Aim: To investigate how previous systemic therapy such as anti-angiogenesis can influence cancer immunotherapy for non-small cell lung cancer (NSCLC).
Methods: A total of 134 patients with advanced NSCLC who were treated with nivolumab were retrospectively reviewed. Correlation between status of prior anti-angiogenesis treatment and clinical characteristics were determined. Impact of prior anti-angiogenesis on therapeutic outcome of nivolumab was investigated for tumor efficacy such as progression-free survival (PFS).
Results: Sixteen patients were treated with at least one anti-angiogenesis agent prior to nivolumab. The prior use of anti-angiogenesis agent was associated with stage IV disease, non-squamous histology, and two or more lines of systemic therapy. Median PFS was significantly shorter in the prior anti-angiogenesis group than in no prior anti-angiogenesis group (8.3 vs. 11.3 weeks, log-rank P = 0.006). Multivariate analyses demonstrated that only prior anti-angiogenesis status was associated with worse PFS. There is also a slight trend for worse disease control rate (P = 0.101, Fisher’s exact test) and overall survival (P = 0.200, log-rank) in prior anti-angiogenesis group.
Conclusion: This retrospective study suggests that prior anti-angiogenesis treatment negatively impacts the therapeutic outcome of immunotherapy in advanced NSCLC.
The functional role of aldehyde dehydrogenases (ALDHs) in prostate cancer remains an area of some controversy. Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties, while evidence is also emerging about the involvement of specific isoforms in migration, invasiveness and metastasis. Identification of specific ALDH isoforms, which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer. The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention.
Cancer immunotherapy has now been conclusively shown to be capable of producing durable responses for a substantial number of patients. Adoptive cell transfer and checkpoint blockade therapies in particular both demonstrate that antigen-specific immune responses can be dramatically effective, even in previously refractory late stage disease. Such developments, together with advances in technology, have strongly encouraged revisiting the concept of neoantigen vaccines. Here we introduce basic ideas in the field to allow investigators from diverse backgrounds to understand these developments, grasp current issues, and contribute to further progress.
Currently, conventional therapies in cancer are improving; chemotherapy, radiotherapy and surgery have increased survival significantly. New therapies have arisen with the same goal; immunotherapy has appeared as a promising option in the fight against cancer stimulating the immune system by inducing innate and adaptive responses. These responses include release of pro-inflammatory cytokines, making the immune system capable to eliminate or protect against multiple tumors. Nowadays, many of these therapies are being used in clinical settings, such as checkpoint inhibitors, monoclonal anti cytotoxic T-Lymphocyte associated protein 4 (CTL-4) and programmed death protein 1 (PD1), with inspiring results; however, they may decrease immunotolerance, limiting their use. At the same time, chemotherapy works by passive transport across the cell membrane, limiting its capacity to penetrate in tumor cells. For these reasons, bacteria employment represents one of the best candidates for cancer treatment. They can surpass these barriers with their selective colonization which also has an oncolytic effect by increasing proliferation and immunostimulation in the tumor environment. Attenuated strains, such as Mycobacterium bovis, Clostridium, Salmonella typhimirium and Listeria monocytogenes have been studied showing promising results in experimental models. However, their application in clinical trials has shown the need to maximize their therapeutic effect. Genetic engineering and synthetic biology are necessary to prove the scope that this novel approach has against cancer due to implications of cancer therapy and public health.
Locally advanced pancreatic carcinoma has an usually poor prognosis despite multimodal approaches and sequential chemotherapy. The authors present a case of a long-term survivor with stage III pancreatic adenocarcinoma achieving partial response after a multimodal approach including local and systemic treatments. However, three years after diagnosis and amidst several episodes of cholangitis, hepatic metastasis were suspected. Despite pancreatic adenocarcinoma being the obvious culprit for metastization, a hepatic biopsy was considered at that time given a stable primary disease and presenting three years since the initial diagnosis. At this point, a biopsy could have specific diagnostic, prognostic and therapeutic implications and after it was performed, an unexpected diagnosis of pancreatic neuroendocrine tumor was made. Therefore, we urge clinicians to consider hepatic biopsy in similar cases - generally when it may change prognosis and treatment strategies - and perform histological confirmation of metastatic disease whenever feasible, even if the answer may seem obvious at first impression.
Peritoneal metastasis is the most common pattern of recurrence and the most frequent cause of death after surgery in patients with gastric cancer. Peritoneal free cancer cells disseminated from the primary lesion site have been considered the main cause of peritoneal metastasis. Peritoneal lavage cytological examination (PLC) has been shown to be an independent predictor of gastric cancer relapse after curative resection and poor overall survival. However, the conventional cytological examinations have high rates of false-positive and false-negative findings. To improve the sensitivity, molecular-based methods using reverse transcriptase polymerase chain reaction have been developed for detecting cancer cells in peritoneal wash fluids of patients with gastric cancer. We performed a PubMed search for articles describing PLC in gastric cancer. Relevant articles were reviewed and data on available outcomes elaborated. The clinical roles and attributes of PLC in gastric cancer were reviewed, and its future application to this disease is discussed.
Gastric cancer is an aggressive malignancy that may metastasize through the bloodstream to the liver, through lymphatics to regional lymph nodes, or by penetration of the peritoneal lining of the stomach to result in seeding of the abdominal and pelvis surfaces. Peritoneal metastases are the most common mode of cancer dissemination. Technologies to prevent or treat peritoneal metastases from advanced gastric cancer are presented in this manuscript. The world’s literature, both recent and over the past three decades, was reviewed in order to identify publications that present information regarding gastric cancer peritoneal metastases. Over one dozen randomized controlled trials to test perioperative chemotherapy for prevention of peritoneal metastases were reviewed. All of the trials performed with regional chemotherapy during or shortly after gastrectomy were positive. The clinical data regarding the treatment of peritoneal metastases diagnosed at the time of primary cancer resection or in follow-up were reviewed. Neoadjuvant intraperitoneal and systemic chemotherapy shows that some long-term survivors occur after these treatments were combined with cytoreductive surgery and gastrectomy. Similar treatments are advocated for primary gastric cancer with cytology positive for gastric cancer but no visible implants. Surgery for gastric cancer should be combined with perioperative systemic and regional chemotherapy in order to maximally benefit patients with this disease by reducing the negative impact of peritoneal metastases on survival.
