Gastrointestinal neuroendocrine neoplasms (GI-NENs) arise from neuroendocrine cells distributed mainly in the mucosa and submucosa of the gastrointestinal tract. In 2010, the World Health Organization (WHO) classification of NENs of the digestive system was changed, categorizing these tumors as grade 1 neuroendocrine tumor (NET), grade-2NET, neuroendocrine carcinoma (large- or small-cell type), or mixed adenoneuroendocrine carcinoma (MANEC). Such a classification is based on the Ki-67 index and mitotic count in histological material. For the accurate pathological diagnosis and grading of NENs, it is important to clearly recognize the characteristic histological features of GI-NENs and to understand the correct method of counting Ki-67 and mitoses. In this review, we focus on the histopathological features of GI-NENs, particularly regarding biopsy and cytological diagnoses, neuroendocrine markers, genetic and molecular features, and the evaluation of the Ki-67 index and mitotic count. In addition, we will address the histological features of GI-NEN in specific organs.
neuroendocrine neoplasm; carcinoid; neuroendocrine carcinoma; gastrointestinal tract; neuroendocrine marker
The SWI/SNF chromatin remodeling complex plays a role in the repair of UV-induced DNA damage. It was proposed that chromatin remodeling activities are utilized to increase the accessibility of nucleotide excision repair (NER) machinery and checkpoint factors to the damaged DNA. It was shown recently that BRCA1 contributes to UV damage response by promoting photoproduct excision, triggering post-UV checkpoint activation and post-replicative repair. In this study, we show that BRCA1 rapidly binds to UV damage sites when cells are undergoing DNA synthesis. In contrast, two phosphorylated forms of BRCA1 do not accumulate at sites of UV damage. Depletion of BRG1, a core subunit of the human SWI/SNF-BAF complex, impairs the recruitment of BRCA1 to the damage sites and attenuates DNA damage induced BRCA1 phosphorylation. At UV lesions-stalled replication forks, BRG1 promotes RPA phosphorylation in response to UV irradiation, since UV-induced phosphorylation of chromatin bound RPA drops significantly when BRG1 is depleted in human cells. Importantly, activation of the ATM/ATR kinases is attenuated when BRG1 is depleted. We propose that BRG1 modulates BRCA1 response to UV irradiation by regulating ATM/ATR activation.
BRG1; SWI/SNF; BRCA1; ATR/ATM; nucleotide excision repair; UV irradiation; DNA damage response,~RPA
Analysis of genetically engineered mice deficient in cell cycle regulators, including E2F1, cdk4, and pRB, showed that the major phenotypes are metabolic perturbations. These key cell cycle regulators contribute to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism. It has been shown that deregulation of these pathways can lead to metabolic perturbations and related metabolic diseases, such as obesity and type II diabetes. The cyclin–cdk–Rb–E2F1 pathway regulates adipogenesis in addition to its well-described roles in cell cycle regulation and cancer. It was also shown that E2F1 directly participates in the regulation of pancreatic growth and function. Similarly, cyclin D3, cdk4, and cdk9 are also adipogenic factors with strong effects on whole organism metabolism. These examples support the emerging notion that cell cycle regulatory proteins also modulate metabolic processes. These cell cycle regulators are activated by insulin and glucose, even in non-proliferating cells. Most importantly, these cell cycle regulators trigger the adaptive metabolic switch that normal and cancer cells require in order to proliferate. These changes include increased lipid synthesis, decreased oxidative metabolism, and increased glycolytic metabolism. In summary, these factors are essential regulators of anabolic biosynthetic processes, blocking at the same time oxidative and catabolic pathways, which is reminiscent of cancer cell metabolism.
