ABSTRACT
BACKGROUND: Management options for the treatment of melanoma have expanded in recent years. In an era of promising, but expensive novel pharmacological treatments, robust stage-specific melanoma-related cost estimates are necessary to support budgetary planning, evaluation of cost-effectiveness and to contribute to the investment case for prevention. METHODS: A detailed decision model, describing the melanoma care pathway (by disease stage) from diagnosis, through treatment and follow-up was developed over a 5-year time frame from the perspective of the Irish healthcare system. The model was populated with real-world data from the National Cancer Registry Ireland. Uncertainty was explored using one-way and probabilistic sensitivity analysis. RESULTS: The cost of managing a case of melanoma diagnosed at Stage IV (122 985) was more than 25 times more expensive than managing a case diagnosed at Stage IA (4269). Total costs were sensitive to the choice of immunotherapeutic and targeted drug, duration of treatment and proportion of patients receiving immunotherapy agents. CONCLUSIONS: The rising incidence of melanoma and high cost of new novel therapies presents an immediate challenge to cancer control and public health globally. This study highlights the cost differential between early and late detection and the potential return on investment for prevention versus high-cost treatment.
Subject(s)
Melanoma , Humans , Ireland/epidemiology , Melanoma/therapy , Health Care Costs , Cost-Benefit AnalysisABSTRACT
BACKGROUND: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. METHODS: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. RESULTS: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. CONCLUSIONS: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.
Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Antineoplastic Agents/therapeutic use , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/genetics , Humans , Male , Mutation/genetics , Oncogenes/genetics , Proteomics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Signal TransductionABSTRACT
It has been historically uncertain if extra centrosomes are a cause or consequence of tumorigenesis. Experiments have recently established that overexpression of polo-like kinase 4 (PLK4) promotes centrosome amplification with consequential promotion of cellular aneuploidy. Furthermore, centrosome amplification drives spontaneous tumorigenesis in mice. Tissues lacking normal functional p53 tolerate extra centrosomes, whereas p53 proficient tissues initiate proliferative arrest in this circumstance. Extra centrosomes trigger activation of the multi-protein PIDDosome complex, with Caspase-2 effecting cleavage of the p53-negative regulator mouse double minute 2, consequent stabilization of p53 and p21-dependent arrest of the cell cycle. The co-occurrence of cellular aneuploidy, complex chromosomal rearrangements and p53 dysfunction is a striking feature of some osteosarcomas. It is postulated that small-molecule PLK4 inhibitors such as CFI-400945, which are in development, may have utility in osteosarcoma given these findings.
Subject(s)
Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Centrosome/drug effects , Molecular Targeted Therapy , Osteosarcoma/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Cell Cycle , Humans , Osteosarcoma/metabolism , Osteosarcoma/pathology , PrognosisABSTRACT
BACKGROUND: Discovery and validation of new antibody tractable targets is critical for the development of new antibody therapeutics to address unmet needs in oncology. METHODS: A highly invasive clonal variant of the MDA-MB-435S cell line was used to generate monoclonal antibodies (MAbs), which were screened for anti-invasive activity against aggressive cancer cells in vitro. The molecular target of selected inhibitory MAb 9E1 was identified using immunoprecipitation/liquid chromatography-tandem mass spectrometry. The potential anti-tumour effects of MAb 9E1 were investigated in vitro together with immunohistochemical analysis of the 9E1 target antigen in normal and cancer tissues. RESULTS: MAb 9E1 significantly decreases invasion in pancreatic, lung squamous and breast cancer cells and silencing of its target antigen, which was revealed as AnxA6, leads to markedly reduced invasive capacity of pancreatic and lung squamous cancer in vitro. IHC using MAb 9E1 revealed that AnxA6 exhibits a high prevalence of membrane immunoreactivity across aggressive tumour types with restricted expression observed in the majority of normal tissues. In pancreatic ductal adenocarcinoma, high AnxA6 IHC score correlated with the presence of tumour budding at the invasive front of tumours (P=0.082), the presence of perineural invasion (P= <0.0001) and showed a weak correlation with reduced survival (P=0.2242). CONCLUSIONS: This study highlights the use of phenotypic hybridoma screening as an effective strategy to select a novel function-blocking MAb, 9E1 with anti-cancer activity in vitro. Moreover, through characterisation of the 9E1 target antigen, AnxA6, our findings support further investigation of AnxA6 as a potential candidate target for antibody-mediated inhibition of pancreatic cancer.
