Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells.

Cancer stem cells are known to play a key role in tumour development, proliferation, and metastases. Their unique properties confer resistance to therapy, often leading to treatment failure. It is believed that research into the identification, targeting, and eradication of these cells can revolutionise oncological treatment. Based on the principle that what cannot be seen, cannot be targeted, a primary step in cancer management is the identification of these cells. The current review aims to encompass the state-of-the-art functional imaging techniques that enable the identification of cancer stem cells via various pathways and mechanisms. The paper presents in vivo molecular techniques that are currently available or await clinical implementation. Challenges and future prospects are highlighted to open new research avenues in cancer stem cell imaging.

Current Role of Delta Radiomics in Head and Neck Oncology.

The latest developments in the management of head and neck cancer show an increasing trend in the implementation of novel approaches using artificial intelligence for better patient stratification and treatment-related risk evaluation. Radiomics, or the extraction of data from various imaging modalities, is a tool often used to evaluate specific features related to the tumour or normal tissue that are not identifiable by the naked eye and which can add value to existing clinical data. Furthermore, the assessment of feature variations from one time point to another based on subsequent images, known as delta radiomics, was shown to have even higher value for treatment-outcome prediction or patient stratification into risk categories. The information gathered from delta radiomics can, further, be used for decision making regarding treatment adaptation or other interventions found to be beneficial to the patient. The aim of this work is to collate the existing studies on delta radiomics in head and neck cancer and evaluate its role in tumour response and normal-tissue toxicity predictions alike. Moreover, this work also highlights the role of holomics, which brings under the same umbrella clinical and radiomic features, for a more complex patient characterization and treatment optimisation.

Opportunities in Cancer Therapies: Deciphering the Role of Cancer Stem Cells in Tumour Repopulation.

Tumour repopulation during treatment is a well acknowledged yet still challenging aspect of cancer management. The latest research results show clear evidence towards the existence of cancer stem cells (CSCs) that are responsible for tumour repopulation, dissemination, and distant metastases in most solid cancers. Cancer stem cell quiescence and the loss of asymmetrical division are two powerful mechanisms behind repopulation. Another important aspect in the context of cancer stem cells is cell plasticity, which was shown to be triggered during fractionated radiotherapy, leading to cell dedifferentiation and thus reactivation of stem-like properties. Repopulation during treatment is not limited to radiotherapy, as there is clinical proof for repopulation mechanisms to be activated through other conventional treatment techniques, such as chemotherapy. The dynamic nature of stem-like cancer cells often elicits resistance to treatment by escaping drug-induced cell death. The aims of this scoping review are (1) to describe the main mechanisms used by cancer stem cells to initiate tumour repopulation during therapy; (2) to present clinical evidence for tumour repopulation during radio- and chemotherapy; (3) to illustrate current trends in the identification of CSCs using specific imaging techniques; and (4) to highlight novel technologies that show potential in the eradication of CSCs.

Is there a dosimetric advantage of volumetric modulated arc therapy over intensity modulated radiotherapy in head and neck cancer?

OBJECTIVE: A planning study was performed to evaluate dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for head and neck cancer (HNC) for sequential boost (Seq-boost) and simultaneous integrated boost techniques (SIB). METHODS: 30 patients with HNC were included, 15 treated with SIB and 15 with Seq-Boost. For all patients both VMAT and IMRT plans were completed. The planning objective for PTV was 95% of dose covering minimum 95% of PTV; for spinal cord and brainstem Dmax was limited to 45 Gy and 54 Gy respectively. The parotids had a mean dose < 26 Gy limitation. The number of monitor units (MU) were scored for treatment delivery time efficiency. RESULTS: Both techniques achieved the set objectives regarding PTV coverage and organ sparing. SIB plans presented a statistically significant better homogeneity for VMAT (p = 0.0096), while Seq-boost showed a statistically significant better conformity for VMAT (p = 0.0049). For parotids only SIB plans showed a lower Dmean value obtained with VMAT, while Seq-boost plans showed statistically insignificant differences. For SIB plans the MU was reduced by 33.4% with VMAT, whereas in Seq-boost plans the reduction was by 19.1%. CONCLUSION: VMAT shows dosimetric superiority to IMRT in some cases, however an adequate coverage of the target volumes and a suitable OAR sparing can be achieved with both techniques. Though IMRT is still the standard in HNC radiotherapy, VMAT can be safely implemented, offering at least similar target coverage and organ sparing, with significantly reduced MU.