Aim: Gastric cancer is the cancer with the highest rate of peritoneal metastization and this type of spread is associated with a higher death rate compared to distant organ metastasis. The systemic chemotherapy has a minimal effect in peritoneal metastasis so new types of treatment have emerged. The authors revised the main studies done in pressurized intraperitoneal aerosol chemotherapy (PIPAC) and presented the main conclusions.
Methods: A PubMed search was conducted focusing on PIPAC in gastric cancer. The MeSH database was searched with the terms: “Gastric cancer [MeSH] and intraperitoneal aerosol chemotherapy”.
Results: Seven studies were analyzed. All the studies performed the technique with aerosol of doxorubicin and cisplatin. All cases were well tolerated, with minor adverse effects. Patients presented resolution of their abdominal symptoms and regression of macroscopic carcinomatosis. Cytoreductive surgery or hypertermic intraperitoneal chemotherapy could be performed in some patients with good response to PIPAC. The peritonitis caused by the chemotherapy was well tolerated.
Conclusion: PIPAC can induce remission in end-stage and resistant disease with acceptable side effects, good safety levels for patients and health professionals, and quality of life improvement.
Gastric cancer (GC) is a major cause of cancer-related deaths worldwide. The existence of cancer stem cells (CSCs) is known to be the main reason for resistance to anticancer agents as well as for the development of distant metastases. Although CSCs themselves harbor self-renewal and differentiation abilities, the tumor microenvironment that surrounds CSCs provides secreted factors and supports angiogenesis and is thus responsible for the maintenance of their CSC properties. The current review provides information regarding the impact of the tumor microenvironment on gastric CSCs, which will support the development of novel therapeutic strategies for targeting gastric CSCs.
Tumor tissues contain cancer cells, other cellular and non-cellular components. Tumor microenvironments consist of cancer cells and various types of stromal cells, cancer associated fibroblasts, bone marrow-derived cells, endothelial cells, and hematopoietic cells, mainly tumor-associated macrophages and tumor-infiltrating lymphocytes. Increasing recent evidence has demonstrated that alteration of tumor microenvironments is deeply implicated in tumor progression and metastasis in gastric cancer (GC) patients. Recent investigations have provided insights into the molecular mechanisms of the interaction between tumor cells and tumor microenvironments. Interactions between cancer cells and their microenvironment with cytokines and microRNA in extracellular vesicles, such as the exosome, can have a substantial impact on tumor characteristics. Alterations in the tumor microenvironment may play a crucial role in facilitating the progression of tumor cells and metastasis, as well as the activation of cell signaling pathways, which are associated with GC cell proliferation and invasion by genetic or epigenetic alterations. In this review, significant molecular insights into the tumor microenvironment, which consist of cancer associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages and tumor-infiltrating lymphocytes; the interactions between cancer cells and their microenvironment; and the clinical impacts of alterations of GC microenvironments will be discussed.
Hypoxia is a well-established characteristic of prostate tumors and is now recognised as a major contributory factor to both tumor progression and increased resistance to therapy. One strategy to target hypoxic tumor cells is the development of hypoxia-activated prodrugs (HAPs), which are activated in low oxygen environments. Several HAPs have been developed but despite encouraging results from preclinical studies many of these have performed disappointingly in clinical trials. In the developing era of precision medicine, it is clear that more strategic deployment of these agents is required, based on reliable methods that can identify patients who will benefit from HAP treatment, either alone or in combination with other drugs. This review discusses the primary limitations of using HAPs to treat hypoxic tumors and explains how these challenges can be addressed. In particular, it emphasises the importance of tumor imaging and identification of reliable biomarkers for measuring hypoxia and monitoring cellular response to treatment in individual patients. Developing predictive assays for clinical use will be paramount in demonstrating the patient impact and effectiveness of HAPs for personalised medicine.
The treatment scenario of colorectal cancer (CRC) has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease. An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices. Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities. The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers, while supporting the rationale for the development of new drugs and treatment combinations. Clinical validation of promising biomarkers, however, is often an issue. More recently, a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field. This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC, in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach, comprising genomics and epigenetics.
The taxanes family of chemotherapy, which includes paclitaxel and docetaxel, has been incorporated in the adjuvant breast cancer treatments since 1990s. Sequential and concurrent use of taxanes was investigated with anthracyclines in many adjuvant early breast cancer randomized clinical trials. Results from taxanes trials showed inconsistent benefits. However, several meta-analyses showed significant survival benefit of adding taxanes. In this review article, data were collected and summarized from eleven large randomized trials and three meta-analyses to show and discuss the magnitude of benefit of taxanes-anthracyclines combination compared to anthracyclines only adjuvant regimens in early breast cancer. This article aims at providing the oncologists with a well-organized, inclusive and updated evidence.
Aim: Upper alveolar ridge and hard palate squamous cancer is an infrequent malignancy. We evaluated factors associated with neck involvement and with p16-staining.
Methods: Head and neck squamous-cell carcinoma (SCC) patients who went to Head and Neck Department between 1997 and 2011 were screened, and 73 resected upper alveolar ridge and 5 hard palate SCC were selected. Tumors with available tissue were stained with p16 immunohistochemistry.
Results: Median age was 64.4 years, 55.1% were female, and 73.1% were in clinical stage IV. Neck dissections were performed in 24 and pathologically confirmed node metastases were found in 19 (24.3%). Cervical recurrence was found in 18 patients (23.1%) and was associated with histological grade (P = 0.037). Three (7.3%) of 41 lesions were positive for p16 and tended to be younger (P = 0.067). Lymphovascular invasion was associated with shorter disease-free survival (DFS) (P = 0.026) and overall survival (OS) (P = 0.021). Larger cT (P = 0.019), perineural invasion (P = 0.039) and neck dissection (P = 0.010) were associated with shorter OS. Neck node involvement tended to have shorter DFS (31% vs. 48.7%, P = 0.278) and OS (25.1% vs. 48.5%, P = 0.340), and neck recurrence tended to have shorter OS (9.3% vs. 52.3%, P = 0.064).
