S-100β Protein – Serum Levels in Children with Brain Neoplasms and its Potential as a Tumor Marker

OBJECTIVE: To determine if serum S-100beta levels are elevated in children with brain neoplasms and if it can be used as a tumor marker for children with brain neoplasms. DESIGN: Prospective cohort study. SETTING: Urban, tertiary care, children's teaching hospital. PATIENTS: 136 healthy children and 27 children with brain neoplasms. METHODS: Serum levels of S-100beta were measured in 136 healthy children to serve as controls and 27 children with brain neoplasms, who underwent biopsy or resection of the mass. Patients were then classified into astrocytoma or non-astrocytoma groups. MEASUREMENTS AND MAIN RESULTS: The median serum S-100beta level for the control group was 0.27 mcg/l (range, 0.06-2.6 mcg/l), and for the brain neoplasm group was 0.2 mcg/l (range, 0.01-2.1 mcg/l), (p = 0.09). There were 13 children with astrocytomas and 14 with non-astrocytomas. The S-100beta levels for the astrocytoma group was 0.25 mcg/l (range, 0.05-1.1 mcg/l) and for the non-astrocytoma group 0.17 mcg/l (range, 0.01-2.1 mcg/l), (p = 0.47). CONCLUSIONS: Serum S-100beta levels are not elevated in children with brain neoplasms compared to healthy children, nor are they elevated in children with astrocytomas compared to non-astrocytomas. The S-100beta protein does not appear to be useful as a serum tumor marker in children with brain neoplasms.     

Do Protocadherins Show Prognostic Value in the Carcinogenesis of Human Malignant Neoplasms? Systematic Review and Meta-Analysis

Background: Protocadherins (PCDHs) have been reported as tumor suppressor genes, implying that these genes may be involved in tumor suppression in a variety of cancers. However, a thorough understanding of the functions and mechanisms of PCDHs remains limited. Our aim was to investigate the methylation profile of PCDHs in human malignant neoplasms. Methods: This systematic review has been recorded in PROSPERO (#42019117844) and conducted according to PRISMA’s checklist; search was conducted in LILACS, PubMed, Science Direct, Scopus, and Web of Science databases, manually, with search queries and without date or language restrictions. Results: We found 91 articles, of which 26 were used for this meta-analysis and categorized according to the origin of the neoplasia. In total, 3,377 cases were compiled, with PCDH10, PCDH17, and PCDH8 being the most studied; males were 2.22 times more affected than females. Studies have shown significant heterogeneity (p <0.001), with the odds ratio varying between cases and controls [2.20 (95% CI = 1.11– 4.35) to 209.05 (95% CI = 12.64– 2,457.18)], and the value of association between methylation and cancers studied was 26.08 (95% CI = 15.42–44.13). Conclusion: In this systematic review, we have demonstrated using meta-analysis that PCDHs could emerge as potential tumor suppressor genes and that a significant increase in methylation may be useful for early detection of different cancers. This work may help in the identification of new prognostic biomarkers in malignant neoplasms.     

Spatially Resolved Transverse Relaxation Times T2 of Human Articular Cartilage – an in vitro and in vivo MRI Study

The transverse MR relaxation time T₂ of articular cartilage could be a helpful parameter for the noninvasive early diagnosis of degenerative joint diseases because it is related to collagen orientation and water content. T₂ maps were determined for human tibial plateau samples in vitro (5 patients) and for patellar cartilage in vivo (5 volunteers) in a standard whole-body MR scanner operating at a field strength of 1.5 Tesla by means of a multi-spin-echo sequence. A high spatial resolution with pixel sizes between 156 μm (in vitro) and 470 μm (in vivo) was achieved. Cartilage T₂ maps showed increases from approximately 10 ms at the bone interface to approximately 50 ms at the articular surface. The short-time reproducibility of the mean T₂ value was approximately 1.4 %. Our results demonstrate that T₂ maps of articular cartilage can be acquired in vivo with good precision. This method may have potential for noninvasive assessment of material properties of cartilage, e.g. to study degenerative changes with aging and disease.     

Targeting of ��v-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α_v-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that α_v-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking α_v-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.     

Predicting Response to Radiotherapy in Cancer-Induced Bone Pain: Cytokines as a Potential Biomarker?