cell cycle; metabolism; mitochondria; cdk4; E2F1 transcription factor
Despite therapeutic advances, glioblastoma multiforme (GBM) remains a lethal disease. The infiltrative nature of this disease and the presence of a cellular population resistant to current medical treatments account for the poor prognosis of these patients. Growing evidence indicates the existence of a fraction of cancer cells sharing the functional properties of adult stem cells, including self-renewal and a greater ability to escape chemo-radiotherapy-induced death stimuli. Therefore, these cells are commonly defined as cancer stem cells (GBM-SCs). The initial GBM-SC concept has been challenged, and refined according to the emerging molecular taxonomy of GBM. This allowed to postulate the existence of multiple CSC types, each one driving a given molecular entity. Furthermore, it is becoming increasingly clear that GBM-SCs thrive through a dynamic and bidirectional interaction with the surrounding microenvironment. In this article, we discuss recent advances in GBM-SC biology, mechanisms through which these cells adapt to hostile conditions, pharmacological strategies for selectively killing GBM-SCs, and how novel CSC-associated endpoints have been investigated in the clinical setting.
glioblastoma multiforme; cancer stem cells; chemo-radioresistance; canonical pathway inhibitors; self-renewal pathway inhibitors; differentiation-inducing agents; hypoxia; stem cell-based endpoints
It is well known that Neuroblastoma (NB) patients whose tumors have an undifferentiated histology and a transcriptome enriched in cell cycle genes have a worse prognosis. This contrasts with the good prognoses of patients whose tumors have histologic evidence of differentiation and a transcriptome enriched in differentiation genes. Tumor cell lines from poor prognosis, high-risk patients contain a number of genetic alterations, including amplification of MYCN, 1pLOH, and unbalanced 11q or gains of Chr 17 and 7, and exhibit uncontrolled growth and an undifferentiated phenotype in in vitro culture. Yet treatment of such NB cell lines with retinoic acid results in growth control and induction of differentiation. This indicates that the signaling pathways that regulate cell growth and differentiation are not functionally lost but dysregulated. Agents such as retinoic acid normalize the signaling pathways and impose growth control and induction of differentiation. Recent studies in embryonic stem cells indicate that polycomb repressor complex proteins (PRC1 and PRC2) play a major role in regulating stem cell lineage specification and coordinating the shift from a transcriptome that supports self-renewal or growth to one that specifies lineage and controls growth. We have shown that in NB, the PRC2 complex is elevated in undifferentiated NB tumors and functions to suppress a number of tumor suppressor genes. This study will review the role of MYC genes in regulating the epigenome in normal development and explore how this role may be altered during tumorigenesis.
MYCN; EZH2; epigenetics; nucleosome; RNA polymerase II; HDAC; HAT; transcriptional activation
Purpose: To report our experience with a sequential regimen of induction TPF-C followed by radioimmunotherapy with cetuximab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
Patients and Methods: Toxicity and outcome was retrospectively analyzed in 22 patients receiving sequential therapy with induction TPF-C followed by radioimmunotherapy between October 2008 and December 2011. Outcome was estimated using Kaplan–Meier analyses. In addition, we performed mutation analysis for PIK3CA genes and high risk HPV DNA detection using PCR.
Results: Mean time of follow-up was 16 months. Six patients were TNM Stage III, 15 patients IV (IVA or IVB), and one patient Stage II with bulky disease. During TPF-C, Grade 3 and 4 toxicities occurred in eight patients, dose modifications in seven, delays in one, and unplanned admissions in five. Clinical tumor response was documented in 18 of the 21 patients who completed at least three cycles of TPF-C with three patients developing complete response and 15 partial responses. Grade 3/4 mucositis was observed in six patients. At a median follow-up of 19 months, 13 patients were alive and nine had died including seven patients as a result of disease persistence or recurrence and two as a result of unrelated causes. PIK3CA mutations were not identified and our two oropharynx cases were HPV negative.
Conclusion: The combination of induction TPF-C with concurrent cetuximab radioimmunotherapy in patients with locally advanced HNSCC is tolerable, with encouraging efficacy.
