Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy

BackgroundPrevious preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists’ follistatin/follistatin-like 3 in intrathoracic tumors.Materials and MethodsPatients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non–small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzyme-linked immunosorbent assay and compared with clinicopathologic parameters.ResultsCirculating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028).ConclusionActivin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response.     

Heparanase Expression Correlates with Angiogenesis and Lymphangiogenesis in Human Lung Cancer

Background and objective Heparanase has been thought to be a good molecular marker of tumor,and the heparanase expression level was correlated closely with tumor metastasis. In this study,we investigate the effects of heparanase on angiogenesis and lymphangiogenesis of lung cancer and the relationship between heparanase expression and vascular endothelial growth factor (VEGF),vascular endothelial growth factor-C (VEGF-C). Methods Immunohistochemistry was used to detect the expression of heparanase,VEGF,VEGF...     

肝素酶及Ki-67在非小细胞肺癌中的表达及临床意义

背景与目的 已有的研究表明,肝素酶与Ki-67抗原与肺癌的发生和转移有关,本研究通过检测非小细胞肺癌(Non-small cell lung cancer,NSCLC)组织中肝素酶(heparanase,Hpa)和Ki-67的表达,以探讨他们的临床意义及相互关系.方法 采用免疫组化方法 (S-ABC法和S-P法)检测70例NSCLC和20例同期良性病变肺组织中肝素酶和Ki-67的表达.结果 肝素酶和Ki-67的阳性表达率分别为72.9%和85.7%,而正常肺组织中两者均无表达;肝素酶表达水平与患者TNM分期及淋巴结转移有关(P=0.044,P=0.001);Ki-67的表达水平与原发肿瘤大小、组织学类型、癌细胞分化程度、淋巴结转移及TNM分期有关(P<0.05);肝素酶和Ki-67的表达差异无统计学意义(P=0.323).结论 肝素酶和Ki-67参与了肺癌的发生和发展,并与预后相关;而肝素酶和Ki-67的表达无相关性,两者可能通过不同的机制参与了肿瘤的发生和发展.     

Heparanase/Syndecan-1 Axis Regulates the Grade of Liver Cancer and Proliferative Ability of Hepatocellular Carcinoma Cells

Background: Although heparanase/syndecan-1 axis is involved in malignant progression of many cancers, its significance in liver cancer is not well understood. In this study, we explored the value of heparanase/syndecan-1 axis expression in liver cancer and the intervention mechanisms that target this axis by inhibiting the proliferation of hepatocellular carcinoma cells. Materials and Methods: We conducted tissue microarray analysis that included 90 primary liver cancer and their corresponding adjacent samples to evaluate the expression of heparanase and syndecan-1 and their correlation with clinicopathologic characteristics. RNA interference and western blot assays were performed to analyze the effect of heparanase on syndecan-1 expression in human hepatocellular carcinoma cells MHCC97-H. Cell proliferative capability, Erk and Akt signaling molecules were respectively detected with CCK- 8, cell colony formation and western blot assays after the treatment of low molecular weight heparin (LMWH) and syndecan-1 monoclonal antibody. Results: Heparanase showed a high positive rates (75.56%) in liver cancer patients. The cellular positivity for membrane-located syndecan-1 was less in liver cancer (36.67%) compared with adjacent tissue (57.78%, P < 0.05). Heparanase expression was positively correlated with tumor grade, stages, and Ki- 67 expression (P < 0.05). In contradistinction, both cytoplasmic and membranal syndecan-1 expression exhibited negative correlations with tumor grade, stages, and Ki-67 expression (P < 0.05). Transfection with a heparanase small-interfering RNA resulted in a significant rise in membrane syndecan-1 expression but a marked decline in shed syndecan-1. LMWH and syndecan-1 monoclonal antibody notably inhibited cellular proliferation. Further studies revealed that LMWH and syndecan-1 monoclonal antibody significantly down-regulated Erk and Akt phosphorylation. Conclusions: Heparanase and syndecan-1 present a contrary correlation with the malignant capability of liver cancer, but work together to facilitate the proliferation of hepatocellular carcinoma cells that can be attenuated by LMWH and syndecan-1 monoclonal antibody by inhibiting Erk and Akt signals.     

