular biology of lung carcinogenesis to be elucidated.Our understanding of the physiologic processes of tumor development provide a means to design more effective and specific drugs with less toxicity,thereby accelerating the delivery of new drug therapies to the patient’s bedside.