HNSCC; TPF-C; cetuximab radiotherapy; toxicity and outcome; mutation analysis; PIK3CA, HPV DNA
Innate and adaptive immunity plays important roles in the development and progression of cancer and it is becoming apparent that tumors can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumors of patients with cancer is increased and the presence of these cells appears to present a major barrier to the induction of tumor immunity. One aspect of tumor-mediated immunoregulation which has received comparatively little attention is that which is directed toward natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating. Although the precise mechanisms underlying these localized and systemic immunoregulatory effects remain unclear, tumor-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumors to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer. This article reviews current knowledge relating to the influence of tumors on protective anti-tumor immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype, and function of innate and adaptive immune cells in patients with cancer.
tumor immunity; T cells; NK cells; tumor microenvironment; immunoregulation
Purpose: EGFR amplification and mutation (i.e., EGFRvIII) are found in 40% of primary GBM tumors and are believed to contribute to tumor development and therapeutic resistance. This study was designed to investigate how EGFR mutational status modulates response to multimodality treatment with cetuximab, an anti-EGFR inhibitor, the chemotherapeutic agent, temozolomide (TMZ), and radiation therapy (RT).
Methods and Materials:
In vitro and in vivo experiments were performed on two isogenic U87 GBM cell lines: one overexpressing wildtype EGFR (U87wtEGFR) and the other overexpressing EGFRvIII (U87EGFRvIII).
Results: Xenografts harboring EGFRvIII were more sensitive to TMZ alone and TMZ in combination with RT and/or cetuximab than xenografts expressing wtEGFR. In vitro experiments demonstrated that U87EGFRvIII-expressing tumors appear to harbor defective DNA homologous recombination repair in the form of Rad51 processing.
Conclusion: The difference in sensitivity between EGFR-expressing and EGFRvIII-expressing tumors to combined modality treatment may help in the future tailoring of GBM therapy to subsets of patients expressing more or less of the EGFR mutant.
GBM; cetuximab; temozolomide; Rad51; radiation therapy; EGFR
Data from over 20 years ago demonstrated potential use for insulin-like growth factor (IGF) signaling modulators, specifically with IGF-1R antagonists, in a variety of pediatric and adolescent cancers, particularly in sarcomas. However, in spite of promising preclinical data, IGF-1R inhibitors have not had the success as single agents that was originally hoped for in clinical trials. Several potential mechanisms exist by which tumors are resistant to IGF-1R inhibitors. Notably, these resistance mechanisms are currently best understood in Ewing sarcoma and alveolar rhabdomyosarcoma. Various treatment schema have been proposed as a potential way to overcome this resistance. The use of IGF-1R inhibitors, mechanisms of resistance, and current ongoing clinical studies using IGF-1R inhibitors in pediatric cancers are reviewed here.
insulin-like growth factor pathway; pediatric cancer; sarcoma; resistance mechanisms; IGF-1R
Objectives: Some patients are medically unfit for or averse to undergoing a brachytherapy boost as part of cervical cancer radiotherapy. In order to be able to definitively treat these patients, we assessed whether we could achieve a boost plan that would mimic our brachytherapy plans using external beam radiotherapy.
Methods: High dose rate brachytherapy plans of 20 patients with stage IIB cervical cancer treated with definitive chemoradiotherapy were included in this study. Patients had undergone computer tomography (CT) simulations with tandem and ovoids in place. Point “A” dose was 600–700 cGy. We attempted to replicate the boost dose distribution from brachytherapy plans using intensity-modulated radiotherapy (Varian Medical Systems, Palo Alto, CA, USA), volumetric modulated arc therapy (Rapid Arc, Varian Medical Systems, Palo Alto, CA, USA), or TomoTherapy (Accuray, Inc., Sunnyvale, CA, USA) with the brachytherapy 100% isodose line as our target. Target coverage, normal tissue dose, and brachytherapy point doses were compared with ANOVA. Two-sided p-values ≤0.05 were considered significant.
Results: External beam plans had excellent planning target volume (PTV) coverage, with no difference in mean PTV V95% among planning techniques (range 98–100%). External beam plans had lower bladder Dmax, small intestine Dmax, and vaginal mucosal point dose than brachytherapy plans, with no difference in bladder point dose, mean bladder dose, mean small intestine dose, or rectal dose. Femoral head dose, parametria point dose, and pelvic sidewall point dose were higher with external beam techniques than brachytherapy.