Subject(s)
Annexin A6/metabolism , Antibodies, Monoclonal/immunology , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Squamous Cell/metabolism , Lung Neoplasms/metabolism , Pancreatic Neoplasms/metabolism , Animals , Annexin A6/antagonists & inhibitors , Annexin A6/immunology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Female , Humans , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Mice , Neoplasm Staging , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Prognosis , Survival RateABSTRACT
OBJECTIVES: To evaluate participant-reported atypical dysphagia symptoms and their association with oxaliplatin treatment. METHODS: This observational study recruited 73 adults with solid tumours outside the head, neck or upper gastrointestinal tract. All had dysphagia, were in hospital or hospice and were treated by Medical Oncology, Radiation Oncology or Palliative Care. Participants reported their experiences of swallowing difficulties by semistructured interview. Oral Health Assessment Tool was used to ensure swallow difficulties were not due to mucositis. Responses were transcribed and analysed by content analysis. Atypical difficulties were examined for association with oxaliplatin treatment by Fischer's Exact. RESULTS: Oxaliplatin treatment was associated with three unusual dysphagia symptoms: problems with cold or hot bolus (p=0.01), pins and needles (p=0.001) and throat spasm (p=0.035). Carbonation was problematic for one participant. Chemotherapy commencement coincided with swallow problem onset for 67%. Dysphagia symptoms were unrelated to mucositis (p=0.165). CONCLUSIONS: Swallowing difficulties in oxaliplatin-treated patients are atypical and attributable to chemotherapy commencement. Previous research suggests that dysphagia is triggered by cold exposure, but hot and carbonated boluses also caused problems here. Dysphagia symptoms and triggers should be studied more fully to help patients safely enjoy their meals and prevent food avoidance, which could exacerbate malnutrition.
ABSTRACT
Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.
Subject(s)
Neoplasms/genetics , Neoplasms/metabolism , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Molecular Targeted Therapy , Neoplasms/drug therapy , Receptors, Fibroblast Growth Factor/antagonists & inhibitorsABSTRACT
BACKGROUND: Oncology patients have had to make many changes to minimise their exposure to COVID-19, causing stress. Despite education, some patients still do not recognise potential COVID symptoms. AIMS: We assessed patient knowledge of COVID, and its impact on their behaviours, concerns, and healthcare experience. METHODS: A 16-page questionnaire was distributed to 120 oncology patients attending the day unit of a tertiary Irish cancer centre for systemic anti-cancer therapy (May/June 2020). The Irish 7-day COVID incidence during this period ranged from 2 to 11 cases/100,000 people. RESULTS: One hundred and one responses were received, 1% had tested positive for COVID, and 31% had undergone testing. Participant insight into their knowledge about COVID and their own behaviour was limited in some cases. Seventy-five percent reported total compliance with restrictions, but many were not fully compliant. Self-reported confidence in knowledge was high, but did not predict demonstrated knowledge. Sixty percent did not recognise two or more symptoms; 40% did not self-identify as high-risk. Patients reported more health-related worry (72%), loneliness (51%), and lower mood (42%) since the pandemic began. Financial toxicity worsened, with increased financial worry (78%), reductions in household income (40%), and increased costs due to lockdown (62%). Use of facemasks introduced new communications barriers for 67% of those with hearing loss. CONCLUSIONS: Despite self-reported confidence in knowledge, some patient's recognition of COVID symptoms and the preventative strategies they should use are not optimal, highlighting the need for further education in this regard. COVID has been a significant stressor for patients and more practical, financial, and psychological supports are needed.
