As has been well described, a hallmark of cancer is marked disruption of metabolic and inflammatory processes. Depending on the salience and timing of these inputs, the brain responds via neural and humoral routes to alter whole-body physiology. These responses have consequences for tumor growth and metastasis, directly influencing patient quality of life and subsequent mortality.
Additionally, environmental inputs such as light, diet, and stress, can promote inappropriate neural activity that benefits cancer. Here, I discuss evidence for brain-tumor interactions, with special emphasis on subcortical neuromodulator neural populations, and potential ways of harnessing this cross-talk as a novel approach for cancer treatment. Proviral integration site for Moloney murine leukemia virus PIM has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 STAT3 and interleukin-6 signaling.
Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 STAT3 as well as other signaling nodes. The combination decreased the osimertinib-induced STAT3 phosphorylation. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance. Aim: The convergence of tumorigenic and embryonic signaling pathways drives us to exploit the embryonic stem cell ESC microenvironment to restrict metastatic potential of cancer cells. We have previously demonstrated that bioengineered ESC microenvironments could restrict growth and metastatic potential of highly aggressive breast cancer cell BCC.
Increased NKD2 mRNA and protein expression coinciding with dual signaling pathway inhibition within co-cultured BCCs suggests that this reversal may be attributable to restored regulation of NKD2 within these pathways. Conclusion: ESC-microstrands are able to reverse oncogenic signaling pathway hyperactivation and restore signaling pathway regulation in metastatic BCCs. Further studies could provide insight into what role NKD2 up-regulation plays in BCC inhibition, leading to the development of a new targeted therapy for metastatic breast cancer.
Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data.
Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells. Alternative splicing is a major contributor to transcriptome and proteome diversity in eukaryotes. Some alternative splicing isoforms and their encoded proteins contribute to specific cancer hallmarks. In this review, we will discuss recent progress regarding the contributions of alternative splicing to breast cancer metastasis. We believe an in-depth understanding of the mechanism underlying the contribution of splicing to breast cancer metastasis will provide novel strategies to the management of breast cancer.
Aim: To investigate whether AF1q, overexpressed in metastatic cells compared with the primary tumor cells, plays a pivotal role in breast cancer metastasis. Methods: To investigate whether AF1q has a responsibility in the acquisition of a metastatic phenotype, we performed RNA-sequencing RNA-Seq to identify the gene signature and applied the Metacore direct interactions network building algorithm with the top 40 amplicons of RNA-Seq. Likewise, we identified that ICAM-1 expression is attenuated in metastatic cells compared to primary tumor cells. Conclusion: Attenuation of ICAM-1 by AF1q on tumor cells disadvantages host anti-tumor defenses through the trafficking of lymphocytes, which affects tumor progression and metastasis.
Head and neck squamous cell carcinoma HNSCC has a large global burden of disease and poor survival outcomes. Recent targeted therapies and immunotherapies have been explored in HNSCC, but there has been limited translation to clinical practice outside of recurrent or metastatic cases. Window of opportunity settings, where novel agents are administered between cancer diagnosis and planned definitive therapy, have begun to be employed in HNSCC.
Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, along with other biospecimens and radiographic exams. Early window studies have also identified potential biomarkers to predict sensitivity or resistance to treatments. However, these early investigations have revealed multiple challenges associated with this trial design. In this review, we discuss recent window of opportunity trials in HNSCC and how they inform design considerations for future studies.
Epithelial-mesenchymal transition EMT is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes.
Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer. The epithelial-mesenchymal transition EMT , in which cells undergo a switch from a polarized, epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer.
Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs. Although numerous transcriptional regulatory factors are currently well-characterized, the post-transcriptional control of EMT requires continued investigation. The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms, and this role is exemplified when E1 is absent.
Globally, hnRNP E1 appears to control proteome reprogramming during cell plasticity, either by direct or indirect regulation of protein translation. Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively.
Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone.
Furthermore, no additive effects on tumor cell apoptosis were observed in the combination group. Ovarian cancer OC is a serious condition that often presents at advanced stages and has high mortality rates, with the current mode of early-stage screening lacking sensitivity and specificity. OC often presents asymptomatically, which renders early diagnosis difficult.
Furthermore, many patients lack significant risk factors or family history of the disease. Five-year survival rates differ between patients with OC among racial, ethnic, and social groups as a result of different social barriers. This review article aims to present the currently existing data regarding health care disparities among OC patients of different ethnic, demographic, and socioeconomic backgrounds, and what next steps should be taken to better understand and eventually eliminate these potentially devastating health care disparities.