Conclusions: External beam plans had comparable target coverage and potential for improved sparing of most normal tissues compared to tandem and ovoid brachytherapy.
cervical cancer; brachytherapy; external beam radiotherapy
Eukaryotic cells are continuously threatened by unavoidable errors during normal DNA replication or various sources of genotoxic stresses that cause DNA damage or stalled replication. To maintain genomic integrity, cells have developed a coordinated signaling network, known as the DNA damage response (DDR). Following DNA damage, sensor molecules detect the presence of DNA damage and transmit signals to downstream transducer molecules. This in turn conveys the signals to numerous effectors, which initiate a large number of specific biological responses, including transient cell cycle arrest mediated by checkpoints, DNA repair, and apoptosis. It is recently becoming clear that dephosphorylation events are involved in keeping DDR factors inactive during normal cell growth. Moreover, dephosphorylation is required to shut off checkpoint arrest following DNA damage and has been implicated in the activation of the DDR. Spatial and temporal regulation of phosphorylation events is essential for the DDR, and fine-tuning of phosphorylation is partly mediated by protein phosphatases. While the role of kinases in the DDR has been well documented, the complex roles of protein dephosphorylation have only recently begun to be investigated. Therefore, it is important to focus on the role of phosphatases and to determine how their activity is regulated upon DNA damage. In this work, we summarize current knowledge on the involvement of serine/threonine phosphatases, especially the protein phosphatase 1, protein phosphatase 2A, and protein phosphatase Mg2+/Mn2+-dependent families, in the DDR.
DNA damage response; phosphorylation; protein phosphatase; DNA repair; chromatin
The forkhead box (FOX) M1 transcription factor is required to maintain the proliferation of cancer cells. Two transcriptionally active isoforms of FOXM1, FOXM1b and FOXM1c, have been identified, but their functional differences remain unclear. FOXM1c is distinguished from FOXM1b by an extra exon (exon Va) that contains an ERK1/2 target sequence. Based on a literature search and quantitative PCR analysis, we concluded that FOXM1b is the predominant isoform that is overexpressed in cancers. The further characterization of FOXM1b and FOXM1c revealed two interesting differences. First, FOXM1b exhibited a higher transforming ability than FOXM1c in a soft agar assay. Second, the transactivating activity of FOXM1c, but not that of FOXM1b, was sensitive to activation by RAF/MEK/MAPK signaling. Importantly, the MEK1 activation of FOXM1c was associated with proteolytic processing to generate short forms that might represent constitutively active forms missing the N-terminal inhibitory domain; in contrast, the proteolytic processing of FOXM1b did not require MEK1 activation. Our findings suggest that FOXM1b is functionally more active. These results provide novel insights into the regulation of FOXM1 activity and its role in tumorigenesis.
FOXM1b; FOXM1c; transforming potential; MEK1; proteolytic processing
GSK-3 is a multifunctional kinase that is located in the cytosol, nucleus, and mitochondria of all cell types, and it is involved in the pathogenesis of a variety of diseases. In cancer, GSK-3 modulates the response of the cell death machinery to stress stimuli, including chemotherapeutics. Mitochondria are at the heart of the integration between survival and noxious signals; therefore, modulation of the mitochondrial functions carried out by GSK-3 is profoundly involved in the apoptosis escape capabilities that hallmark neoplasms. This review briefly covers the mechanistic interactions among oncogenic kinase pathways, GSK-3 activity and subsequent modulation of mitochondrial functions that shape the pro-survival phenotype of cancer cells, such as control of redox homeostasis and inhibition of the mitochondrial permeability transition pore.