Conclusion: Neck involvement and recurrence are frequent in this location. P16-positive cases were present in 7.3% and tended to be associated with younger age.
Aim: Several previous studies have evaluated the potential role of programmed cell death protein 1 (PD-1) expressed by tumor-infiltrating lymphocytes (TILs) in various solid tumors and performed its prognosis role in patients’ survival with inconsistent results. This study aims to further systematically evaluate the association of PD-1 by TILs with clinicopathological parameters and clinical outcomes in solid tumor patients.
Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, CNKI and Wanfang databases for relevant studies. The potential prognostic and predictive roles of PD-1 were assessed by pooled hazard ratio (HR), odds ratio (OR) and 95% confidence intervals (CI). A total of 1863 patients were selected for in-depth analysis.
Results: The results demonstrated that PD-1 by TILs was correlated to overall survival for ovarian cancer (HR = 0.40, 95% CI: 0.26-0.61, P < 0.00001). Higher PD-1 expression was associated with lymph node metastasis (OR = 2.55, 95% CI: 1.22-5.29, P = 0.01) and tumor grade (OR = 3.08, 95% CI: 2.07-4.57, P < 0.00001).
Conclusion: The prognostic role of PD-1 by TILs is variant in different tumor types, which highlights the role of PD-1 by TILs as a potential predictive and prognostic biomarker and the development of strategies against the PD-L1/PD-1 axis would be a promising therapeutic target for some solid tumors.
In a normal prostate, the process of controling cell death is essential to maintain tissue homeostasis and its inhibition may lead to the development of cancer. Androgen receptor signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer. The main treatment for prostate cancer is a combination of androgen deprivation therapy (ADT) using anti-androgens and docetaxil administration. However, ADT eventually fails due to a pathological unbalance of cell death processes, in particular apoptosis and autophagy. As a result prostate tumors may re-grow and progress into the castration resistant stage. The role of autophagy in tumorigenesis is complex and it could be a double-edged sword process, as autophagy defects promote cancer progression in association with various dangerous cellular processes, while functional autophagy enables cancer cell survival under stress and likely contributes to the resistance of treatment. Autophagy is often impaired in prostate cancer, due to either activation of the Akt/mTOR pathway, which normally inhibits autophagy, or through allelic loss of Beclin-1 (BECN1), an essential autophagy gene. In particular, elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and to develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.
Gastric adenocarcinoma (GAC) is estimated as the fifteenth most common cancer in the USA. Incidence rate has been gradually decreasing, but prognosis remains dismal. For patients with locally advanced GAC (stage > T1B and < T4B), multimodality therapies, such as surgery, chemotherapy, and radiation therapy, are needed. Perioperative chemotherapy or postoperative chemoradiation/chemotherapy is recommended. For metastatic GAC patients, combination of two cytotoxics (platinum compound and fluoropyrimidine) has become a common place in the USA, and when HER2 is positive, trastuzumab is added. When GAC progresses after the first line therapy, additional biomarkers (microsatellite instability and programmed death ligand 1) should be tested so that checkpoint inhibitors can be used. Overall, the options for advanced GAC patients are limited and more research is needed.
Signaling pathways are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Proliferation, apoptosis and metabolic pathways are just a few examples of the signaling pathways that require fine-tuning, so as to control the proper development of a particular tissue type or organ system. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) in particular, are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein. lncRNAs are essential transcriptional and post-transcriptional regulators that control the expression of genes in a spatial, temporal, and cell context-dependent manner. The aberrant expression of lncRNAs is therefore linked with a number of chronic diseases including cardiac dysfunction, diabetes, and cancer. In this review, we highlight the specific role lncRNAs have in promoting the metastatic cascade across a number of epithelial cancer models.
Aim: To investigate if the genetic information provided by sequencing of both solid and liquid biopsies can shed light on tumor heterogeneity, and to understand the clinical usefulness of adding blood profiling to standard tissue analysis in cancer care.
Methods: Data from 351 patients with stage IV solid tumors for whom molecular profiling of their solid and liquid biopsies was available were studied, with a focus on the discrepant molecular information found between tissue and blood samples.
Results: In 86% of patients, solid and liquid biopsies provided different molecular information. Discrepant gene mutations with a functional impact on the corresponding protein were studied in detail. In 97% of cases, these additional mutations provided clinical value, mainly predicting sensitivity or resistance to targeted therapies. Specifically, 42% of the mutations found only in the liquid biopsy were directly predictive of approved therapies (80% targeted therapies), while 54% were inclusion criteria for molecularly-matched trials.
Conclusion: This study suggests that the addition of blood profiling should be considered in routine clinical oncology, especially for patients with metastatic disease where integrated analysis of solid and liquid biopsies provides a more complete characterization of tumor heterogeneity and provides valuable clinical information for patient treatment.
Gastric cancer with distant metastases, such as para-aortic lymph node metastases, hepatic metastases, and peritoneal dissemination, is classified as stage IV. In this situation, cancer cells have formed micrometastases throughout the body; therefore, according to the algorithm of the Japanese guidelines, stage IV cancer is outside the indication for curative resection. Recent advances in some chemical agents have been remarkable, and some patients have survived for long periods even with stage IV gastric cancer. Thus, even in patients with stage IV gastric cancer, there is a possibility that gastrectomy as conversion surgery could play an important role in the treatment strategy. Gastrectomy as conversion therapy can be safely conducted without perioperative mortality and is considered a sufficiently acceptable treatment strategy. However, the significance of conversion surgery for stage IV gastric cancer remains controversial. In this review, we summarize the treatment strategies and outcomes of conversion surgery for stage IV gastric cancer.
