Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. ...Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including
,
and
. Furthermore,
and
, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.
Incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is rising in several countries. Intriguingly, large variations of HPV16 viral load and different ...proportions of the physical viral status among HNSCC have been reported. We analysed fresh biopsies of 275 HNSCC patients from the South Swedish Health Care Region for HPV types with modified general primer PCR and Luminex. Seventy-eight HPV16-positive HNSCC cases were further investigated for viral DNA load and physical status using quantitative PCR for HPV E2 and E7 genes. Presence of intact E2 gene, as a surrogate marker for episomal HPV, was investigated with conventional PCR. Fifteen different HPV types were detected in HNSCC cases and HPV16 was present in 74 % of the HPV-positive cases. HPV was detected in 65 % (92/141) and 11 % (15/134) of oropharyngeal and non-oropharyngeal carcinomas, respectively (P<0.0001). HPV was detected in 73 % (75/103) of tonsillar carcinomas. The median load of HPV16 was 13 copies cell-1 (range 0.003-1080). Among HPV16-positive patients with oropharyngeal carcinoma, metastases to regional lymph nodes were observed in 100 % (17/17) and 68 % (40/58) for those with <1 HPV16 copy cell-1 and >1 HPV16 copy cell-1, respectively (P=0.007). Among HPV16 cases, purely integrated HPV16 was found in 6 %, whereas entirely episomal and mixed virus was detected in 51 and 42 % of cases, respectively. Conclusively, HPV16 viral DNA load demonstrated a large diversity among HNSCCs. Although integration of HPV16 is common (48 %), the episomal HPV16 is salient (93 %) among HPV16 HNSCCs. In addition, low amount of HPV16 was associated with lymph node metastases among oropharyngeal carcinomas.
The incidence of oropharyngeal cancer (OPC) is increasing, particularly human papillomavirus (HPV)-associated OPC. The aim of this study was to specify the total societal cost of OPC by HPV status, ...cancer stage, and subsite using a bottom-up cost-of-illness approach.
We analyzed 121 consecutive patients with OPC from the Southern Health Care Region of Sweden. We estimated the direct medical costs and indirect costs (e.g., disease-related morbidity and premature death) from 1 month prior to OPC diagnosis until 3 years after treatment completion.
The mean total cost per patient was €103 386 for HPV-positive and €120 244 for HPV-negative OPC. Eighty-one percent of the patients analyzed were HPV-positive: Accordingly, HPV-positive OPC represented 79% of the total cost of OPC. The mean total cost of stage I, II, III, IVA, IVB, and IVC, regardless of HPV status, was €59 424, €57 000, €69 246, €115 770, €234 459, and €21 930, respectively, of which indirect costs were estimated at €22 493 (37.8%), €14 754 (25.9%), €28 681 (41.4%), €67 107 (58%), €166 280 (70.9%), and €0. Tonsillar cancer represented 64% of OPC, with a mean total cost of €117 512 per patient.
The societal cost of OPC is substantial. HPV-associated OPC comprises 79% of the total cost of this disease. The data presented in this study may be used in analytical models to aid decision makers in determining the potential value of gender-neutral HPV vaccination.
High-risk (HR) human papillomavirus (HPV) infection is an established cause of malignant disease. We used a societal perspective to estimate the cost of HR HPV-related cervical, vulvar, vaginal, ...anal, and penile precancer and cancer, and oropharyngeal cancer in Sweden in 2006, 1 year before HPV vaccination became available in the country.
This prevalence-based cost-of-illness study used diagnosis-specific data from national registries to determine the number of HR HPV-related precancers and cancers. The HR HPV-attributable fractions of these diseases were derived from a literature review and applied to the total burden to estimate HR HPV-attributable costs. Direct costs were based on health care utilization and indirect costs on loss of productivity due to morbidity (i.e., sick leave and early retirement) and premature mortality.