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy.

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

Solutions to Gender Balance in STEM Fields Through Support, Training, Education and Mentoring: Report of the International Women in Medical Physics and Biomedical Engineering Task Group.

The aim of this article is to offer a view of the current status of women in medical physics and biomedical engineering, while focusing on solutions towards gender balance and providing examples of current activities carried out at national and international levels. The International Union of Physical and Engineering Scientists in Medicine is committed to advancing women in science and health and has several initiatives overseen by the Women in Medical Physics and Biomedical Engineering Task Group. Some of the main strategies proposed by the Task Group to attain gender balance are: (a) identify and promote female role models that achieve successful work-life balance, (b) establish programs to develop female leaders, (c) create opportunities for females to increase the international visibility within the scientific community, and (d) establish archives and databases of women in STEM.

The role of hypofractionated radiotherapy in the management of head and neck cancer - a modelling approach.

INTRODUCTION: Cancer stem cells (CSCs) and hypoxia are key contributors towards radioresistance and they influence the choice of radiotherapy schedule for optimal tumour control. Since hypofractionation is becoming more popular in head and neck cancer (HNC) management, the aim of this work is to use a modelling approach to evaluate the efficacy of hypofractionated radiotherapy on both early stage and advanced tumours. METHODS: An in silico HNC was developed starting from one CSC. For a biologically indorsed tumour, CSCs generate all heterogeneous cell lineages with a 1.9% probability of symmetrical division, 33 h mean cell cycle time and 52 days volume doubling time. The simulated schedules include conventional, hyperfractionated, and hypofractionated radiotherapy and they target tumours with various oxygenation levels. RESULTS: Oxic and mildly hypoxic tumours can benefit from hypofractionation, which reduces treatment time without increasing adverse events. Advanced tumours are only controlled by hyperfractionation, however a tumour with oxygen levels below 6 mmHg and 5.9% pre-treatment CSCs, needs either a dose greater than 81.6 Gy to be eradicated or the addition of adjuvant therapies. CONCLUSIONS: Hypofractionation is suited for early stage tumours, whereas aggressive HNC require hyperfractionation. The interplay between CSCs and hypoxia dictates the optimal treatment strategy.

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.

Cocktail without hangover: in search for the optimal chemotherapy in the combined management of non-operable esophageal carcinomas.

BACKGROUND: The worldwide incidence of esophageal cancer has greatly increased over the past few decades making it the sixth deadliest cancer. The disease is often detected in advanced stages when surgery is no longer an option. The standard treatment in these situations is combined chemoradiotherapy, by employing drug cocktails that lead to optimal treatment outcomes both from the perspective of tumor control and normal tissue toxicity. METHODS: The aim of this work was to collate the existing trials and clinical studies reported on non-operable esophageal cancer and to analyze the results based on treatment outcomes after various drug combinations. RESULTS: Of all drug combinations, cisplatin/5-FU is the most well established chemotherapy regimen for esophageal cancer as both neoadjuvant therapy, an alternative option to surgery, and for palliative purposes. Although this regimen is associated with the most toxicity, it also appears to have the best survival benefit and relief of symptoms. CONCLUSIONS: More research is warranted to further increase the therapeutic ratio in non-operable esophageal cancers.

Risk estimation of second primary cancers after breast radiotherapy.