Despite recent progress in diagnostic imaging, gastric cancer (GC) is occasionally found at an advanced stage with distant metastasis. As metastatic GC is difficult to cure, the treatment strategy should be considered individually based on the physical and socioeconomic status of patients as well as on the GC symptoms. The first choice of treatment for metastatic GC is chemotherapy, and several chemotherapeutic regimens for metastatic or recurrent GC have been developed through randomized controlled trials. Ongoing clinical trials will provide novel therapeutic options for patients with metastatic GC in the near future, while individualization of treatment based on detailed molecular information, so-called precision medicine, is eagerly anticipated. In this article, we review recent publications and guidelines focusing on recent progress in the treatment of metastatic GC in Japan.
The prognosis of metastatic disease of esophagogastric junction adenocarcinoma remains poor, despite using a variety of regimens using cytotoxic agents. Recent understanding of molecular characteristic and tumor microenvironment of this cancer is currently instigating new therapeutic options. In this review, we summarized previous evidences of cytotoxic agents widely used worldwide, and updated recent developments of molecular targeted drugs, and immune checkpoint inhibitors.
Aim: Breast cancer is typically detected either during a screening examination or after a woman notices a lump. Breast cancers have different phenotypes depending on the presence/absence of an estrogen receptor (ER) and/or an epidermal growth factor (Her-2) receptor. The objective of the present investigation was to investigate growth inhibitory activity of methanol-, ethanol-, and water-extracts from papaya fruit and leaves on MDA-MB-231 (ER-/Her-2-), MCF-7 (ER+/Her-2-), SK-BR- 3 (ER-/Her-2+) and MDA-MB-361, AU565 (ER+/Her-2+) breast cancer cells.
Methods: The anti-oxidation potential of papaya extracts was determined by assessing their total polyphenol content, total flavonoid content and by assaying their anti-oxidation capacity. The effects on breast cancer cells proliferation were determined using a WST-1 assay.
Results: The seeds and leaves contained higher anti-oxidation potential than that of the skin and pulp fractions. Our data indicate that methanol- and ethanol-extracts of papaya leaves, skin, pulp, and seeds have no effect on any of the breast cancer cell lines, whereas water-extract of leaves and seeds caused low to modest cytotoxic effects only on ER-negative breast cancer cell lines.
Conclusion: Our data suggest that bioactive compound in papaya leaves can be potentially used to develop anti-cancer agents for ER-negative breast cancer.
Pancreaticoduodenectomy (PD) is performed to achieve an R0 resection for gastric cancer with pancreatic and/or duodenal invasion. Several retrospective case series have been published, but the sample cohorts in each study were heterogeneous and small. Moreover, the absence of prospective studies results in a lack of solid evidence that will help determine who can benefit from this procedure. Although the morbidity and mortality of PD have been reported by most studies to be acceptable and that the procedure is feasible, these remained to be much higher than those of standard gastrectomy. Therefore, careful selection of patients should be considered. Based on a review of previous case series and our own experience, PD appears to be beneficial to patients with gastric cancer with pancreatic invasion when R0 resection is possible. In addition, multidisciplinary treatment such as neoadjuvant chemotherapy, is anticipated to improve survival. Nevertheless, considering that prospective randomized studies are difficult to perform, a large-scale multicenter retrospective cohort study is required to evaluate this highly invasive procedure.
The majority of cancer deaths can be attributed to cancer cell metastases that migrate to distant target organs. Brain metastases constitute one of the leading causes of morbidity and mortality among cancer patients, occurring in about 40% of patients with metastatic disease. Thus, there exists an unmet need for early detection, diagnosis, and treatment directed against early stage cancer cell metastasis. Previous studies have reported the development of methods to detect and identify early circulating tumor cells (CTCs) in the bloodstream prior to their seeding into distant organs. Using a comprehensive analysis of total CTCs mRNA content, investigators have developed a mRNA “transcriptome signature” of 126 genes involved in CTC metastatic events. The genes were parsed into various metastatic-related activities indicating that CTCs sustained a semi-dormancy state bent on: (1) stress survival; (2) metabolic maintenance; (3) DNA and translational stability; and (4) chemotactic pro-inflammatory capabilities. These activities suggested that CTCs might be susceptible to interactions with protein-derived peptide segments whose actions are involved with metastatic activities such as cell invasiveness, contact, adhesion, motility, spreading, and migration. The use of protein-derived (encrypted) peptides to impede CTC metabolic activities and disrupt signaling pathways could have therapeutic potential in patients with early metastatic disease.
In the last few years, the success of anti-PD1 and anti-PDL1 drugs in solid cancers treatment and the advances in molecular biology have provided new potential treatment strategies for patients with metastatic colorectal cancer. Unfortunately, only patients with mismatch repair deficiency seem to benefit from immunotherapy and they represent a small subset of the metastatic population. New ongoing studies focus on converting an immune ignorant tumour into an inflamed one by combination therapies and on introducing an immunotherapeutic approach in earlier stages of disease (neoadjuvant and adjuvant setting). In this review we summarize the current knowledge about the molecular and immune landscape of colorectal cancer and propose new potential combination strategies to enhance the efficacy of immunotherapy.
Pancreatic cancer is one of the most challenging diseases due to its often late diagnose which results in limited therapeutic options and poor prognosis. To date, the only curative treatment is complete tumor removal surgery but only a few patients are eligible to do it. The median survival period after surgery followed by chemotherapy adjuvant treatment is about 2 years. Since its approval by the FDA, Gemcitabine has become the first-line chemotherapy agent for treatment of advanced pancreatic cancer. The FOLFIRINOX regimen is also used as a treatment scheme for pancreatic cancer; however, this regimen has resulted in small improvements in overall patient’s survival. It is appropriated to clarify that the FOLFIRINOX regimen can only be administered in patients with good performance status. Due to the absence of outstanding result after patient’s treatment with diverse chemotherapeutic agents combinations or unsuccessful administration of single-agent drugs to treat pancreatic cancer, the immunotherapy has become a new hope. A more comprehensive understanding of cancer microenvironment and the chemical communication between cancer cells and immune cells can result in new therapeutic approaches that will improve the elimination of pancreatic cancer cells, enhancing life quality for these patients and increasing the overall survival.
