Characterization of passive dosimeters in proton pencil beam scanning – A EURADOS intercomparison for mailed dosimetry audits in proton therapy centres

The lack of mailed dosimetry audits of proton therapy centres in Europe has encouraged researchers of EURADOS Working Group 9 (WG9) to compare response of several existing passive detector systems in therapeutic pencil beam scanning.Alanine Electron Paramagnetic Resonance dosimetry systems from 3 different institutes (ISS, Italy; UH, Belgium and IFJ PAN, Poland), ^natLiF:Mg, Ti (MTS-N) and ^natLiF:Mg, Cu, P (MCP-N) thermoluminescent dosimeters (TLDs), GD-352M radiophotoluminescent glass dosimeters (RPLGDs) and Al₂O₃:C optically stimulated dosimeters (OSLDs) were evaluate. Dosimeter repeatability, batch reproducibility and response in therapeutic Pencil Beam Scanning were verified for implementation as mail auditing system.Alanine detectors demonstrated the lowest linear energy transfer (LET) dependence with an agreement between measured and treatment planning system (TPS) dose below 1%. The OSLDs measured on average a 6.3% lower dose compared to TPS calculation, with no significant difference between varying modulations and ranges. Both GD-352M and MCP-N measured a lower dose than the TPS and luminescent response was dependent on the LET of the therapeutic proton beam. Thermoluminescent response of MTS-N was also found to be dependent on the LET and a higher dose than TPS was measured with the most pronounced increase of 11%.As alanine detectors are characterized by the lowest energy dependence for different parameters of therapeutic pencil beam scanning they are suitable candidates for mail auditing in proton therapy. The response of luminescence detector systems have shown promises even though more careful calibration and corrections are needed for its implementation as part of a mailed dosimetry audit system.     

Cardiotoxicity of breast cancer radiotherapy – overview of current results

Adjuvant radiotherapy after breast cancer surgery is an important part of breast cancer treatment improving local control and overall survival. However, a higher risk of cardiac mortality was observed when conventional radiotherapy techniques were used. Cardiac morbidity and mortality after radiation therapy have been studied in many meta-analyses. In those focused on modern radiotherapy techniques, cardiac morbidity and mortality were no longer presented. However, an extremely long follow-up period is required. Importantly, the cardiac morbidity rates vary depending not only on the dose delivered to the heart, but also on the systemic therapies administrated and the pre-existing cardiac disease. Systematic heart dose monitoring is of great importance, as are efforts to constantly decrease doses, using advanced radiotherapy techniques. Nowadays, it is essential to individualize treatment according to tumor characteristics and anatomical predispositions, and to consider the cost and benefits.     

Survival of breast cancer patients in German-Danish border regions – A registry-based cohort study

Background and AimDenmark reports slightly lower breast cancer survival before 2010 than its neighbouring country Germany. Previous research is limited by lacking stage and treatment information. This study aims to investigate differences in breast cancer survival between the bordering regions Schleswig-Holstein (Germany), Southern Denmark and Zealand (Denmark) using registry data including stage and treatment information.MethodInvasive female breast cancer cases diagnosed during 2004−2013 with follow up through 31st December 2014 were extracted from cancer registries. Cases notified by death certificates only and those aged 90+ years were excluded. Kaplan-Meier curves and log-rank tests were computed. Cox regression analysis was conducted with adjustment for year of diagnosis, age, stage, and treatment.ResultsThe analytical sample included 42,966 cases. Kaplan-Meier curves and log-rank tests show significant survival differences between the regions. The Cox regression model adjusted for year of diagnosis and age shows significantly worse overall survival of breast cancer patients in both Danish regions compared to Schleswig-Holstein with hazard ratios (HR) of 1.09 (95 % CI: 1.04; 1.15) for patients from Southern Denmark (SD) and 1.25 (95 % CI: 1.18; 1.32) for residents of Zealand (ZL). This effect diminished after adjustment for stage and treatment (HR: 1.05 (SD), 1.09 (ZL) 95 % CI: 0.99; 1.10 (SD), 1.03; 1.15 (ZL)).ConclusionSurvival differences can be explained by differing stage distribution and treatment administration, which formerly were more favourable in Schleswig-Holstein. The survival gap will probably close due to Denmark’s national screening program and increased use of adjuvant cancer therapy.     