AIMS: There is evidence towards the induction of second primary cancers (SPCs) after breast radiotherapy (RT). Organs, such as the lungs and the esophagus, have been identified as common sites for SPC formation. As a result, the current study investigated the risk of secondary carcinogenesis associated with particular RT techniques for breast cancer; including whole breast, segmented breast, partial breast and mammosite brachytherapy. METHODS: In this study, seven breast cancer patients had all major organs contoured on their planning computed tomography (CT) images. Whole breast, segmented breast, accelerated partial breast irradiation (APBI) and mammosite boost treatment plans were generated for each patient using Pinnacle3 treatment planning system. Differential dose-volume histograms were generated for a number of critical structures: bladder, brain and central nervous system (CNS), breast, colon, liver, lung, mouth and pharynx, esophagus, ovary, salivary gland, small intestine, stomach, and uterus. The lifetime attributed risk (LAR) of cancer induction was estimated using the Schneider et al. excess absolute risk models and dose-volume histograms for the above organs. RESULTS: The sites with the highest LAR estimates were the ipsilateral and contralateral lungs, and contralateral breast for all treatment techniques. For all sites, the LAR estimates for the segmented breast and mammosite treatments were lower than those for the whole breast and APBI treatments. For right-sided target volumes the liver also resulted in high LAR estimates, with all techniques having a LAR greater than 20 per 10 000 person-years (PY), except for mammosite with a mean LAR estimate of 13.2 per 10 000 PY. For left-sided target volumes the stomach also resulted in high LAR estimates, with both whole breast and APBI having a LAR greater than 20 per 10 000 PY, and mammosite the lowest with a LAR of 8.3 per 10 000 PY. CONCLUSION: It is concluded that the lungs and contralateral breast showed high LAR estimates.

Experimental investigation of the cell survival in dose cold spot.

The aim of this work was to investigate the impact of intercellular contact during radiation exposure on cell survival in regions of reduced dose. Methods. The PC3 human prostate adenocarcinoma cell line was irradiated using a 6 MV x-ray beam to assess clonogenic cell deaths with the specific aim to investigate cell survival in a dose cold spot. Radiation-induced cell survival in a 20% lower dose region, compared to that of cells receiving 100% of the prescribed dose (2 Gy), was assessed for experimental set-ups when under-irradiated cells were either in direct contact with cells receiving 2 Gy or irradiated separately. In addition, the results were compared against non-irradiated controls. Results. A significant (p < 0.001) decrease in cell survival was found when cells, collocated in the same flask, received either 100% or 80% of the prescribed dose (the dose distribution contained a cold spot of 20% lower dose) compared to non-irradiated cells. However, in the experiment in which the entire flask was exposed to only 80% of the prescribed dose, the mean difference in cell survival compared to non-irradiated control was not significant (p > 0.05). This was contrary to a significant decrease (p < 0.001) in survival of cells receiving 100% of the prescribed dose versus the control. Additionally, significant reduction (p < 0.05) in cell survival was observed for cells which were under-irradiated by 20% but collocated in the same flask with cells receiving 100% dose compared to cells where the entire flask was irradiated with 80% of the prescribed dose. Conclusion. For the given cell line, under existing growing and treatment conditions, the cell survival in the dose cold spot region was significantly lower when under-irradiated cells were in contact with the cells receiving 100% of the prescribed dose compared to survival of cells under-irradiated by the same amount of radiation but treated separately to cells receiving 100% dose.

Circadian rhythm-based cancer therapy in randomised clinical trials.

INTRODUCTION: Since the 2017 Nobel Prize awarded to J. Hall, M. Rosbash and M.W. Young for their discoveries of molecular mechanisms behind the biological clock, circadian rhythm-based therapy, also known as chronotherapy, is receiving more attention in oncology and the number of anatomical sites of interest in this field is increasing. This observation is in line with the clinical evidence provided by trials on head and neck, lung, colorectal and cervical cancers, as well as the presently ongoing chronotherapy trials for breast and brain cancers. AREAS COVERED: The aim of this review was to collate all randomized trials conducted on chronotherapy for various tumor sites and to appraise the evidence for chrono-oncology to advance personalized therapy. Relevant literature was collected from Pubmed/Medline databases and from clinicatrials.gov. EXPERT OPINION: Current randomized clinical trials offer a certain level of evidence for the potential of chronotherapy to personalize oncologic treatment. However, comparison of trial results is hindered by the differences in timing of radiation/chemotherapy, the absence of harmonized recommendations for treatment outcome evaluation and not ultimately, the general lack of considering gender as a matched variable in trials, which was found to be a powerful factor influencing response to treatment.