Gastric cancer (GC) remains one of the most common cancers and serious health problems worldwide. For unresectable or metastatic advanced gastric cancer, chemotherapy treatment is first selected. Although chemotherapy has improved survival in patients with advanced gastric cancer (AGC), the prognosis of these patients remains poor. In recent years, some therapies targeting biological molecules have been reported to prolong the survival of patients with AGC. Since trastuzumab, a monoclonal antibody that targets HER2, was established as standard therapy for unresectable GC in a HER2-positive patient, many other targets have been reported as new therapy targets. Many molecular targeted therapies, such as HER2, VEGFR or EGFR, have been verified as established standard treatments with or without chemotherapy in clinical trials. Furthermore, immunotherapy is expected to be an effective treatment with promising clinical trial data. Especially, immune checkpoint inhibiters, such as PD-1/PD-L1 or CTLA-4, have demonstrated innovative progression in GC therapy. Moreover, ongoing clinical trials including targeted therapy and immunotherapy have shown promising results in improving clinical outcomes, safety, and tolerability. In this article, we review targeting therapies and immunotherapies for GC and summarize future prospective treatments.
Circulating tumor cells (CTCs) have received a lot of attention as a novel biomarker for cancer research in past decades. CTCs infiltrate the bloodstream derived from the primary tumor, and are significantly involved in cancer metastasis and recurrence. Although clinical applications have been challenging owing to the difficulties of CTC identification, recent development of technology for specific enrichment and detection of CTCs contributes to diagnosis and treatment. Furthermore, CTC analyses will shed new light on the biological mechanisms of cancer progression and metastasis. A number of clinical studies have already been carried out on the basis of CTC technology. Nevertheless, the clinical utility of CTCs is still unknown in gastric cancer. In this review, we elaborate on the latest advances of CTC research in gastric cancer.
Aim: To analyze clinical features and survival outcomes of patients with surgically-treated stage IV gastric cancer, in order to evaluate the suitability of surgery in these patients.
Methods: We performed a systematic literature search using PubMed, MEDLINE, and Embase on October 9th, 2017. Survival outcomes data were collected.
Results: The original search returned 2434 papers. Thirty-nine studies were included in the final review, of which 26 evaluated liver metastasis resection, four pulmonary metastasis resections and nine palliative gastrectomies. In total 933 patients underwent hepatectomy for liver metastasis from gastric cancer and median survival rates were 73%, 37% and 27% at 1-, 3- and 5-year respectively, with a median overall survival of 22 months (9-52 months). Data regarding resection of lung metastases were scarce and extremely heterogeneous. In total 1115 patients underwent palliative gastrectomy and median overall survival of patients was 12 months (8-53 months). In the only randomized controlled trial, no survival benefit of additional gastrectomy over chemotherapy alone was found, in contrast with the retrospective studies.
Conclusion: Survival benefit of surgery in advanced gastric cancer is still unclear. Surgery may play an important role in highly selected patients. However, further randomized controlled trials are necessary to clarify the actual impact of surgery in these patients.
Necrotizing fasciitis is a rare complication of chemotherapy, however, few reports were published as a specific complication of taxanes. We are reporting this rare complication of a lady who was treated with taxanes as an adjuvant therapy for her breast cancer who was referred to us from the medical department and turned out to be necrotizing fasciitis in her right thigh. We are also presenting the literature review of this type of complication.
Gastric cancer is one of the major causes of cancer-related deaths, despite the gradual decrease of its incidence in the West. Minimally invasive procedures, such as endoscopic resection and laparoscopic gastrectomy, have been successfully introduced in European high-volume centres, in the treatment of early gastric cancer. Regarding advanced, localized gastric cancer a number of prospective trials have been completed in search of better therapeutic options, aiming to optimize the efficacy vs. adverse effect ratio. From the results of these prospective randomized trials, the therapeutic strategy has in the last decades shifted emphasis from adjuvant therapy to neoadjuvant or perioperative chemotherapy, in curatively intended treatment. Moreover, recent studies have shown promising results in the use of molecular targeted agents, both in perioperative and palliative settings. The introduction of molecularly targeted therapy will enable a personalized approach based on each patient’s and tumor’s characteristics, maximizing the benefits from chemotherapy. The present review article focuses on recent therapeutic trends, as well as future perspectives, of surgical and oncological gastric cancer treatment in the Western setting, mainly based on landmark clinical trials.
Accumulating evidence has suggested the potential clinical utility of novel body fluid biomarkers, or “liquid biopsy”, using circulating tumor cells and cell-free nucleic acids from cancer patients. Noninvasive and reproducible, liquid biopsy could provide the basis for individualized therapeutic strategies by identifying genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. MicroRNAs (miRNAs) are short noncoding RNAs that post-transcriptionally regulate gene expression. They also play important roles in various physiological and developmental processes as oncogenic or tumor-suppressive regulators. Specific miRNA expression signatures have been identified in a number of human cancers. Circulating miRNAs have been detected in plasma and serum, and this in blood has attracted the attention of researchers for their potential as noninvasive biomarkers. Circulating miRNAs have emerged as tumor-associated biomarkers that reflect not only the existence of cancer, but also the dynamics, malignant potential, and drug resistance of tumors. Herein, we review the recent biological and clinical research on the circulating miRNAs of gastric cancer and discuss future perspectives for their clinical applications as a liquid biopsy.
Aim: Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis. The discovery of intra-tumor genetic heterogeneity (ITGH), has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes. In addition, accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects. This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.
Methods: ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes, i.e., complex single gene variance (CSGV).
Results: CSGV was identified in the androgen receptor genes in all breast tumors examined.
Conclusion: Evidence of CSGV suggests that a selection - as opposed to a mutation - centric hypothesis could better explain carcinogenesis. Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations. Thus, the role of selection pressures, such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.