Elevated Levels of Plasma Transforming Growth Factor-β in Patients with Hepatocellular Carcinoma

We measured the plasma transforming growth factor-β (TGF-β) concentration in 14 patients with human hepatocellular carcinoma (HCC) and 9 age-matched normal subjects using growth inhibition assay of mink lung epithelial cells. The calculated plasma TGF-β concentration in the patients with HCC was 28.6 ± 27.9 ng/ml (mean± SE), showing significant elevation compared with that in 9 normal subjects (5.3 ± 3.3 ng/ml, P<0.01). In three cases, we could measure plasma TGF-β levels before and after their treatment for HCC. The plasma TGF-β levels decreased from 59.0 to 18.2 ng/ml after hepatic resection in one case, and from 24.0 to 10.7 ng/ml and from 12.4 to 3.4 ng/ml after transhepatic arterial embolization in the other two cases. These data indicate that plasma TGF-β level is elevated in patients with HCC, probably due to release from HCC tissues.     

Low Plasma IL-8 Levels During Chemotherapy Are Predictive of Excellent Long-Term Survival in Metastatic Breast Cancer

BackgroundInterleukin (IL)-8 is a proinflammatory cytokine, and high levels of IL-8 are associated with poor prognosis in many malignancies. The objective of this study was to explore the clinical benefit of monitoring plasma IL-8 levels during breast cancer chemotherapy.Patients and MethodsWe conducted an exploratory analysis of several circulating proteins, including IL-8, in the plasma. Plasma samples were obtained from 58 metastatic breast cancer patients who took part in a prospective phase 2 first-line bevacizumab chemotherapy trial. Samples were analyzed before therapy, after 6 weeks and 6 months of treatment, and at the final study visit. On the basis of a trajectory analysis of the plasma IL-8 levels, the patients were divided into 3 trajectory groups.ResultsPlasma IL-8, IL-6, IL-18, matrix metalloproteinase (MMP)-2, MMP-9, YKL-40, resistin, and high-mobility group box 1 (HMGB1) concentrations were measured, and the most pronounced predictor of patient survival was IL-8. On the basis of the trajectory analysis of the IL-8 levels, the majority of patients (n = 35, 60%) belonged to trajectory group 1, and these patients had significantly lower IL-8 levels before and during the entire chemotherapy treatment period than did the patients in the other groups. Trajectory group 1 patients had significantly better overall survival compared to patients in trajectory group 2 (n = 17; age-adjusted HR = 2.45; 95% confidence interval, 1.21-5.97; P = .012) and 3 (n = 6; age-adjusted HR = 8.65; 95% confidence interval, 3.16-23.7; P < .001).ConclusionLow IL-8 levels during chemotherapy treatment might help identify patients with prolonged survival.     

IL-17A Levels in the Sera of Patients with Gastric Cancer Show Limited Elevation

Background: Inflammation plays a major role in the development and progression of gastric and othergastrointestinal tumors. The IL-17 family of cytokines has been under investigation as targets of immunotherapy.Materials and Methods: We investigated the levels of IL-17A inflammatory cytokine in the sera of 57 patients withgastric cancer (GC) and 90 healthy age/sex matched controls using ELISA methods. Results: In only 5 (8.8%) ofthe patients’ sera was IL-17A detectable. No IL-17A was apparent in the sera of healthy controls. The maximumconcentration of IL-17A in patients was 7.004 pg/ml. Vascular and lymphatic invasions were only seen in oneof the 5 positive cases. Although all of them were in the age group >60 years, no correlation was seen betweenage and IL-17A level. These results are somewhat different from our findings for colorectal cancer (CRC) in thesame population. Conclusions: It is possible that the inflammopathology of CRC and GC are rather different,at least in Fars, a southern province of Iran.     

乳腺癌患者血浆CXCL12 水平的检测及临床意义

 目的 探讨乳腺癌患者血浆CXCL12水平的变化及意义。方法 采用酶联免疫吸附法（ELISA）检测54例乳腺癌患者，20例乳腺良性病变者，18例正常健康志愿者血浆中CXCL12的水平，分析CX-CL12与乳腺癌临床病理参数的相关性及临床治疗对其的影响。结果 乳腺癌患者血浆CXCL12水平高于两对照组，Ⅲ＋Ⅳ期高于Ⅰ＋Ⅱ期，有腋窝淋巴结及远处转移者更高，治疗后低于治疗前（P〈0．05），CXCL12与其他临床病理参数无显著相关性，两对照组血浆CXCLl2水平无显著性差异（P〉0．05）。结论 趋化因子CXCL-12在乳腺癌的转移中发挥了重要作用，可作为乳腺癌新的肿瘤标志物。     

