Loredana G. Marcu

In vitro investigation of head and neck cancer stem cell proportions and their changes following X-ray irradiation as a function of HPV status

Introduction Some head and neck squamous cell carcinomas (HNSCC) have a distinct aetiology, which depends on the presence of oncogenic human papilloma virus (HPV). Also, HNSCC contains cancer stem cells (CSCs) that have greater radioresistance and capacity to change replication dynamics in response to irradiation compared to non-clonogenic cells. Since there is limited data on CSCs in HNSCC as a function of HPV status, better understanding of their radiobiology may enable improved treatment outcome. Methods Baseline and post-irradiation changes in CSC proportions were investigated by flow cytometry in a HPV-negative (UM-SCC-1) and a HPV-positive (UM-SCC-47) HNSCC cell line, using fluorescent staining with CD44/ALDH markers. CSC proportions in both irradiated and unirradiated cultures were compared for the two cell lines at various times post-irradiation. To assess repopulation of CSCs, untreated cultures were depleted of CD44+/ALDH+ cells and re-cultured for 3 weeks before flow cytometry analysis. Results CSC proportions in untreated cell lines were 0.57% (UM-SCC-1) and 2.87% (UM-SCC-47). Untreated cell lines depleted of CD44+/ALDH+ repopulated this phenotype to a mean of 0.15% (UM-SCC-1) and 6.76% (UM-SCC-47). All UM-SCC-47 generations showed elevated CSC proportions after irradiation, with the most significant increase at 2 days post-irradiation. The highest elevation in UM-SCC-1 CSCs was observed at 1 day post-irradiation in the 2nd generation and at 3 days after irradiation in the 3rd generation. When measured after 10 days, only the 3rd generation of UM-SCC-1 showed elevated CSCs. Conclusions CSC proportions in both cell lines were elevated after exposure and varied with time post irradiation. UM-SCC-47 displayed significant plasticity in repopulating the CSC phenotype in depleted cultures, which was not seen in UM-SCC-1.

Radiotherapy and Clinical Radiobiology of Head and Neck Cancer

Common factors that lead to treatment failure in head and neck cancer are the lack of tumour oxygenation, the accelerated division of cancer cells during treatment, and radioresistance. These tumou ...

Global comparison of targeted alpha vs targeted beta therapy for cancer: In vitro, in vivo and clinical trials

Targeted therapy for cancer is a rapidly expanding and successful approach to the management of many intractable cancers. However, many immunotherapies fail in the longer term and there continues to be a need for improved targeted cancer cell toxicity, which can be achieved by radiolabelling the targeting vector with a radioisotope. Such constructs are successful in using a gamma ray emitter for imaging. However, traditionally, a beta emitter is used for therapeutic applications. The new approach is to use the short range and highly cytotoxic alpha radiation from alpha emitters to achieve improved efficacy and therapeutic gain. This paper sets out to review all experimental and theoretical comparisons of efficacy and therapeutic gain for alpha and beta emitters labelling the same targeting vector. The overall conclusion is that targeted alpha therapy is superior to targeted beta therapy, such that the use of alpha therapy in clinical settings should be expanded.

Gender Balance in Medical Physics—Lost in Transition?

Before the toppling of the communist regime in Romania in 1989, the gender distribution in physics college students was bent towards males with an approximate two-thirds to one-third ratio. A recent statistical analysis made among researchers that have applied for research grants in the area of health science (including medical physics) shows that the number of male applicants is around double the number of female applicants. However, a look at the current gender balance among clinical medical physicists shows a clear bend towards females. Theoretically, this could result in an increased number of female researchers in medical physics, though practically this does not happen due to the large clinical workload in the Romanian hospitals which limits the time and effort necessary for scientific explorations. This fact leads us to the actual category of skilled people who undertake research: the academic staff. Among them, the gender balance is off, as the male to female ratio is nearing 3. Given these facts, it is interesting to think about the choices made by males and females after graduation, entering the workforce. Despite the general decline in science students over the last few decades, medical physics keeps being an attractive educational offer presented by several Romanian universities. An interesting shift is that among current medical physics students, the large majority are female both at undergraduate and postgraduate levels. Does this mean that in 20 years we will see a dominance of females in higher academic positions and research grant applications? Can we afford to just let nature take its course, or do we have to actively intervene to encourage women to choose an academic and research career after graduation?

Experimental investigation of radiobiology in head and neck cancer cell lines as a function of HPV status, by MTT assay

Head and neck cancers (HNCs) are aggressive epithelial tumours frequently treated using radiation. HNC biology shows distinctions dependent on the oncologic involvement of the human papilloma virus (HPV). Clinically, HPV positive HNCs respond better to radiotherapy but few in vitro data demonstrate radiobiological differences explaining differences in clinical outcomes. This pilot study examined radiobiological responses to irradiation and subsequent regeneration in two HNC cell lines (HPV positive and negative). A novel approach was taken to develop generational cultures of HNC cell lines, UM-SCC-1 (HPV negative) and UM-SCC-47 (HPV positive). MTT assays were used to determine surviving metabolic activity as a function of dose following 6u2009MV X-ray irradiation. Parallel cultures surviving 4u2009Gy irradiation (not analysed) were re-cultured and passaged to develop subsequent generations which were re-irradiated and analysed for generational change in radiation response. Second and 3rd generations of UM-SCC-1 showed decreasing metabolic activity with dose but little difference was evident in surviving fractions between these generations. Significantly lower metabolic activity in the 3rd generation at <6u2009Gy, compared to the 2nd generation, showed UM-SCC-47 becoming progressively more radiosensitive. HPV positive UM-SCC-47 showed generational progression in radiosensitisation not seen in the HPV negative UM-SCC-1.