Increasing data support the notion that a combination of genomic, socioeconomic status, social factors, and cultural differences lead to differential treatments and therefore health care disparities. While genomic and biological factors are important, language barriers, geographic and travel barriers, differences in comorbidity likelihood between populations, and different treatment plans seem to have a greater impact on 5-year survival rates of patients from diverse backgrounds.
Language barriers limit a shared-decision model of care. Transportation limitations and geographic differences can lead to limited follow-up and insufficient care in resource and equipment restrictive settings.
Patients with these barriers also tend to have a higher incidence of comorbidities that raise the mortality rate of OC. Further research needs to explore effective solutions to bridge health care disparities and understand why they occur. The carcinogenic mechanism proposed considers that stem cells committed to repair tissues and differentiated cells, acquire different metabolic properties, if there is an associated GABA deficiency suppressing a control system of the endocrine pancreas.
This control system mediated by GABA, released with insulin, normally turns off glucagon and somatostatin release when insulin is released. A consequence of the GABA deficiency in pancreas and adrenals is a hybrid insulin-glucagon-somatostatin message, received by new mitotic stem cells displaying then a hybrid metabolic rewiring. This gives them a selective metabolic advantage over differentiated cells that become insulin resistant and only receive the glucagon- somatostatin part of the hormonal message.
Indeed, their insulin receptors are desensitized by the persistent leakage of insulin resulting from the GABA deficiency that fails to close the insulin release mechanism. Thus differentiated cells are simply rewired to be plundered by stem cells. The metabolic advantage gained by stem cells blocks their own differentiation and maintains their mitotic capacity. Inevitable mutations of mitotic cells follow, the immune system is unable to eliminate a geometrically increasing number of altered stem cells, a selection of the most aggressive but metabolically successful population takes place when cancer is declared.
Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inaccessibility. Currently, breast cancer and its metastasis are the second leading cause of death among women.
Tumor microenvironment and blood brain barrier BBB represent great obstacles in targeting breast cancer and its metastasis. Chemotherapy is a safer treatment modality for brain metastasis compared with risky surgical resection and brain radiotherapy. Unfortunately, conventional chemotherapy lack penetration of BBB and suffer from multiple resistance mechanisms.
Current treatment technologies for brain metastases of breast cancer have limited long-term success and numerous side effects, illustrating the urgent need for novel smart strategies. Various novel drug entities and nanosystems have been employed to improve diagnosis and targeted treatment of breast cancer and its metastasis. Immunotherapy agents and small tyrosine kinase inhibitors have been shown to reduce tumor size and increase survival in patients with breast cancer, but still poorly penetrate BBB.
Tailored sized nanoparticles to some extent crossed brain tumor barrier and enhanced drug accumulation in tumors by taking advantage of enhanced permeability and retention. Furthermore, various active targeting strategies have been adopted to improve accessibility to brain malignancies. Therefore, to achieve enhanced antitumor therapy against breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment.
This review focuses on the various active and passive targeting technologies for the treatment of breast cancer brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid in designing the optimal smart, safe, targeted and effective systems to combat brain metastases of breast cancer.
Breast cancer is a common malignancy among women. Due to the improvement of social awareness and advances in imaging technologies, significant achievements are obtained at its diagnosis and treatment each passing day. A year-old, multiparous and postmenopausal woman, who presented with a palpable lymph node in the right supraclavicular region and a right adnexal mass but had no findings from the breast examination, is reported in this article.
Following advanced assessment, metastatic carcinoma was identified in the lymph node biopsy and the adnexal mass. During the exploration for the primary origin, microinvasive breast cancer was diagnosed following mammographic imaging and an excisional biopsy from the right breast. Microinvasive breast cancer, which did present itself with clinical findings with metastases despite the lack of local findings, was discussed with the review of the literature.
Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer PPBC , or those cases diagnosed within 10 years of most recent childbirth.
Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a SEMA7A , cyclooxygenase-2 COX-2 , and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer.
Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. Brain metastases risk at the time of diagnosis or during the course of disease is high in non-small cell lung cancer NSCLC. Even the incidence of brain metastases has increased in recent years, due to detection of smaller asymptomatic lesions with MRI screening as well as improved survival as a consequence of developments in systemic therapies.