Affinity of PET-MRI Tracers for Hypoxic Cells in Breast Cancer: A Systematic Review.

Tumour hypoxia is a known microenvironmental culprit for treatment resistance, tumour recurrence and promotion of metastatic spread. Despite the long-known existence of this factor within the tumour milieu, hypoxia is still one of the greatest challenges in cancer management. The transition from invasive and less reliable detection methods to more accurate and non-invasive ways to identify and quantify hypoxia was a long process that eventually led to the promising results showed by functional imaging techniques. Hybrid imaging, such as PET-CT, has the great advantage of combining the structural or anatomical image (offered by CT) with the functional or metabolic one (offered by PET). However, in the context of hypoxia, it is only the PET image taken after appropriate radiotracer administration that would supply hypoxia-specific information. To overcome this limitation, the development of the latest hybrid imaging systems, such as PET-MRI, enables a synergistic approach towards hypoxia imaging, with both methods having the potential to provide functional information on the tumour microenvironment. This study is designed as a systematic review of the literature on the newest developments of PET-MRI for the imaging of hypoxic cells in breast cancer. The analysis includes the affinity of various PET-MRI tracers for hypoxia in this patient group as well as the correlations between PET-specific and MRI-specific parameters, to offer a broader view on the potential for the widespread clinical implementation of this hybrid imaging technique.

Dosimetric Parameters in Hypofractionated Stereotactic Radiotherapy for Brain Metastases: Do Flattening Filter-Free Beams Bring Benefits? A Preliminary Study.

PURPOSE: This study aimed to compare the dosimetric results of flattening filter-free (FFF) vs. flattened (FF) treatment plans for fractionated stereotactic radiotherapy (fSRT), with the goal to highlight potential advantages of FFF beams. METHODS: A group of 18 patients with brain metastases treated with fSRT (30 Gy delivered in 5 fractions) were included. The dosimetric parameters evaluated were: (1) physical dosimetric parameters (number of monitor units (MUs), conformity index (CI), dose gradient index (DGI), beam on time (BOT)); (2) clinical dosimetric parameters pertaining to target volume (PTV) and organs at risk (OARs). Two treatment plans were performed for all patients: one used 6 MV FFF beams and the other used 6 MV flattened beams. RESULTS: A slight increase in MUs was observed for the FFF mode (+23.3 MUs). The CI showed a difference of -2.7% for the FF plans (p = 0.28), correlated with a poorer coverage of the PTV. DGI values reported in terms of PTV are in line with international recommendations and showed a +1.9% difference for FFF plans. An average BOT of 90.3 s was reported for FFF plans, which was 2.3 times shorter than that required for FF plans delivery (p ≤ 0.001). A slight decrease of PTV coverage (-1.26%, p = 0.036) for FF plans can be considered relevant, but no other significant differences were observed between the two optimizations. No statistically significant benefit of using FFF beams to reduce V20 for normal brain could be demonstrated. CONCLUSION: These dosimetric results encourage the implementation of fSRT with standard flattened beams in centers where FFF linacs are not available.

Dosimetric and clinical aspects of head and neck cancer reirradiation with intensity modulated radiotherapy techniques over the last decade.