AimsRadiotherapy (XRT) for cancer-induced bone pain (CIBP) has varying levels of efficacy. A biomarker that predicts likely efficacy could stratify XRT to those most likely to benefit. No biomarker is used in clinical practice, but potential candidate cytokines have been identified. The aim of the present study was to examine the relationship between candidate cytokines and analgesic response after XRT.Materials and methodsAn exploratory analysis was undertaken on biobank data from patients who had received single fraction (8 Gy) XRT for CIBP. The biobank data were prospectively collected from multiple centres in the UK as part of a larger clinical trial, which had institutional review board approval and all patients provided written informed consent for the use of their data in future research. Phenotypic data, pain assessments as well as plasma samples were collected at baseline (within the 24 h before the XRT) and at follow-up (4 weeks after XRT). Baseline and follow-up samples were analysed and levels of 16 pre-identified cytokines were compared in patients classified as XRT ‘responders’ or ‘non-responders’.ResultsData from 60 patients were analysed. Insulin-like growth factor binding protein 9 (NOV/CCN3/IGFBP-9) and interleukin-1ß (IL-1ß) were identified as potential predictors of response to XRT. A significant relationship was shown between the response to XRT and the ratio of the median level of NOV/CCN3/IGFBP-9 at baseline:follow-up (P = 0.024). Furthermore, for the patients up to 64 years of age, the median level of NOV/CCN3/IGFBP-9 was significantly different between responders and non-responders (P = 0.047). For IL-1ß, the median level was significantly different between responders and non-responders in patients with breast cancer (P = 0.006).ConclusionAlthough the present findings do not identify robust biomarkers, this is the first such study to examine the role of cytokines in predicting response to XRT in patients with CIBP, and studies that build on these findings are encouraged.     

Bevacizumab in advanced breast cancer: an opportunity as second-line therapy?

Bevacizumab is approved for use as first-line therapy in advanced breast cancer according to pivotal ECOG 2,100 trial. Recently, Food and Drug Administration (FDA) voted unanimously against this licensed indication from the product’s labeling. This is because 2 other trials have been conducted (AVADO and RIBBON-1) and both have shown a statistically significant improvement in progression-free survival, although of a much smaller magnitude than was seen in E2100 study. After meta-analysing 2-s-line randomized bevacizumab trials that addressed a little bit different populations (a pure second-line population in RIBBON2 and an heavily pretreated [1–2 previous lines] population in Miller trial), we have discovered that overall response rate (relative risk 1.63; 95% CI 1.02–2.62; P = 0.04) and progression-free survival (hazard ratio 0.85; 95% CI 0.73–0.98; P = 0.03) were significantly increased with the addition of bevacizumab to chemotherapy. Despite both trials, the results are not significant in terms of duration of responses; however, bevacizumab appears not to increase the toxicity of chemotherapy (in particular febrile neutropenia). In conclusion, bevacizumab label in breast cancer could be reconsidered at least for second-line setting where a standard option does not exist, and a real difference in OS is unproven and unnecessary with any regimen in randomized trials.     

Opium Consumption and the Incidence of Cancer: Does Opium Account as an Emerging Risk Factor for Gastrointestinal Cancer?

Purpose

Some epidemiological studies have shown an association between opium consumption and the incidence of gastrointestinal (GI) cancer. The present study was designed to investigate the effects of opium on the initiation of GI cancer in rats.

Methods

Forty-five rats were randomly divided into three groups; each received different treatment for 40 weeks. The rats in group 1 received purified water, while animals in group 2 were treated with 5 mg/kg diethylnitrosamine (DEN) orally for 8 weeks and continued with purified water by the end of the experiment. The third experimental group received 300 mg/kg opium for 16 weeks and then continued with 50 mg/kg phenobarbital by the end of the 40th week. The growth of tumors in the treated groups was assessed by histological changes and the up/down expression of p53, cdkn1, cdk2, e-cdh, and n-cdh genes in different parts of GI tract.

Results

Histological examinations revealed that DEN was able to induce the growth of tumor in GI tract as shown by active mitotic figure in different regions of GI system and hyperplasia of hepatocytes associated with infiltration of inflammatory cells, intestinal villous hypertrophy, and colorectal adenoma. There was also significant (p?<?0.05) overexpression of p53, cdk2, and n-Cdh genes in different parts of digestive system in DEN-treated group. However, these pathological changes and the degradation of gene expression were not observed in the opium-treated group.