Subject(s)
COVID-19 , Neoplasms , Humans , Pandemics , COVID-19/epidemiology , Communicable Disease Control , Medical Oncology , Neoplasms/epidemiologyABSTRACT
CONTEXT: Dysphagia is common in cancer, but underlying pathophysiology and manifestations within patients are unknown. OBJECTIVES: To examine dysphagia characteristics in those with solid malignancies outside the head, neck and upper gastrointestinal tract. METHODS: Seventy-three individuals with dysphagia (46 male, 27 female, aged 37-91) were recruited from a parent trial conducted in two acute hospitals and one hospice. Cranial nerve function, Oral Health Assessment Tool (OHAT), Mann Assessment of Swallowing Ability (MASA) and Functional Oral Intake Scale (FOIS) evaluated swallow profile. RESULTS: Only 9/73 (12%) had documented dysphagia prior to study enrollment. MASA risk ratings found n=61/73 (84%) with dysphagia risk and n=22/73 (30%) with aspiration risk. Food texture modification was required for n=34/73 (47%), fluid texture modification for n=1/73 (1%). Compensatory strategies for food were needed by n=13/73 (18%) and for fluids by n=24/73 (33%). Cranial nerve deficits were present in n=43/73 (59%). Oral health problems were common, with xerostomia in two-thirds. Worse dysphagia on MASA was associated with disease progression, affecting hospice, and palliative care the most. Worse performance status was indicative of poorer MASA raw score (P<0.001, OR 2.2, 95% CI 1.5-3.4), greater risk of aspiration (P=0.005, OR 2.1, 95% CI 1.3-3.6) and lower FOIS (P=0.004, OR 2.0, 95% CI 1.2-3.2). CONCLUSION: Dysphagia management in those with cancer requires robust assessment to uncover clinically important needs like food texture modification and safe swallowing advice. Better assessment tools should be developed for this purpose. Oral health problems should be routinely screened in this population since they exacerbate dysphagia.
Subject(s)
Deglutition Disorders , Neoplasms , Upper Gastrointestinal Tract , Female , Humans , Male , Deglutition/physiology , Deglutition Disorders/diagnosis , Deglutition Disorders/etiology , Deglutition Disorders/epidemiology , Palliative Care , Adult , Middle Aged , Aged , Aged, 80 and over , Clinical Trials as TopicABSTRACT
OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.
Subject(s)
Hedgehog Proteins/physiology , Pancreatic Neoplasms/etiology , Signal Transduction/physiology , Adenocarcinoma/etiology , Anilides/therapeutic use , Animals , Clinical Trials as Topic , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/chemistry , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/physiology , Pancreatic Neoplasms/drug therapy , Pyridines/therapeutic useABSTRACT
Basal cell carcinomas occur in up to 39% of Caucasian men and 28% of women. Rarely it can present a management dilemma in patients with neglected locally advanced disease of large dimension or involvement of critical structures. The Hedgehog pathway is constitutively active in almost all basal cell carcinomas and patients with Naevoid Basal Cell Carcinoma Syndrome have germline mutations in the Patched tumor suppressor gene, a Hedgehog pathway component, on chromosome 9q. This case describes an elderly patient with an untreated sporadic Basal cell carcinoma whose dimensions precluded local management approaches. The Hedgehog pathway inhibitor Vismodegib had a dramatic response allowing definitive treatment to be pursued.