Laparoscopic gastrectomy is considered as an indispensable option between endoscopic resection and standard gastrectomy with open laparotomy for patients with early-stage gastric cancer. However, the extent of gastrectomy and remnant gastric function may affect patients’ quality of life (QOL) after surgery. Therefore, function-preserving gastrectomy in addition to laparoscopic surgery could be considered in patients with early-stage gastric cancer. A prospective multicenter trial and meta-analyses of sentinel node (SN) mapping and biopsy for early-stage gastric cancer have demonstrated favorable SN detection rates and accuracy of nodal metastatic status. Although a combination of radioactive colloids with blue dyes as tracers is currently considered as the promising procedure of SN mapping in early-stage gastric cancer, several new technologies, such as indocyanine green fluorescence imaging, may markedly improve its accuracy. For early-stage gastric cancer, the development of laparoscopic personalized minimized gastrectomy with SN mapping may help retain patents’ QOL after surgery. A recently developed full-thickness partial gastrectomy with SN mapping and basin dissection would become a reliable minimally invasive gastrectomy for treating patients with cN0 early-stage gastric cancer.
Peritoneal dissemination (PD) is the most common cause of metastasis in gastric cancer (GC). Because there are no standard treatments for PD, it is associated with a poor prognosis. Although clinicians have performed intraperitoneal chemotherapy for GC with PD, the outcome remains unsatisfactory. Therefore, the development of novel treatments and diagnostic tools for PD is expected to improve the prognosis of GC patients with PD. Notably, it is essential to elucidate the molecular mechanisms involved in the development of PD in GC. In this review, the molecular mechanisms of PD (three steps: detachment from the primary tumor, adaptation to the microenvironment of the peritoneal cavity, and attachment to peritoneal mesothelial cells) and new topics in GC are highlighted.
Robotic gastrectomy (RG) is increasingly performed, particularly in East Asia. With articulated devices, surgeons are able to perform every procedure more comfortably and meticulously, which makes RG ideal from the surgeon’s standpoint. However, it is still unclear whether it is a suitable treatment strategy from the patient’s viewpoint, due to the lack of solid evidence obtained from randomized controlled trials. The feasibility of RG has been demonstrated in many retrospective comparative studies, which showed similar trends, including relatively less estimated blood loss and longer operation time with RG than laparoscopic gastrectomy (LG), equivalent number of harvested lymph nodes and similar length of postoperative hospital stay between RG and LG. However, considering the higher medical expenses associated with RG, its superiority in terms of long-term survival outcomes will need to be confirmed for it to be accepted more widely.
Aim: Current cancer treatments are challenged by the plasticity of cancer cells, largely influenced by chromosomal instability (CIN) leading to variations in karyotype known as tumor-specific aneuploidy, which in turn, leads to intra-tumor cellular heterogeneity (TH). Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors. Modulation of the CIN rate seems to reside within the tumor itself. In an attempt to develop a therapy targeting cancer plasticity, we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.
Methods: Chr7-fluorescence in situ hybridization was applied on various grades of gliomas, in vitro cultures and intracranial xenografts of two syngeneic glioma lines (U251 and U251-NS) derived from various cell-inoculating densities, with or without EFEMP1 overexpression.
Results: A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas. A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.
Conclusion: Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells, and EFEMP1 is one of these factors.
Changes in cellular energetics and genomic instability are two characteristics of cancers that have been studied independently. Evidence of cross-talk between mitochondria function and nuclear function has started to emerge, suggesting that these pathways can influence one another. Here we review recent evidence that links the mitochondria and the cell cycle. This evidence indicates bidirectional cross-talk where mitochondria function can regulate the cell cycle and induce genomic instability, and conversely, the cell cycle machinery regulates mitochondria function. Implications for this cross-talk in the development of cancer are discussed.
Centrosomes serve as the major microtubule organizing centers in cells and thereby contribute to cell shape, polarity, and motility. Also, centrosomes ensure equal chromosome segregation during mitosis. Centrosome aberrations arise when the centrosome cycle is deregulated, or as a result of cytokinesis failure. A long-standing postulate is that centrosome aberrations are involved in the initiation and progression of cancer. However, this notion has been a subject of controversy because until recently the relationship has been correlative. Recently, it was shown that numerical or structural centrosome aberrations can initiate tumors in certain tissues in mice, as well as invasion. Particularly, we will focus on centrosome amplification and chromosome instability as drivers of intra-tumor heterogeneity and their consequences in cancer. We will also discuss briefly the controversies surrounding this theory to highlight the fact that the role of both centrosome amplification and chromosome instability in cancer is highly context-dependent. Further, we will discuss single-cell sequencing as a novel technique to understand intra-tumor heterogeneity and some therapeutic approaches to target chromosome instability.
Aim: The effects of hepatocyte growth factor (HGF) on a non-invasive prostate cancer cell line (CAHPV-10), expressing cMET were studied, to mimic the possible effects neo-adjuvant androgen deprivation therapy may have in promoting tumour progression.
Methods: Prostate epithelial cells and prostate cancer cells derived from cancer metastatic sites were analysed using cell culture assays, immunofluorescence, quantitative real-time polymerase chain reaction and western blotting, with or without HGF stimulation.
Results: HGF significantly enhanced cell proliferation and induced cell scattering and invasion in CAHPV-10 cells compared to untreated controls. Active adenosine diphosphate-ribosylation factor 6 (ARF6) was found to be present in all metastatic prostate cancer cells, with levels highest in the most aggressive cell line, PC-3. Following stimulation with HGF, active ARF6 expression was substantially elevated in CAHPV-10 cells.
Conclusion: These findings provide further molecular insight into the progression of prostate cancer and highlights potential issues for early prostate cancer therapeutic strategies.