GSK-3; mitochondria; ROS; chemotherapeutics; PTP; cancer; apoptosis
Secreted proteins including cytokines, chemokines, and growth factors represent important functional regulators mediating a range of cellular behavior and cell–cell paracrine/autocrine signaling, e.g., in the immunological system (Rothenberg, 2007), tumor microenvironment (Hanahan and Weinberg, 2011), or stem cell niche (Gnecchi etal., 2008). Detection of these proteins is of great value not only in basic cell biology but also for diagnosis and therapeutic monitoring of human diseases such as cancer. However, due to co-production of multiple effector proteins from a single cell, referred to as polyfunctionality, it is biologically informative to measure a panel of secreted proteins, or secretomic signature, at the level of single cells. Recent evidence further indicates that a genetically identical cell population can give rise to diverse phenotypic differences (Niepel etal., 2009). Non-genetic heterogeneity is also emerging as a potential barrier to accurate monitoring of cellular immunity and effective pharmacological therapies (Cohen etal., 2008; Gascoigne and Taylor, 2008), but can hardly assessed using conventional approaches that do not examine cellular phenotype at the functional level. It is known that cytokines, for example, in the immune system define the effector functions and lineage differentiation of immune cells. In this article, we hypothesize that protein secretion profile may represent a universal measure to identify the definitive correlate in the larger context of cellular functions to dissect cellular heterogeneity and evolutionary lineage relationship in human cancer.
intra-tumor heterogeneity; protein secretion profile; single-cell analysis; immunomonitoring; tumor microenvironment
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.
invasive fungal infection; allogeneic hematopoietic stem cell transplantation; immunotherapy; granulocyte; T cell; natural killer cell
Glioblastoma (GBM) is one of the most common and dismal brain tumors in adults. Further elucidation of the molecular pathogenesis of GBM is mandatory to improve the overall survival of patients. A novel small non-coding RNA molecule, microRNA (miRNA), appears to represent one of the most attractive target molecules contributing to the pathogenesis of various types of tumors. Recent global analyses have revealed that several miRNAs are clinically implicated in GBM, with some reports indicating the association of miRNA dysregulation with acquired temozolomide (TMZ) resistance. More recent studies have revealed that miRNAs could play a role in cancer stem cell (CSC) properties, contributing to treatment resistance. In addition, greater impact might be expected from miRNA-targeted therapies based on tumor-derived exosomes that contain numerous functional miRNAs, which could be transferred between tumor cells and surrounding structures. Tumor-derived miRNAs are now considered to be a novel molecular mechanism promoting the progression of GBM. Establishment of miRNA-targeted therapies based on miRNA dysregulation of CSCs could provide effective therapeutic strategies for TMZ-resistant GBM. Recent progress has revealed that miRNAs are not only putative biological markers for diagnosis, but also one of the most promising targets for GBM treatment. Here in, we summarize the translational aspects of miRNAs in the diagnosis and treatment of GBM.
glioblastoma; temozolomide; microRNA; exosome
Receptor tyrosine kinases (RTKs) drive breast cancer progression, particularly in human epidermal growth factor receptor 2 and basal tumors, the two worst prognosis subtypes. Tumor cells recruit host stromal components, including immune cells, which strongly influence disease progression. This has been studied in human breast cancer and translated to murine models of breast cancer. Stromal immune components including cytotoxic T lymphocytes (CTLs) and natural killer cells, destroy cancer cells through a process termed immune surveillance. Unfortunately, clinically detectable tumors escape these immune protective effects through their ability to limit the infiltration, activation, and/or survival of CTLs in breast tumors. The immunosuppressed state of established tumors limits the success rate of immune-based therapies, and possibly other therapeutic modalities that depend on host immunity. Published studies demonstrate that RTKs facilitate breast cancer progression, in part, by establishing immune suppression. This raises the intriguing possibility that pharmacological RTK inhibitors may be exploited to sensitize breast cancer patients to immune-based therapies.
breast cancer; cytotoxic T lymphocyte; immune suppression; HER2/basal; receptor tyrosine kinase
Apoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer.
apoptosis; signaling; Bcl-2; TRAIL; IAP proteins
The forkhead protein, FOXA1, is a critical interacting partner of the nuclear hormone receptors, oestrogen receptor-α (ER) and androgen receptor (AR), which are major drivers of the two most common cancers, namely breast and prostate cancer. Over the past few years, progress has been made in our understanding of how FOXA1 influences nuclear receptor function, with both common and distinct roles in the regulation of ER or AR. Recently, another level of regulation has been described, with the discovery that FOXA1 is mutated in 1.8% of breast and 3–5% prostate cancers. In addition, a subset of both cancer types exhibit amplification of the genomic region encompassing the FOXA1 gene. Furthermore, there is evidence of somatic changes that influence the DNA sequence under FOXA1 binding regions, which may indirectly influence FOXA1-mediated regulation of ER and AR activity. These recent observations provide insight into the heterogeneity observed in ER and AR driven cancers.