PURPOSE: Tumor recurrence in head and neck cancer (HNC) is very common, given that locoregional disease relapse occurs in up to 50% of patients. The clinical approach towards cancer recurrence is either by surgery and/or chemo-radiotherapy. Irrespective of the treatment, the management of HNC recurrence is highly challenging and often administered with palliative intent only. The aim of this work was to analyze clinical and dosimetric aspects, such as dose prescription, organ at risk sparing, overall survival and locoregional control of HNC after reirradiation with intensity modulated radiotherapy techniques based on studies published over the last decade, due to the wide clinical implementation of the intensity modulated radiotherapy and particularly of volumetric modulated arc therapy (VMAT) for this malignancy. METHODS: A systematic search of the literature was conducted within Pub-med/Medline databases to find relevant studies. Of the 130 articles fulfilling the initial search criteria, 15 were selected for final analysis that encompassed all set requirements. RESULTS: Clinical studies revealed the multitude of factors influencing treatment outcome, including anatomical location, histological tumor type, patient-related factors (smoking / comorbidities), cumulative dose and fractionation schedule, reirradiated volume and time between the irradiation of primary and recurrent tumor. CONCLUSIONS: Since the literature reports no specific data related to the type of intensity modulation used in reirradiation or any correlation with treatment outcome, IMRT and VMAT might offer comparable result after HNC reirradiation. Patient selection is potentially the main factor leading to an efficient outcome.

Dosimetric characteristics of 6MV flattening filter free and flattened beams among beam-matched linacs: a three-institutional study.

BACKGROUND: Beam matching is a concept in radiotherapy applied to clinics where more than one linac is employed to harmonise beam characteristics across linacs for allowing patients interchange without replanning. In view of this, the current study analyzes and compares dosimetric characteristics of 6MV flattening filter free and flattened beams of three beam-matched linear accelerators (linacs) from three different clinics with the aim to evaluate the matching under tight criteria for gamma analysis. METHODS: Three Elekta linacs from three different clinics were included. The linacs have the same collimator assembly, Elekta Agility. Beam data were collected during commissioning process using PTW dosimetry systems. Dose profiles and percentage depth doses (PDD) were analyzed using 1D gamma analysis (1 mm/1%) as well as the following parameters: depth of maximum dose, PDD10, flatness, unflattnes, symmetry, penumbra, output factors. Additionally, five stereotactic treatment plans were optimized in one clinic and calculated by all three planning systems (Monaco) for a dosimetric comparison. RESULTS: Gamma analysis of dose profiles and PDDs showed clinically acceptable results of 96.3% passing rate for profiles and 100% passing rate for PDDs. All dosimetric parameters were in good agreement with the reference data. Furthermore, dosimetric comparisons between stereotactic treatment plans showed a maximum standard deviation of 0.48 Gy for the maximum dose to PTV, and a maximum standard deviation of 0.1 Gy for the dose to the organs at risk. CONCLUSIONS: All three linacs showed a strong agreement between parameters and passed the gamma analysis using 1% DD/1mm DTA criteria. This study confirmed the matching between linacs, offering the possibility to interchange patients with no replanning.

EFOMP policy statement 18: Medical physics education for the non-physics healthcare professions.

Although Medical Physics educators have historically contributed to the education of the non-physics healthcare professions, their role was not studied in a systematic manner. In 2009, EFOMP set up a group to research the issue. In their first paper, the group carried out an extensive literature review regarding physics teaching for the non-physics healthcare professions. Their second paper reported the results of a pan-European survey of physics curricula delivered to the healthcare professions and a Strengths-Weaknesses-Opportunities-Threats (SWOT) audit of the role. The group's third paper presented a strategic development model for the role, based on the SWOT data. A comprehensive curriculum development model was subsequently published, whilst plans were laid to develop the present policy statement. This policy statement presents mission and vision statements for Medical Physicists teaching non-physics users of medical devices and physical agents, best practices for teaching non-physics healthcare professionals, a stepwise process for curriculum development (content, method of delivery and assessment), and summary recommendations based on the aforementioned research studies.

Science diplomacy in medical physics - an international perspective.