The intratumoral heterogeneity orchestrated by the tumor intrinsic and extrinsic mechanisms enable cancers to persist and spread notwithstanding the use of aggressive interventional therapies. The heterogeneity is revealed at multiple levels - at the level of individual tumor cells, in the cellular composition of tumor infiltrates and in the chemical microenvironment in which the cells reside. Deconvoluting the complex nature of the cell types present in the tumor, along with the homo and heterotypic interactions between different cell types can produce novel insights of biological and clinical relevance. However, most techniques analyze tumors at a gross level missing key inter-cell-type genotypic and phenotypic differences. The advent of single-cell sequencing has given an unprecedented opportunity to analyze the tumor at a resolution that not only captures the diversity of the cellular composition of a tumor but also provides information on the genetic, epigenetic and functional states of different cell types. In this review, we summarize the genesis of tumor heterogeneity, its impact on tumor growth and progression and their clinical consequences. We present an overview of the currently available platforms for isolation and sequencing of single tumor cells and provide evidence of its utility in precision medicine and personalized therapy.
Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phosphorylation (OxPhos) and increases mitochondrial production of reactive oxygen species (ROS). In primary tumors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly metastatic cancer cells. Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxia-inducible factors in response to changes in oxygen and ROS levels. Hence, hypoxia-induced pro-oxidative stress drives invasion and metastasis. However, it is also the Achilles’ heel of metastatic cancer cells because pro-oxidative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis, whereas antioxidant agents promote their survival and tumor progression. Herein lies the metastatic tumor cell sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and we and others have shown that the NSAID celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS production and trigger cancer cell death, including metastatic cancer cells and cancer stem cells. This review highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease where they are already showing significantly improved clinical outcomes.
T-lymphoblastic lymphoma (T-LBL) is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background. However, complex karyotypes were already related to this group of malignancy and associated with poor outcome. Here, we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa (GTG)-banding. However, further analyses including high-resolution molecular approaches, array-comparative genomic hybridization (aCGH), multiplex ligation-dependent probe amplification, fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype, NUP214-ABL1 gene fusion, episomes and intra-tumor genetic heterogeneity. In addition, homozygous loss of CDKN2A, as well as amplification of oncogene TLX1 (HOX11) were detected. Actually, NUP214-ABL1 fusion gene replicated autonomously in this case as episomes. Overall, highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors. As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.
Aim: Strong evidence reveals important differences between cancers in the proximal vs. distal colon. Animal models of metastatic colon cancer are available but with varying degrees of reproducibility and several important limitations. We explored whether there were regional differences in the location of murine colon cancers and assessed the utility of murine models to explore the biological basis for such differences.
Methods: We re-analyzed data from our previous studies to assess the regional distribution of murine colon cancer. In survival surgery experiments, we injected HT-29 human colon cancer cells into the wall of the cecum or distal colon of Nu(NCr)-Foxn1nu or NOD.Cg-PrkdcscidIl2rgTim1Wji/SzJ mice and compared the development of primary tumors and metastases.
Results: Within 7-17 weeks after intramural cecal injection of HT-29 cells, eight mice failed to develop solid primary tumors or metastases. In contrast, within four weeks after cell injection into the distal colon, 13 mice developed metastases - 12 mice developed subcutaneous metastases; of these, four developed liver metastases and one developed both liver and lung metastases. One mouse developed liver metastases only. Histological examination confirmed these lesions were adenocarcinomas.
Conclusion: Our findings reveal the preferential growth of murine colon neoplasia and invasive human orthotopic xenografts in the distal mouse colon. The new approach of injecting cells into the distal colon wall results in a pattern of colon cancer development that closely mimics the progression of metastatic colon cancer in humans. This novel model of colon neoplasia has great potential for exploring anatomical differences in colon cancer and testing novel therapeutics.
The science of one’s genetic background and its impact on disease susceptibility and drug response has come of age and firmly established its proper place in the clinic. Its impact is felt more in the treatment of cancer than any other disease area several reasons: critical time, narrow therapeutic index and overlapping toxicity window. We realize that the true potential of pharmacogenetics will be realized when we have been able to integrate other variants like insertion-deletion, copy number variation, etc., in addition to single nucleotide polymorphism for their collective influence on drug response and toxicity. Technology has rapidly evolved and has become affordable to be used in the clinic once it gets standardized and validated not only in one population but in several major world population -particularly those which are under-represented in human variant database.
Aim: Secondary malignancy estimation after radiotherapy of post mastectomy patients is becoming an important subject for comparative treatment planning. The data from modern treatment planning systems provide accurate three-dimensional dose distributions for each individual patients, thereby opening up new possibilities for more precise estimates of secondary cancer incidence rates in the irradiated organs.
Methods: This study estimates the probability of secondary malignancy using radiobiological model for post mastectomy patients in a low-resource center, Nigeria. The secondary cancer complication probability (SCCP) was computed for linear, linear-exponent and linear-plateau models.
Results: The result shows that comparing the three models the mean SCCP for the contralateral breast ranged between 0.41%-0.93%; for the lung (0.34%-5.93%); while for the chest wall is between 0.65%-31.95%. Also, the result showed that based on the differential dose volume histogram, the SCCP in the chest wall is highest compared to the lung and contralateral breast; while the linear model overestimate the risk of secondary malignancy, the linear-exponent and the linear plateaus gave values not outrageously high.
Conclusion: The models in this study have shown that the risk of secondary malignancy in these post mastectomy patients is low.
Despite improvements achieved in terms of early detection and therapeutic approach, metastatic breast cancer remains one of the principal worldwide causes of death. In recent years, due to the heterogeneous response of each patient to chemotherapy, clinical research highlights the need of a personalized approach. Circulating tumor cells (CTCs) represents a promising tool for this purpose. Unfortunately, even if their correlation with severity, outcome and metastatic nature of the tumor has been established, several issues, mainly concerning their characterization and isolation, need to be solved. In this review, latest knowledge on CTCs and metastatic process in breast cancer were analyzed, aiming to understand their clinical utility and validity for a prospective therapeutic scenario.