早期乳腺癌患者手术、化疗后血清HER-2/neu ECD水平变化

目的：探讨乳腺癌患者手术或化疗后血清HER-2／neu ECD水平变化的临床意义。方法：双抗体夹心ELISA法检测早期乳腺癌患者及其配对手术、化疗前后血清HER-2／neu ECD水平，进行统计分析。结果：82例乳腺癌患者手术后，血清HER-2／neu ECD水平90．24％（74／82）下降，3．66％（3／82，C．V≤5％）未变化，6．10％（5／82）升高；46例乳腺癌患者化疗后HER-2／neu ECD水平升高组（15／46）对化疗的反应率73．33％（11／15）与HER-2／neu ECD水平非升高组（HER-2／neu ECD水平下降或不变，C．V≤5％，31／46）对化疗的反应率77．42％（24／31）无差别（P〉0．05）。结论：检测乳腺癌患者血清HER-2／neu ECD水平变化对预后可能具有一定的临床提示意义。     

Preparation of a Monoclonal Antibody Specific for 1-Methyladenosine and Its Application for the Detection of Elevated Levels of 1-Methyladenosine in Urines from Cancer Patients

A monoclonal antibody specific for a modified nucleoside, 1-methyladenosine, was prepared and characterized. This antibody, termed AMA-2, reacts with 1-methyladenosine and 1-methyladenine but not with other nucleosides, particularly methylated adenosines other than 1-methyladenosine and methylated guanosines, tested in this investigation. In our experiments, AMA-2 was used in an enzyme-linked immunosorbent assay (ELISA) system for the quantitation of the levels of 1-methyladenosine in urine. Sensitivity was in the picomole range and accuracy was nearly equal to that of the high-performance liquid chromatography (HPLC) assay system. Urinary levels of 1-methyladenosine in healthy donors and patients with various advanced cancers were determined by the inhibition ELISA. The amount of 1-methyladenosine in urine of 33 healthy donors was 1.91±0.66 nmol/μmol creatinine. In 54% (51/94) of patients, urinary 1-methyladenosine was elevated above the mean plus 2 standard deviations for the healthy donors (3.23 nmol/μmol creatinine). In patients with leukemia, esophageal cancer, stomach cancer, colon cancer, and bladder cancer, urinary levels of 1-methyladenosine were significantly elevated. In patients with leukemia, urinary 1-methyladenosine levels changed almost in parallel with the change in the clinical response during chemotherapy. These results suggest that urinary 1-methyladenosine might be useful in monitoring the effectiveness of therapy.     

桥本氏病患者血清促甲状腺激素水平升高对甲状腺组织癌变的影响

目的分析桥本氏病患者血清促甲状腺激素水平升高对甲状腺组织癌变的影响。方法选取167例桥本氏病患者为研究对象,根据患者是否合并甲状腺乳头状癌(papillary thyroid carcinoma,PTC),将其分为无PTC组和合并PTC组,分别为94例和73例。检验两组患者的血清促甲状腺激素水平,并探讨其与甲状腺组织癌变的相关性。结果合并PTC组的血清TSH水平(3.34±1.36)mIU/L,明显高于无PTC组[(2.19±1.17)mIU/L](P<0.05),而其血清TGAb及血清TPOAb水平明显低于无PTC组(P<0.05);合并PTC组患者中血清TSH水平升高者比例(32.88%)明显高于无PTC组(23.40%)(P<0.05);年龄、性别及血清TSH水平可能是影响桥本氏病患者诱发甲状腺组织癌变的危险因素(P<0.05)。结论桥本氏病患者血清促甲状腺激素水平的升高可能会促进甲状腺组织的癌变。     

Antibody Response to COVID-19 mRNA Vaccines in Oncologic and Hematologic Patients Undergoing Chemotherapy