Treatment-Related Adverse Effects in Lung Cancer Patients after Stereotactic Ablative Radiation Therapy

Introduction Lung cancer is a disease which, despite the advancements in treatment, still has a very poor 5-year survival rate. Stereotactic ablative radiation therapy (SABR) is a highly advanced, sophisticated, and safe treatment which allows patients with early stage lung cancer to be treated effectively without invasive procedures and with excellent clinical outcomes. Avoiding surgery minimises morbidity and recovery time, bettering patients quality of life. Furthermore, SABR allows patients unsuitable for surgery to still undergo curative treatment. Methods We aimed to review SABR-related normal tissue toxicities reported in the literature. While many studies assess safety, clinical efficacy, and disease control of SABR for lung cancer, the number of comprehensive reviews that analyse SABR-related side-effects is scarce. This integrative review summarises the toxicities reported in literature based on published clinical trials and tumour location (central or peripheral tumours) for available SABR techniques. Given that the majority of the clinical studies did not report on the statistical significance (e.g., p-values and confidence intervals) of the toxicities experienced by patients, statistical analyses cannot be performed. As a result, adverse events are compiled from clinical reports; however, due to various techniques and nonstandard toxicity reports, no meta-analysis is possible at the current stage of reported data. Results When comparing lobectomy and SABR in phase III trials, surgery resulted in increased procedure-related morbidity. In phase II trials, very few studies showed high grade toxicities/fatalities as a result of SABR for lung cancer. Gross target volume size was a significant predictor of toxicity. An ipsilateral mean lung dose larger than 9 Gy was significantly associated with radiation pneumonitis. Conclusions Based on the studies reviewed SABR is a safe treatment technique for lung cancer; however, further well-designed phase III randomised clinical trials are required to produce timely conclusive results and to enable their comparison and statistical analysis.

Imaging of Tumor Characteristics and Molecular Pathways With PET: Developments Over the Last Decade Toward Personalized Cancer Therapy

PURPOSEnImprovements in personalized therapy are made possible by the advances in molecular biology that led to developments in molecular imaging, allowing highly specific inxa0vivo imaging of biological processes. Positron emission tomography (PET) is the most specific and sensitive imaging technique for inxa0vivo molecular targets and pathways, offering quantification and evaluation of functional properties of the targeted anatomy.nnnMATERIALS AND METHODSnThis work is an integrative research review that summarizes and evaluates the accumulated current status of knowledge of recent advances in PET imaging for cancer diagnosis and treatment, concentrating on novel radiotracers and evaluating their advantages and disadvantages in cancer characterization. Medline search was conducted, limited to English publications from 2007 onward. Identified manuscripts were evaluated for most recent developments in PET imaging of cancer hypoxia, angiogenesis, proliferation, and clonogenic cancer stem cells (CSC).nnnRESULTSnThere is an expansion observed from purely metabolic-based PET imaging toward antibody-based PET to achieve more information on cancer characteristics to identify hypoxia, proangiogenic factors, CSC, and others. 64Cu-ATSM, for example, can be used both as a hypoxia and a CSC marker.nnnCONCLUSIONSnProgress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life.

The Promise of Novel Biomarkers for Head and Neck Cancer from an Imaging Perspective

It is an agreed fact that overall survival among head and neck cancer patients has increased over the last decade. Several factors however, are still held responsible for treatment failure requiring more in-depth evaluation. Among these, hypoxia and proliferation-specific parameters are the main culprits, along with the more recently researched cancer stem cells. This paper aims to present the latest developments in the field of biomarkers for hypoxia, stemness and tumour proliferation, from an imaging perspective that includes both Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) as well as functional magnetic resonance imaging (MRI). Quantitative imaging of biomarkers is a prerequisite for accurate treatment response assessment, bringing us closer to the highly needed personalised therapy.

Do SABR-related toxicities for lung cancer depend on treatment delivery?

Stereotactic ablative radiation therapy for lung cancer is an advanced technique where tumours are ablated with hypofractionated radiation doses, with a high degree of accuracy. The aim of this paper is to review the available literature and to discuss the SABR-induced toxicities for lung malignancies as a function of radiation delivery technique. A Medline search was conducted to identify the appropriate literature to fulfil the aim of this review and data from all applicable papers were collated and analysed. The most common techniques of SABR delivery employ linear accelerators, CyberKnife robotic radiosurgery system, TomoTherapy and the Novalis beam surgery system. Linear accelerator-based treatments give rise to a variety of toxicities that are strongly dependent on both patient-related factors and planning/dosimetry-related factors. The limited number of studies using CyberKnife reported low grade toxicities. Grade three toxicities mainly include fatigue and chest pain, usually in less than 10% of patients. All treatment techniques presented show efficiency in SABR delivery with various toxicities which, at this stage, cannot render one technique better than the other. For more conclusive results, well-designed phase three randomised clinical trials are required with better patient selection criteria, including dose and fractionation, treatment machine and technique, along with the consistent selection of a common toxicity grading criterion.

The effect of targeted therapy on recruited cancer stem cells in a head and neck carcinoma model

Head and neck cancers (HNC) are known for their repopulation ability driven by cancer stem cells (CSCs). While a small fraction of CSCs proliferates, there are quiescent CSCs that are long‐lived and reside outside the cell cycle. Recruitment of quiescent CSCs into the cycle occurs as a response to cell loss and their proliferation may lead to treatment failure. Therefore, CSCs require a more targeted approach to be destroyed. An agent that sensitizes CSC response to treatment is all‐trans‐retinoic acid (ATRA). The aim of this work is to assess the impact of ATRA combined with radiotherapy on HNC and to analyse the interplay between these agents and cell recruitment.