Colorectal cancer (CRC) represents the second most common cancer in Europe with marked differences in prognosis and response to treatments. In the past years research showed emerging interest in genomic and immunologic fields. The clinical heterogeneity, that occurs during the pathogenesis of CRC, is driven by chromosomal alterations and defective function of DNA mismatch repair genes. CRC is classified in four consensus molecular subtypes (CMS) with different immunogenic characteristics and prognosis. CMS1 microsatellite instable (MSI)-like and CMS4, both characterized by high levels of immune infiltration, are recognized as the most immunogenic subtypes, even though functional characteristic leading to different prognosis are reported. In particular, MSI tumors have been identified as the best candidates for immunotherapy treatment and a number of studies have evaluated the efficacy of anti-programmed cell death ligand-1 (PDL-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) in this setting. However, literature data show that the majority of patients with CRC have microsatellite stable (MSS) tumors and this status seems related to lower response to PDL-1/programmed cell death-1 or CTLA4 blockade. The aim of this paper is to investigate the role of immunotherapy in MSI and MSS CRC.
Aim: To investigate whether tumor cells in a lymph node (LN) can invade from the marginal sinus into extranodal veins via vessel branches that communicate with intranodal veins and whether this can be a starting point for hematogenous metastasis at the early stage of LN metastasis.
Methods: Vascular and lymphatic networks of LNs in MXH10/Mo-lpr/lpr mice were investigated using three-dimensional micro-computed tomography and histological methods. Flow in the blood vessel networks of LNs was investigated by fluorescence microscopy. Tumor cells were injected into the subiliac LNs of MXH10/Mo-lpr/lpr mice to induce metastasis to the proper axillary LNs. Tumor development in the proper axillary LN was detected using an in vivo bioluminescence imaging system. A two-dimensional image of the proper axillary LN microvasculature was reconstructed using a contrast-enhanced high-frequency ultrasound system.
Results: Extranodal veins communicated with intranodal veins via branches that penetrated the capsule, and blood flowed from intranodal veins to extranodal veins. Tumor cells that had metastasized to the marginal sinus invaded these communicating veins to develop hematogenous metastases.
Conclusion: Metastatic LNs that would be considered by clinical imaging to be stage N0 can be a starting point for hematogenous metastasis. The study findings highlight the need for the development of novel techniques for the diagnosis and treatment of early-stage LN metastasis, i.e., when standard diagnostic imaging might incorrectly classify the LN as stage N0.
Over the past two decades, the treatment outcomes in metastatic colorectal cancer (mCRC) have been remarkably improved, largely from the evolution of systemic therapy. Also, the molecular biomarkers have played a major role in this improvement by their predictive value in current treatment paradigm in mCRC. Currently, extended RAS mutation analysis is required for consideration of anti-epidermal growth factor receptor therapy in patients with mCRC. Several uncommon gene alterations have emerged as the potential targets for their matched molecular targeted therapy. Although, most patients with mCRC do not derive benefit from immunotherapy. By using microsatellite instability or mismatch repair test, we are now able to identify a small subgroup of patients with mCRC who have a very good response to immune checkpoint inhibitors. With the increasing number of required biomarkers in mCRC management, multiplex gene panel testing is now replacing single gene testing strategy. In patients accessible to matched molecular targeted therapy, especially for clinical trials, the comprehensive genomic profiling might be the preferred testing method. Although, it is potentially benefit in mCRC treatment, the liquid biopsy is not yet clinically applicable. The optimal utilization of molecular biomarker testing is required for best treatment outcomes in individual patients.
Aim: Despite current advances in therapies and the gradual decline in breast cancer-related mortality, metastasis remains a major therapeutic challenge for treatment. Energy reprogramming is now recognized to be an important part of tumorigenic processes, but its relevance in metastatic dissemination has yet to be elucidated.
Methods: Using the MDA-MB-231HM.LNm5 cell line, a novel, highly metastatic variant line derived from TN human breast adenocarcinoma MDA-MB-231 line, alteration in growth and energy metabolisms associated with enhanced metastatic potential were described. Glycolysis and oxidative phosphorylation (OXPHOS) was characterized using the seahorse XF analyzer. Whole transcriptome sequencing (RNA-seq) and quantitative real-time PCR was used to ascertain expression differences in metabolic genes.
Results: We observed reduced proliferation, and an elevation of both glycolytic and OXPHOS metabolism in the highly metastatic daughter line. The elevated metabolic rate is only partially reflected by transcript levels of relevant metabolic regulators. Heightened mitochondrial respiration is potentially underpinned by increased expression mitochondrial electron transport chain components. However, increased glycolysis was not underpinned by up-regulation of metabolic genes encoding enzymes participating in glycolysis.
Conclusion: Our results indicate breast tumour cells with elevated metastatic propensity are more metabolic active. We also identified differentially expressed metabolic genes, such as IDH2, that may play a part in the metastatic process beyond energy reprogramming.
One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication. To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics: memantine, methylphenidate and donepezil. The use of memantine after brain irradiation showed a delay in cognitive deterioration, although at 24 weeks this did not reach significance (P = 0.059). Lack of significance is likely to be the result of the limited statistical power of 35% and memantine did show significant differences in secondary outcomes. The study on methylphenidate was not conclusive. Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found. In addition, larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.
Aim: Thyroid cancer is an internationally important health problem. The aim of this exploratory study was to evaluate whether significantchanges in the thyroid tissue levels of Al, B, Ba, Br, Ca, Cl, Cu, Fe, I, K, Li, Mg, Mn, Na, P, S, Si, Sr, V, and Zn exist in the malignantly transformed thyroid.
Methods: Thyroid tissue levels of twenty chemical elements were prospectively evaluated in 41 patients with thyroid malignant tumors and 105 healthy inhabitants. Measurements were performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma atomic emission spectrometry, respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for trace element analysis.
Results: It was found that contents of Al, B, Br, Ca, Cl, Cu, K, Mg, Mn, Na, P, S, and Si were significantly higher (approximately 3.2, 4.6, 9.3, 1.8, 2.3, 3.6, 1.6, 1.6, 1.6, 1.2, 2.5, 1.1, and 2.8 times, respectively) while content of I lower (nearly 26 times) in cancerous tissues than in normal tissues.
Conclusion: There are considerable changes in chemical element contents in the malignantly transformed tissue of thyroid.