Background: Information on immune responses in cancer patients following mRNA COVID-19 vaccines is still insufficient, but generally, patients had impaired serological responses, especially those with hematological malignancies. We evaluated serological response to COVID-19 mRNA vaccine in cancer patients receiving chemotherapy compared with healthy controls. Methods: In total, 195 cancer patients and 400 randomly selected controls who had been administered a Pfizer-BioNTech or Moderna COVID-19 vaccines in two doses were compared. The threshold of positivity was 4.33 BAU/mL. Patients were receiving anticancer treatment after the first and second dose of the vaccines. Results: a TOTAL OF 169 patients (87%) had solid tumors and 26 hemolymphopoietic diseases. Seropositivity rate was lower in patients than controls (91% vs. 96%), with an age/gender-adjusted rate ratio (RR) of 0.95 (95% CL = 0.89–1.02). Positivity was found in 97% of solid cancers and in 50% of hemolymphopoietic tumors. Both advanced and adjuvant therapy seemed to slightly reduce seropositivity rates in patients when compared to controls (RR = 0.97, 95% CL = 0.89–1.06; RR = 0.94, 95% CL = 0.87–1.01). Conclusions: the response to vaccination is similar in patients affected by solid tumors to controls. On the contrary, hemolymphopietic patients show a much lower response than controls.     

HLA-G Expression in Tumor Tissues and Soluble HLA-G Plasma Levels in Patients with Gastrointestinal Cancer

Background: Overexpression of human leukocyte antigen G (HLA-G) and increased plasma levels of solubleHLA-G (sHLA-G) have been reported in different human malignancies, and are believed to be involved in tumor immuneevasion. Objectives: This study was designed to evaluate the expression of HLA-G in tumor tissues and the plasmalevels of sHLA-G in patients with gastrointestinal cancer, and to determine their associations with clinicopathologicalfactors. The link between Helicobacter pylori infection and increased HLA-G expression or sHLA-G levels was alsoinvestigated in patients with gastric cancer. Methods: HLA-G expression was investigated in tumor tissues from 100patients with gastric and colorectal adenocarcinoma using immunohistochemistry test, and plasma levels of sHLA-Gwere measured in 82 patients with ELISA method. The presence of H. pylori genome was investigated in tumortissues from 25 patients with gastric cancer by PCR method. Results: HLA-G expression was observed in 43% ofcolorectal cancers and 34.6% of gastric cancers, and was not related with any of the clinicopathological factors. Therewas a significant correlation between increased sHLA-G level and stage I tumors. Eight of 25 (32%) gastric cancerspecimens were positive for H. pylori, of which 3 samples were positive for HLA-G. Soluble HLA-G levels were abovethe cut-off value in all H. pylori-positive patients. Conclusion: Plasma levels of sHLA-G were significantly increasedin our patients with a sensitivity of 89% and a specificity of 62%. Soluble HLA-G level can be considered a usefulindicator for the early diagnosis of gastric and colorectal adenocarcinoma.     

No Evaluation of Serum P53 Levels in Iraqi Female Breast Cancer Patients

Breast cancer is the most common cancer diagnosed and the second leading cause of cancer death among Iraqi women. The population was exposed to high levels of depleted uranium following the first and second Gulf Wars and this might be a risk factor. Protein 53 (p53) or Tumor protein 53 (Tp53) was originally defined as an oncogenic protein. The aim of the study was to evaluate P-53 serum concentrations in fifty Iraqi female breast cancer patients and twenty five healthy volunteers using the ELISA technique. All these patients attended the Teaching Hospital of AL Diwaniyah during the period between June 2016 to March 2017. The mean values for TP53 concentration in patients with breast cancer and apparently healthy groups were 47+33.5 U/ml and 27. 8+12.7 U/ml, respectively. The results showed no significantly difference , in contrast to most studies conducted elsewhere in the world.     

Pretreatment Levels of Serum Vascular Endothelial Growth Factor do not Correlate with Outcome in Patients with Locally Advanced Cervical Cancer

Objective: To evaluate pretreatment levels of serum VEGF in locally advanced cervical cancer patients, andassess any association with clinocopathological parameters and response to radiotherapy. Methods: Patientswith histologically proven and diagnosed locally advanced cervical cancer or stages IIB-IVA were included inthis study. Blood serum was obtained by peripheral venous puncture about 24 hours before the beginning ofradiotherapy. All patients were followed up at one and three month intervals from the last day of the completetreatment for evaluating the responses to radiotherapy. Results: Mean age of the 40 patients was 52.8±11.1years. Sixty percent were in stage IIB and 90% had squamous cell carcinoma. The median pretreatment level ofserum VEGF was 611.3 pg/ml (0.00-4,067.20 pg/ml). The pretreatment levels of serum VEGF did not correlatewith stage (p=0.75), tumor histology (p=0.91), tumor size (p=0.46) or tumor characteristics (p=0.49). Almost allpatients received concurrent chemoradiation as a curative treatment, with a complete response found in 94.9%.Values for patients who were completed response was rather lower than patients with persistent disease, butwithout statistical significance (581.4 pg/ml vs 759.6 pg/ml, p=0.37). Conclusion: Pretreatment levels of serumVEGF do not correlate with clinicopathological factors or response to radiation therapy.     