Conclusion

The results of this study suggest that the opium does not promote the initiation of cancer in GI tract.

     

Looking for Metastasis in Early Breast Cancer: Does Bone Scan Help? A Retrospective Review

BackgroundRoutine staging investigations are not recommended for early breast cancer (EBC). Staging scans and further confirmatory tests add to the cost of breast cancer treatment. Despite recommendations from international guidelines, whole body bone scan (BS) is commonly used for staging EBC. We examined our experience with BS as a staging investigation when selectively used in EBC.Patients and MethodsAll EBC patients who underwent treatment through the Eastern Health breast unit during a 50-month period from January 2012 were included in this study. All staging BS results were reviewed to evaluate yield and false-positive rate. The causes of false-positive results were analyzed. The role of BS when performed along with computed tomographic scans of chest, abdomen, and pelvis (CTCAP) was evaluated.ResultsEven with the selective use of BS, we could only achieve a yield of 1% (95% confidence interval, ?0.6, 2.7) in EBC. When combined with CTCAP, only one additional metastasis was detected in 194 BSs.ConclusionBS plays only a limited role in staging EBC. Patients who have undergone CTCAP will experience minimal benefit by undergoing additional BS.     

Does an organised screening programme reduce the inequalities in breast cancer survival?

BackgroundThe aim of the present study was to examine whether the implementation of an organised mammographic screening programme in Florence has been successful in reducing socioeconomic inequalities in breast cancer survival.Patients and methodsAll invasive breast cancer cases diagnosed in women resident in the city of Florence in a prescreening period and in the first 10 years of the screening programme were selected. Their socioeconomic status (SES) was determined by using the national census 2001 data. All breast cancers were followed up to 10 years after the diagnosis.ResultsIn the prescreening period, the survival of deprived women was 12 percentage points lower than the reference class, both in the younger age class (<50 years old) and in the age class target of the screening programme (50–69 years old). This difference progressively decreases until disappearing completely during the first 10 years of the screening programme for the age class invited to screening, whereas it remains stable in the younger age class. Participation in breast cancer screening and diagnostic accuracy were similar by SES.ConclusionThe organised breast cancer screening implemented in the Florentine area achieved the goal of reducing inequalities in breast cancer survival.     

Does excess iron play a role in breast carcinogenesis? an unresolved hypothesis

Free iron is a pro-oxidant and can induce oxidative stress and DNA damage. The carcinogenicity of iron has been demonstrated in animal models, and epidemiologic studies have shown associations with several human cancers. However, a possible role of excess body iron stores or of elevated iron intake in breast carcinogenesis has received little attention epidemiologically. We propose that iron overload and the disruption of iron homeostasis with a resulting increase in free iron may contribute to the development of breast cancer, and we summarize the relevant evidence from mechanistic studies, animal experiments, and studies in humans. Over time a high intake of iron can lead to iron overload. Furthermore, body iron stores increase in women following menopause. Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation—three established risk factors for breast cancer. In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake. Ultimately, it is important to determine whether iron levels in the breast and iron-induced pathology are higher in women who go on to develop breast cancer compared to women who do not.     

Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?

Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.     

Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures. Many small studies have demonstrated that cancer therapy—induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting. Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of earlystage breast cancer. Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.     

Does resection of an intact breast primary improve survival in metastatic breast cancer?

The recommended primary treatment approach for women with metastatic breast cancer and an intact primary tumor is the use of systemic therapy. Local therapy of the primary tumor is recommended only for palliation of symptoms. However, a series of retrospective studies examining practice patterns for this problem show that about half the women presenting with de novo metastatic disease undergo resection of the primary tumor, and suggest that women so treated survive longer than those who do not undergo resection of the intact primary. In analyses that adjust for tumor burden (number of metastatic sites), types of metastases (visceral, nonvisceral), and the use of systemic therapy, the hazard ratio for death is reduced by 40% to 50% in women receiving surgical treatment of the primary tumor. The benefit of surgical treatment appears to be confined to women whose tumors were resected with free margins. However, these results may simply reflect a selection bias (ie, younger, healthier women with a smaller tumor burden are more likely to receive surgical treatment). In addition, the role of other locoregional therapy such as axillary dissection and radiotherapy is not addressed in these studies. In view of these data, the role of local therapy in women with stage IV breast cancer needs to be reevaluated, and local therapy plus systemic therapy should be compared to systemic therapy alone in a randomized trial.