In the last decade, there have been many trials in the management of NSCLC patients with brain metastases, questioning the role of adjuvant whole brain radiotherapy WBRT after surgery or stereotactic radiosurgery SRS , WBRT, compared to best supportive care in patients not amenable to surgery, aggressive local therapies in solitary brain metastases, postsurgical cavity SRS, SRS in non-oligometastatic patients, cranial radiotherapy in patients with driver mutations, thyrosine kinase inhibitors, immune check point inhibitors and the impact of therapies on neurocognitive functions and quality of life.
The main objective of this review is to provide an update on current trends in radiotherapy in the management of newly diagnosed brain metastases from NSCLC. Retrograde trafficking is a well-regulated, multi-component pathway that can result in endosomal trafficking to the trans-Golgi network, the perinuclear space, or the nucleus. Either clathrin or the retromer complex can travel with proteins endocytosed from the plasma membrane, guided by Rabs including 5, 6, 7, 9, 22A , interacting with a host of sorting nexin proteins, and fusing with Golgi-specific anchors to allow transport of activated receptor tyrosine kinases to a potential end within the nucleus.
Amplification in these constituents is common in cancer, leading to increased retrotranslocation and a reduction in degradation of receptor tyrosine kinases, an event highly associated with cancer metastasis. Here, we review the role of retrograde trafficking in altering transmembrane receptor localization and activity and the relationship to metastasis, focusing on all four members of the ErbB family, with comparison to other receptor tyrosine kinases including the insulin receptor and fibroblast growth factor receptor, as well as other transmembrane proteins dysregulated in metastasis.
By examining how these receptors are being alternatively trafficked and the cancer-associated events resulting from this process, we hope to identify novel therapeutic targets. Here, as an alternative to ionizing radiation therapy and chemotherapy and their associated side effects, we explored a new combination approach using capecitabine CPBN and aminolevulinate-based photodynamic therapy PDT.
We had previously developed a combination PDT approach in which 5-fluorouracil 5FU , a differentiation-promoting agent, increases the levels of protoporphyrin IX PpIX in cancer cells when given as a neoadjuvant prior to aminolevulinic acid ALA. However, 5FU can be toxic when administered systemically at high levels. Methods: Murine 4T1 BCA cells harboring a luciferase transgene were injected into breast fat pads of female nude mice.
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Tumor growth and regression were monitored in vivo using bioluminescence imaging. Histological changes in primary tumors and metastases were assessed by immunohistochemistry after necropsy. Results: CPBN pretreatment of 4T1 tumors increased cellular differentiation, reduced proliferation, raised PpIX levels, enhanced tumor cell death, and reduced metastatic spread of 4T1 cells post-PDT, relative to vehicle-only controls. Aim: The aim of the study is to test visible resonance Raman VRR spectroscopy for rapid skin cancer diagnosis, and evaluate its effectiveness as a new optical biopsy method to distinguish basal cell carcinoma BCC from normal skin tissues.
Methods: The VRR spectroscopic technique was undertaken using nm excitation. Normal and BCC human skin tissue samples were measured in seconds. The molecular fingerprints of various native biomolecules as biomarkers were analyzed. A principal component analysis - support vector machine PCA-SVM statistical analysis method based on the molecular fingerprints was developed for differentiating BCC from normal skin tissues. Results: VRR provides a rapid method and enhanced Raman signals from biomolecules with resonant and near-resonant absorption bands as compared with using a near-infrared excitation light source.
The VRR technique revealed chemical composition changes of native biomarkers such as tryptophan, carotenoids, lipids and proteins. The VRR spectra from BCC samples showed a strong enhancement in proteins including collagen type I combined with amide I and amino acids, and a decrease in carotenoids and lipids. Conclusion: VRR can enhance molecular vibrational modes of various native biomarkers to allow for very fast display of Raman modes in seconds.
It may be used as a label-free molecular pathology method for diagnosis of skin cancer and other diseases and be used for combined treatment with Mohs surgery for BCC. Few studies have reported on the analyses of drugs targeting enriched populations of cancer stem cells CSCs as a means for identifying potent anti-CSC agents. This review evaluates recent information on the identification and functions of specific CSC surface markers, with particular emphasis on colorectal cancers and the screening of drugs to eliminate such cells.
Many of these CSC markers are found commonly expressed on CSCs from different cancer types as well as embryonic stem cells. By effectively using drugs that inhibit these pathways to kill the CSC population, or otherwise forcing them out of dormancy into active cell division, cancers should become more susceptible to chemotherapy.