Subject(s)
Anilides/pharmacology , Carcinoma, Basal Cell/drug therapy , Carcinoma, Basal Cell/genetics , Hedgehog Proteins/drug effects , Pyridines/pharmacology , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Aged, 80 and over , Carcinoma, Basal Cell/pathology , Humans , Male , Neoadjuvant Therapy/methods , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Systemic anti-cancer treatment (SACT) can improve symptoms and survival in patients with incurable cancer but there may be harmful consequences. Information regarding the use of SACT at the end-of-life and its impact on patients has not been described in Ireland. AIMS: The study aimed to quantify and describe the use of SACT at end-of-life. The primary outcome of interest was the number of patients who received treatment in the last 12, 4 and 2 weeks of life. Secondary outcomes included the frequency of admissions and procedures, location of death, and timing of specialist palliative care (SPC) referral. METHODS: Retrospective review. Fisher exact testing was used for analyses. Patients were included if they died between January 2015 and July 2017 and received at least 1 dose of treatment for a solid tumor malignancy. RESULTS: Five hundred and eighty two patients were included. Three hundred and thirty eight (58%), 128 (22%) and 36 (6%) received treatment in the last 12, 4 and 2 weeks of life respectively. Patients who received chemotherapy in the last 12 weeks of life were more likely to be admitted to hospital, undergo a procedure, and die in hospital than those who did not (P < 0.001 for all). Median time of SPC referral before death was shorter in those patients who received chemotherapy than those who did not (61 v129 days, p = 0.0001). CONCLUSION: Patients who received chemotherapy had a higher likelihood of hospital admission, invasive procedure, and in-hospital death. They were less likely to have been referred early to SPC services.
Subject(s)
Neoplasms , Terminal Care , Hospital Mortality , Humans , Ireland , Neoplasms/drug therapy , Palliative Care , Retrospective StudiesABSTRACT
BACKGROUND: Encephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10-30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA). CASE PRESENTATION: This is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms. CONCLUSION: The rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.
ABSTRACT
CONTEXT: Dysphagia is usually associated with malignancies of the head, neck, and upper gastrointestinal tract but also occurs in those with tumors outside anatomic swallow regions. It can lead to aspiration pneumonia, malnutrition, reduced quality of life, and psychosocial distress. No studies have yet reliably described dysphagia prevalence in those with malignancies outside anatomic swallow regions. OBJECTIVE: The objective of this study was to establish the prevalence and predictors of dysphagia in adults with solid malignancies outside the head, neck, and upper gastrointestinal tract. METHODS: A cross-sectional, observational study using consecutive sampling was conducted. There were 385 participants (mean age 66 ± 12 years) with 21 different primary cancer sites from two acute hospitals and one hospice. Locoregional disease was present in 33%, metastatic in 67%. Dysphagia was screened by empirical questionnaire and confirmed through swallow evaluation. Demographic and clinical predictors were determined by univariate and multivariate binary regression. RESULTS: Dysphagia occurred in 19% of those with malignancies outside anatomic swallow regions. Prevalence was 30% in palliative care and 32% in hospice care. Dysphagia was most strongly associated with cough, nausea, and worse performance status. It was also associated with lower quality of life and nutritional difficulties. CONCLUSION: Dysphagia was common and usually undiagnosed before study participation. It occurred at all disease stages but coincided with functional decline. It may therefore represent a cancer frailty marker. Oncology and palliative care services should routinely screen for this symptom. Timely dysphagia identification and management may improve patient well-being and prevent adverse effects like aspiration pneumonia and weight loss.