FoxA1; breast cancer; prostate cancer; exome sequencing; SNP; androgen receptor (AR); estrogen receptor alpha
Background: Previous molecular characterizations of mammary stem cells (MaSC) have utilized fluorescence-activated cell sorting or in vitro cultivation of cells from enzymatically dissociated tissue to enrich for MaSC. These approaches result in the loss of all histological information pertaining to the in vivo locale of MaSC and progenitor cells. Instead, we used laser microdissection to excise putative progenitor cells and control cells from their in situ locations in cryosections and characterized the molecular properties of these cells. MaSC/progenitor cells were identified based on their ability to retain bromodeoxyuridine for an extended period.
Results: We isolated four categories of cells from mammary epithelium of female calves: bromodeoxyuridine label retaining epithelial cells (LREC) from basal (LRECb) and embedded layers (LRECe), and epithelial control cells from basal and embedded layers. Enriched expression of genes in LRECb was associated with stem cell attributes and identified WNT, TGF-β, and MAPK pathways of self renewal and proliferation. Genes expressed in LRECe revealed retention of some stem-like properties along with up-regulation of differentiation factors.
Conclusion: Our data suggest that LREC in the basal epithelial layer are enriched for MaSC, as these cells showed increased expression of genes that reflect stem cell attributes; whereas LREC in suprabasal epithelial layers are enriched for more committed progenitor cells, expressing some genes that are associated with stem cell attributes along with those indicative of cell differentiation. Our results support the use of DNA label retention to identify MaSC and also provide a molecular profile and novel candidate markers for these cells. Insights into the biology of stem cells will be gained by confirmation and characterization of candidate MaSC markers identified in this study.
label retention; mammary stem cells; mammary progenitor cells; stem cell markers; laser microdissection
To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT). Many molecular details of the ALT pathway are unknown, and even less is known regarding the mechanisms by which this pathway is activated. Here, we review current findings about telomere structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state. We speculate that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype.
telomere; alternative lengthening of telomeres (ALT); chromatin; shelterin; DNA damage response (DDR); recombination; variant telomeric repeats; nuclear receptors
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future.
cell death; signal transduction; immunotherapy; childhood cancer
Radiotherapy is safely employed for treating wide variety of cancers. The radiotherapy workflow includes a precise positioning of the patient in the intended treatment position. While trained radiation therapists conduct patient positioning, consultation is occasionally required from other experts, including the radiation oncologist, dosimetrist, or medical physicist. In many circumstances, including rural clinics and developing countries, this expertise is not immediately available, so the patient positioning concerns of the treating therapists may not get addressed. In this paper, we present a framework to enable remotely located experts to virtually collaborate and be present inside the 3D treatment room when necessary. A multi-3D camera framework was used for acquiring the 3D treatment space. A client–server framework enabled the acquired 3D treatment room to be visualized in real-time. The computational tasks that would normally occur on the client side were offloaded to the server side to enable hardware flexibility on the client side. On the server side, a client specific real-time stereo rendering of the 3D treatment room was employed using a scalable multi graphics processing units (GPU) system. The rendered 3D images were then encoded using a GPU-based H.264 encoding for streaming. Results showed that for a stereo image size of 1280 × 960 pixels, experts with high-speed gigabit Ethernet connectivity were able to visualize the treatment space at approximately 81 frames per second. For experts remotely located and using a 100 Mbps network, the treatment space visualization occurred at 8–40 frames per second depending upon the network bandwidth. This work demonstrated the feasibility of remote real-time stereoscopic patient setup visualization, enabling expansion of high quality radiation therapy into challenging environments.
remote visualization; radiotherapy; 3D monitoring; patient positioning; client–server architecture