Such combinational therapies targeting both CSCs and proliferating tumor cells should greatly improve upon the current basis for treatment. Axillary recurrence is a rare event in patients treated with sentinel lymph node biopsy alone with the majority occurring in the first 5 years after surgery. Intramammary lymph node IMLN can be the primary sites of metastasis and sentinel lymph nodes, but the clinical significance, including prognosis and therapeutic approach is yet unclear, even more with capsular extravasation.
IMLN metastases are strongly correlated with axillary lymph nodes involvement and therefore a guide for further surgical management of the axillary nodes. Aim: Prostate cancer PCa is the most commonly diagnosed non-skin cancer among men.
Metastatic Colorectal Cancer: ESMO Clinical Practice Guidelines | ESMO
Serum prostate-specific antigen level is used as a standard PCa biomarker for over 20 years. This leads to overdiagnosis and overtreatment. In-depth insight into PCa metabolomics enables discovery of novel PCa biomarkers. Methods: Metabolomic alternation in PCa serum, urine and interstitial fluid was examined using gold-nanoparticle-based laser mass spectrometry imaging.
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- Breast cancer brain metastases: biology and new clinical perspectives;
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- Capture of Viable Circulating Tumor Cells in the Liver of Colorectal Cancer Patients.
This study included 5 patients who underwent prostate biopsy with positive result, 5 patients with negative result and 10 healthy controls. Results: Over two hundred differentiating metabolites 87 in urine, 54 in serum and 78 in interstitial fluid were detected. Four, twenty two and ten metabolites from urine, serum and interstitial fluid respectively showed statistical significant differential abundance between cancer and control group.
Conclusion: Comprehensive metabolomic profile of PCa has been identified. Out of 36 metabolites, 20 were identified and should be further evaluated in clinical trials as a potential PCa biomarker. Aim: Thyroid cancer is an internationally important health problem. Methods: Thyroid tissue levels of twenty chemical elements were prospectively evaluated in 41 patients with thyroid malignant tumors and 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. Conclusion: There are considerable changes in chemical element contents in the malignantly transformed tissue of thyroid. 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 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: Despite current advances in therapies and the gradual decline in breast cancer-related mortality, metastasis remains a major therapeutic challenge for treatment.
Precision Medicine and Personalized Approach to Illness
Energy reprogramming is now recognized to be an important part of tumorigenic processes, but its relevance in metastatic dissemination has yet to be elucidated. LNm5 cell line, a novel, highly metastatic variant line derived from TN human breast adenocarcinoma MDA-MB line, alteration in growth and energy metabolisms associated with enhanced metastatic potential were described. 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. 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: 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.
Flow in the blood vessel networks of LNs was investigated by fluorescence microscopy. 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. 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. 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. 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.
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.
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. 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: Strong evidence reveals important differences between cancers in the proximal vs. 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. Results: Within weeks after intramural cecal injection of HT 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.
However, complex karyotypes were already related to this group of malignancy and associated with poor outcome. 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, NUPABL1 gene fusion, episomes and intra-tumor genetic heterogeneity. Overall, highly amplification of NUPABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.
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. 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. 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. Aim: The effects of hepatocyte growth factor HGF on a non-invasive prostate cancer cell line CAHPV , 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. 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 Conclusion: These findings provide further molecular insight into the progression of prostate cancer and highlights potential issues for early prostate cancer therapeutic strategies.
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.
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. 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. 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 U and UNS 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. 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. Robotic gastrectomy RG is increasingly performed, particularly in East Asia. 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. 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. Laparoscopic gastrectomy is considered as an indispensable option between endoscopic resection and standard gastrectomy with open laparotomy for patients with early-stage gastric cancer. 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.
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. 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.
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, reads and analysis tools that allowed for identification of distinct minority variants within single genes, i. 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. 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.
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. 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.
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 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.
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. Survival outcomes data were collected. Results: The original search returned 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. Data regarding resection of lung metastases were scarce and extremely heterogeneous. In total patients underwent palliative gastrectomy and median overall survival of patients was 12 months 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. 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.
Organotropism: new insights into molecular mechanisms of breast cancer metastasis
In this review, we elaborate on the latest advances of CTC research in gastric cancer. 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.
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Furthermore, immunotherapy is expected to be an effective treatment with promising clinical trial data. 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.
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. Liver Metastases. London: Springer-Verlag; Kim B, Louie AC: Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission. Arch surg ; HPB oxford ; 8: World J Urol ; N Engl J Med ; Gynecol oncol ; Kawagishi N, shirahata Y, Ishida K et al.
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