Subject(s)
Deglutition Disorders/epidemiology , Deglutition Disorders/etiology , Neoplasms/diagnosis , Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Deglutition , Deglutition Disorders/psychology , Female , Gastrointestinal Neoplasms , Head and Neck Neoplasms , Hospices , Humans , Male , Malnutrition/epidemiology , Malnutrition/etiology , Middle Aged , Neoplasms/psychology , Palliative Care , Predictive Value of Tests , Prevalence , Quality of Life , Surveys and Questionnaires , Upper Gastrointestinal TractABSTRACT
INTRODUCTION: Malignant melanoma of the gastrointestinal tract is usually a metastasis from a cutaneous source. Primary gastric melanoma is an extremely rare clinical entity, with few reported cases worldwide. It is often advanced at time of diagnosis and is associated with a dismal outcome. BACKGROUND: A 76 year old gentleman presenteded with a one month history of fatigue and exertional dyspnoea. Laboratory investigations indicated an anaemia, with a haemoglobin level of 11.0g/dl. Subsequent gastroscopy visualised a large, atypical, crater-like ulcerated lesion distal to the cardia in the proximal stomach.Provisional histology was suggestive of a poorly differentiated adenocarcinoma but subsequent cyto-morphology and immunophenotyping were consistent with melanoma, with positive S100 protein, HMB45 and Melan A. Further molecular genetic testing revealed a V600R mutation in the BRAF gene, which is the first primary gastric melanoma with this mutation to be reported in the literature. Given the rarity of the findings, an extensive secondary work-up was undertaken, which concluded the diagnosis primary gastric melanoma. DISCUSSION: Primary gastric melanoma is a rare disease that can present similarly to other upper gastrointesinal lesions, with weight loss, abdominal pain, malena, and anaemia. Given its rarity, the pathogenesis is poorly understood. Lesions are often endoscopically atypical. Important points to note would include the absence of a primary lesion, as supported by a full skin examination and PET-CT findings, which can help to delineate the limitation to the stomach, thus helping to inform subsequent management. LEARNING POINTS: Primary gastric melanoma (PGM) is a rare clinical entity.Work-up including skin and ophthalmic examination is important to exclude a primary cutaneous source, as this helps dictate both prognosis and subsequent management, including whether surgical resection is advisable.Immunophenotyping and genetic testing inform management but, despite advances in therapy, the prognosis of PGM and other mucosal melanomas remains poor.
ABSTRACT
Macrophages appear to have a fundamental role in the pathogenesis of osteosarcoma. These highly diverse plastic cells are subdivided into classical or inflammatory macrophages known as M1 and alternative macrophages, which decrease inflammation and are reparative, called M2. Although primary and metastatic osteosarcomas are infiltrated with M2 macrophages, targeting the M1 macrophages with the immune adjuvant muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) has been the greatest recent therapeutic advance in osteosarcoma. This discrepancy between the presence of M2 and activation of M1 macrophages is intriguing and is likely explained either by the plasticity of M1 and M2 macrophages or nonclassical patrolling monocytes (PMos). To date, MTP-PE has been approved in combination with chemotherapy for nonmetastatic osteosarcoma, but its use in metastatic tumors has not been investigated. In this review, we focus on macrophages, monocytes, and osteoclasts, their role in osteosarcoma, and the potential for targeting these cells in this disease.
Subject(s)
Bone Neoplasms/etiology , Macrophages/physiology , Monocytes/physiology , Osteoclasts/physiology , Osteosarcoma/etiology , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Cell Transformation, Neoplastic/pathology , Humans , Molecular Targeted Therapy/methods , Osteosarcoma/drug therapy , Osteosarcoma/pathologyABSTRACT
Colonic polyps may arise from BRAF inhibitor treatment of melanoma, possibly due to paradoxical activation of the mitogen-activated protein (MAP)-kinase pathway. In an alternative evidence based scenario, tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment, in the absence of mutations of MAPK genes. A minority of colorectal cancers develop by an alternative "serrated polyp pathway". This article postulates a novel hypothesis, that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps. Serrated polyps are characterized by a CpG island methylation phenotype, MLH1 silencing and cellular senescence. They also have BRAF mutations. The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF: C-RAF heterodimers.