Factors Related to Treatment Refusal in Taiwanese Cancer Patients

Background: Incidence and mortality rates for cancer have increased dramatically in the recent 30 years inTaiwan. However, not all patients receive treatment. Treatment refusal might impair patient survival and lifequality. In order to improve this situation, we proposed this study to evaluate factors that are related to refusalof treatment in cancer patients via a cancer case manager system. Materials and Methods: This study analyseddata from a case management system during the period from 2010 to 2012 at a medical center in NorthernTaiwan. We enrolled a total of 14,974 patients who were diagnosed with cancer. Using the PRECEDE Model asa framework, we conducted logistic regression analysis to identify independent variables that are significantlyassociated with refusal of therapy in cancer patients. A multivariate logistic regression model was also applied toestimate adjusted the odds ratios (ORs) with 95% confidence intervals (95%CI). Results: A total of 253 patients(1.69%) refused treatment. The multivariate logistic regression result showed that the high risk factors for refusalof treatment in cancer patient included: concerns about adverse effects (p<0.001), poor performance(p<0.001),changes in medical condition (p<0.001), timing of case manager contact (p=.026), the methods by which casemanager contact patients (p<0.001) and the frequency that case managers contact patients (≥10times) (p=0.016).Conclusions: Cancer patients who refuse treatment have poor survival. The present study provides evidence offactors that are related to refusal of therapy and might be helpful for further application and improvement ofcancer care.     

Response Assessment With Molecular Characterization of Circulating Tumor Cells and Plasma MicroRNA Profiling in Patients With Locally Advanced Breast Cancer During Neoadjuvant Chemotherapy

BackgroundCells detaching from the primary tumor site are metastasis initiator cells, and the detection of CTC, known as liquid biopsy, is an important test of biomarkers of cancer progression. We investigated the molecular characterization of circulating tumor cells (CTCs), profiled the plasma microRNA (miR) content, and analyzed the relationship with the clinical outcomes by sampling the peripheral blood from patients with locally advanced breast cancer before and after neoadjuvant chemotherapy.Patients and MethodsMarkers of breast cancer, epithelial–mesenchymal transition (EMT), drug resistance, and stem cells were used for CTC isolation and characterization. Plasma miR profiles were obtained from selected patients with CTC positivity determined using next-generation sequencing.ResultsThe proportion of CTC, EMT, and stem cell marker positivity was 16.7%, 8.3%, and 25% before and 18.2%, 15.2%, and 9.1% after treatment, respectively. A significant correlation was found between the pretreatment CTCs and ALDH1 positivity (P = .0245). These CTCs with stemness properties were observed in most hormone receptor–positive, human epidermal growth factor receptor 2–negative cases and were also present with a high incidence in cases of early metastasis. miR-146b-5p and miR-199a-5p, which are involved in metastasis, invasion, and EMT, were accompanied by CTC positivity, and miR-4646-3p was associated with the development of early metastasis.ConclusionsMolecular characterization of CTCs and miR profiling of serial samples from patients with locally advanced breast cancer during neoadjuvant chemotherapy appears to be a very useful in predicting cure and clinical course and might be a key to developing new targeted therapies.     

Clinical Characteristics of Gynecologic Cancer Patients who Respond to Salvage Treatment with Lingzhi

Lingzhi or Ganoderma lucidum is a popular medicinal mushroom used as a health promotion herb in Chinaand other Asian countries for thousands of years. There have many previous studies about the anti-cancereffects of lingzhi especially in vitro. The present study reports the clinical data of 5 gynecologic cancer patientswho achieved stability in the disease after ingestion of lingzhi in the form of fruit body water extract and sporesin a salvage setting. This report has been written to enhance the data describing the effect of lingzhi in cancerpatients.