The total annual cost of all HR HPV-attributable precancers and cancers was €94 million (€10.3/inhabitant). Direct costs accounted for €31.3 million (€3.4/inhabitant) of the total annual cost, and inpatient care amounted to €20.7 million of direct costs. Indirect costs made up €62.6 million (€6.9/inhabitant) of the total annual cost, and premature mortality amounted to €36 million of indirect costs. Cervical precancer and cancer was most costly (total annual cost €58.4 million). Among cancers affecting both genders, anal precancer and cancer, and oropharyngeal cancer were the most costly (€11.2 million and €11.9 million, respectively). For oropharyngeal cancer, males had the highest health care utilization and represented 71% of the total annual cost. Penile precancer and cancer was least costly (€2.6 million).
The economic burden of HR HPV-related precancers and cancers is substantial. The disease-related management and treatment costs we report are relevant as a point of reference for future economic evaluations investigating the overall benefits of HPV vaccination in females and males in Sweden.
The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR ...signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC.
We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC.
We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line.
These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.
Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma (OSCC). The aim was to establish cell lines from HPV-positive tonsil carcinomas to be used for ...treatment development.
Fresh samples from 23 HPV-positive tonsil carcinomas were cultivated in vitro. The established cell line was analyzed for viral characteristics, cell karyotype, TP53 status, and growth capabilities in nude mice. In vitro studies of sensitivities to radiation, cisplatin and cetuximab were performed.
After 19 months (eight passages), one cell line, LU-HNSCC-26, was established in vitro and also grew as xenografts. The tumor was from a 48 year old non-smoking man with non-keratinizing, p16 positive tonsil OSCC, stage T2N0M0 with HPV16. It contained 19.5 (CV% 3.7) HPV16 copies/cell (passage 8). The complete HPV16 genome sequence was obtained. Episomal HPV16 was present with an E2/E7 ratio of 1.1 (CV% 2.6). In addition, HPV16 mRNA specific for the intact E2 gene was detected. The viral expression manifested 1.0 (CV% 0.1) E7 mRNA copies per HPV16 genome. The karyotype was determined and the cell line demonstrated wild type TP53. The ID50 for radiation was 0.90 Gy and the IC50 for cisplatin was 0.99 μmol/L. The cell line was inhibited to a maximum of 18% by cetuximab.
We established an in vitro tonsil carcinoma cell line containing episomal HPV16. This is an important step towards efficient treatment development.
Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed ...whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of
and 9% of
; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of
, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included
(55%), the
promoter (36%), and
(27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.
α‐deuterated carboxylic acids have been synthesized from the corresponding malonic acids via hydrogen/deuterium exchange and decarboxylation in presence of D2O. The method is general, mild and ...efficient and does not require organic solvents or other additives. Yields range between 83% and 94% and purification was not necessary. Starting materials were easy accessible and the α‐deuterated carboxylic acids may easily be transformed to other labeled compounds such as alcohols, aldehydes, esters, and amides. Characterization with NMR confirmed purity and isotopic purity.
An efficient method for synthesis of α‐deuterated carboxylic acids from malonic acid derivatives has been developed. Hydrogen/deuterium exchange followed by decarboxylation take place in the same vessel and resulted in high isotopic purity.
Despite the significant progress in anticancer drug development over recent years, there is a vital need for newer agents with unique, but still effective, mechanisms of action in order to treat the ...disease, particularly the highly aggressive and drug-resistant types. Alkylating agents, in particular nitrogen-based alkylators, are commonly used to treat hematological and solid malignancies; they exert their antineoplastic effects at all phases of the cell cycle and prevent reproduction of tumor cells. Certain alkylating agents have been designed to be more lipophilic, enabling the compound to penetrate the cell and enhance its alkylating activity against tumors. This review details the evolution of currently available alkylating agents and their profiles, with a focus on nitrogen-based alkylating agents, as important anticancer therapy strategies.
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