Subject(s)
Adenomatous Polyps/chemically induced , Colonic Polyps/chemically induced , Colorectal Neoplasms/chemically induced , MAP Kinase Signaling System/drug effects , Melanoma/drug therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyps/genetics , Adenomatous Polyps/pathology , Cellular Senescence , Colonic Polyps/genetics , Colonic Polyps/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , CpG Islands/genetics , DNA Methylation , Epigenesis, Genetic , Humans , Mitogen-Activated Protein Kinases/genetics , MutL Protein Homolog 1/genetics , Mutation , Protein Multimerization/drug effects , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-raf/metabolismABSTRACT
PURPOSE: Circulating tumor DNA (ctDNA) allows noninvasive disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unknown. We assessed the role of ctDNA analysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment. PATIENTS AND METHODS: We performed a comprehensive analysis of serial ctDNA and FDG-PET in 52 patients who received systemic therapy for metastatic melanoma. Next-generation sequencing and digital polymerase chain reaction were used to analyze plasma samples from the cohort. RESULTS: ctDNA levels were monitored across patients with mutant BRAF, NRAS, and BRAF/NRAS wild type disease. Mutant BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment. TERT promoter mutant ctDNA levels also paralleled changes in tumor burden, which provide an alternative marker for disease monitoring. Of note, subcutaneous and cerebral disease sites were not well represented in plasma. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post-treatment had improved progression-free survival compared with patients in whom ctDNA levels remained unchanged or increased over time (hazard ratio, 2.6; P = .05). ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multiregional tumor biopsy specimens at autopsy revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites. CONCLUSION: The findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging that allows real-time monitoring of both tumor burden and genomic changes throughout therapy.
ABSTRACT
FOXM1 is a pro-proliferative transcription factor that promotes cell cycle progression at the G1-S, and G2-M transitions. It is activated by phosphorylation usually mediated by successive cyclin - cyclin dependent kinase complexes, and is highly expressed in sarcoma. p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21. Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.FOXM1 stimulates transcription of pluripotency related genes including SOX2, KLF4, OCT4, and NANOG many of which are important in sarcoma, a disorder of mesenchymal stem cell/ partially committed progenitor cells. In a selected specific, SOX2 is uniformly expressed in synovial sarcoma. Embryonic pathways preferentially used in stem cell such as Hippo, Hedgehog, and Wnt dominate in FOXM1 stoichiometry to alter rates of FOXM1 production or degradation. In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP). A complex involving YAP and the transcription factor TEAD elevates FOXM1 in these sarcoma subtypes. In another scenario 80% of desmoid tumors have nuclear localization of ß-catenin, the Wnt pathway effector molecule. Thiazole antibiotics inhibit FOXM1 and because they have an auto-regulator loop FOXM1 expression is also inhibited. Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.
Subject(s)
Forkhead Box Protein M1/metabolism , Sarcoma/metabolism , Soft Tissue Neoplasms/metabolism , Stem Cells/metabolism , Animals , Cell Cycle , Cell Proliferation , Down-Regulation , Humans , Kruppel-Like Factor 4 , Mesoderm/metabolism , Phosphorylation , Retinoblastoma Protein/metabolism , Thiazoles/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
Peto's paradox is the counterintuitive finding that increasing body mass and thereby cell number does not correlate with an increase in cancer incidence across different species. The Hippo signaling pathway is an evolutionarily conserved system that determines organ size by regulating apoptosis and cell proliferation. It also affects cell growth by microRNA-29 (miR-29)-mediated cross-talk to the mTOR signaling pathway. Whether these pathways that decide organ size could explain this paradox merits consideration. Inactivation of most genes of the Hippo pathway in Drosophila melanogaster genetic screens causes excessive tissue-specific growth of developing tissues. Altered Hippo pathway activity is frequently found in diverse tumor types, but mutations of component pathway genes are rare. Most Hippo pathway components are encoded by tumor suppressor genes (TSG), but an exception is the downstream effector gene called YAP. Activity of the Hippo pathway causes deactivating phosphorylation of YES-associated protein (YAP) with nuclear exclusion. YAP can also be phosphorylated at a second site, S127, by AKT. YAP induces the expression of genes responsible for proliferation and suppression of apoptosis. Resolving Peto's paradox may serendipitously provide new insights into the biology and treatment of cancer. This article considers Hippo signaling and Peto's paradox in the context of TSG-oncogene computed models. Interspecies differences in dietary composition, metabolic rates, and anabolic processes are also discussed in the context of Hippo-mTOR signaling. The metabolically important LKB1-AMPK (liver kinase B1-AMP activated protein kinase) signaling axis that suppresses the mTOR pathway is also considered.