Purpose: Science diplomacy in medical physics is a relatively young research field and translational practice that focuses on establishing international collaborations to address some of the questions biomedical professionals face globally. This paper aims to present an overview of science diplomacy in medical physics, from an international perspective, illustrating the ways collaborations within and across continents can lead to scientific and professional achievements that advance scientific growth and improve patients care. Methods: Science diplomacy actions were sought that promote collaborations in medical physics across the continents, related to professional and scientific aspects alike. Results: Several science diplomacy actions have been identified to promote education and training, to facilitate research and development, to effectively communicate science to the public, to enable equitable access of patients to healthcare and to focus on gender equity within the profession as well as healthcare provision. Scientific and professional organizations in the field of medical physics across all continents have adopted a number of efforts in their aims, many of them with great success, to promote science diplomacy and to foster international collaborations. Conclusions: Professionals in medical physics can advance through international cooperation, by building strong communication across scientific communities, addressing rising demands, exchange scientific information and knowledge.

EFOMP Malaga Declaration 2023: An updated vision on Medical Physics in Europe.

In 2006, the European Federation of Organisations for Medical Physics (EFOMP) adopted the "Malaga Declaration". The declaration asserted the fundamental role of Medical Physics professionals in the radiation protection of patients, workers, general public, carers and comforters and research participants in hospitals. However, since that time the Medical Physics profession has evolved in Europe and new regulations and documentation have been issued, such as directive 2013/59/Euratom and the "European Guidelines on Medical Physics Expert" (RP174). EFOMP has published updated core-curricula and strived towards the recognition of the profession at the European level. In view of this, an update of the original Malaga Declaration was deemed necessary, to define the future vision that will guide the actions of the Federation in the years to come. This Declaration, which has been approved by the national member organizations of EFOMP in April 2023, is much broader than the original Malaga version. This is expected considering the rapid evolution of medical device technology over the last 17 years. The Radiation Protection Expert in hospital settings should be an MPE, since the latter has the highest level of radiation protection knowledge and training. Given the passion and energy that animated the debate, which led to the updating of the Malaga Declaration, we are confident that it represents a solid basis for the development of our profession in Europe which is in consonance with the aspirations of us all.

Neoadjuvant cisplatin for head and neck cancer: Simulation of a novel schedule for improved therapeutic ratio.

Current clinical studies support the role of neoadjuvant cisplatin administration prior to curative radiotherapy or radio-chemotherapy for advanced head and neck cancer. Nevertheless, based on locoregional control rates the studies indicate that there is need to redesign cisplatin-based schedules for induction chemotherapy, thus the ideal treatment regimen is yet to be established. While the pharmacokinetics/dynamics of daily cisplatin regimens correspond better with the cell cycle properties of head and neck cancers, weekly regimens are more commonly employed in clinics due to lower complications. Yet, the high rates of adverse events induced by current cisplatin schedules often represent a limiting factor in the overall success of the treatment. The aim of the present paper was to model the pharmacodynamic properties of cisplatin and to simulate and compare various neoadjuvant treatment regimens in regards to their effect on tumour control. Treatment simulation was undertaken on a virtual squamous cell carcinoma of the head and neck, previously grown by computer-based probabilistic methods. The model suggests that a novel cisplatin treatment, given every three days is comparable, in regards to tumour control, with the daily administration and more effective than the weekly regimen in neoadjuvant settings. Endpoints were assessed in terms of cell population regrowth after treatment cessation followed by two weeks of unperturbed growth. Simulation of two weeks low-dose daily cisplatin followed by two weeks 'free growth' lead to 15% population regrowth, while weekly high-dose cisplatin over three weeks, followed by two weeks unperturbed growth resulted in 52% tumour cell regrowth. The proposed novel schedule of low-dose third-daily cisplatin gives closer tumour regrowth to daily administration (27% versus 15%) than to the weekly regimen (52%) and also similar cell distribution along the cell cycle as the daily one, suggesting therefore comparable response to subsequent treatment. The advantage of using a third-daily drug regimen would be a decrease in normal tissue complication rates compared to daily administration and possibly an increase in tumour control when compared to the 'conventional' weekly cisplatin delivery.