Capsular contraction following immediate reconstructive surgery for breast cancer – An association with methylene blue dye

Capsular contraction following implantation of breast prostheses occurs in 2-33% of patients undergoing breast augmentation. This condition can be debilitating for patients, and often requires revisional surgery. The aetiology of capsular contraction is unclear, but may be due to infection, haematoma or foreign body-type reactions.Methylene blue dye is a substance known to cause localised tissue inflammation, and is often used during breast cancer surgery to allow identification of the sentinel lymph node. We report a case of Baker Grade 4 capsular contraction necessitating revisional surgery, occurring in a patient who underwent immediate breast reconstruction during surgery for breast cancer. Methylene blue dye was used to locate the sentinel nodes during the original surgery, and was found to have heavily discoloured the prosthesis at subsequent revisional surgery. Capsular contraction may have been caused in part by a localised tissue reaction initiated by, or involving the dye.     

Characterization of haemoglobin from Actinorhizal plants – An in silico approach

Plant haemoglobins (Hbs), found in both symbiotic and non-symbiotic plants, are heme proteins and members of the globin superfamily. Hb genes of actinorhizal Fagales mostly belong to the non-symbiotic type of haemoglobin; however, along with the non-symbiotic Hb, Casuarina sp. posses a symbiotic one (symCgHb), which is expressed specifically in infected cells of nodules. A thorough sequence analysis of 26 plant Hb proteins, currently available in public domain, revealed a consensus motif of 29 amino acids. This motif is present in all the members of symbiotic class II Hbs including symCgHb and non-symbiotic Class II Hbs, but is totally absent in Class I symbiotic and non-symbiotic Hbs. Further, we constructed 3D structures of Hb proteins from Alnus and Casuarina through homology modelling and peeped into their structural properties. Structure-based studies revealed that the Casuarina symbiotic haemoglobin protein shows distinct stereochemical properties from that of the other Casuarina and Alnus Hb proteins. It also showed considerable structural similarities with leghemoglobin structure from yellow lupin (pdb id 1GDI). Therefore, sequence and structure analyses point to the fact that symCgHb protein shows significant resemblance to symbiotic haemoglobin found in legumes and may thus eventually play a similar role in shielding the nitrogenase from oxygen as seen in the case of leghemoglobin.     

Styles of coping with stress of cancer in patients treated with radiotherapy and expectations towards medical staff – Practical implications

Background

It is essential to adjust oncological treatment to medical procedures but also to the expectations of patients themselves. Expectations of patients may depend on the way of coping with the stress of cancer. Many researchers have dealt with this issue. However, it is difficult to find studies concerning relations between the styles of coping and expectations of patients towards medical staff.

Aim

To demonstrate the relationship between the style of coping with stress of cancer shown by patients undergoing radiotherapy at the Greater Poland Cancer Centre and the nature of their expectations towards the medical staff, and to present work of the Clinical Psychology Unit in response to the expectations of patients.

Materials and methods

Questionnaire survey. The respondents filled in a questionnaire consisting of a patient request form (PRF), the mini-mental adjustment to cancer scale (Mini-MAC), and personal data. Obtained results were subjected to statistical analysis.

Results

Significant associations: the expectation to have the disease explained is associated with anxious preoccupation, fighting spirit, helplessness–hopelessness; the expectation of emotional support is associated with anxious preoccupation and helplessness–hopelessness; and the expectation of information on examinations and treatment is associated with anxious preoccupation and helplessness–hopelessness.

Conclusions

Expectations of patients undergoing radiotherapy in the Greater Poland Cancer Centre towards the medical staff depend on their styles of coping with the stress of cancer.     

Escalated hyperfractionation in radiotherapy for head and neck cancer – 5-year results

PurposeTo evaluate 5-year results of escalated hyperfractionation schedule in aspect of local tumour control (LTC) and late radiation toxicity.Material and methodsForty eight patients with squamous cell carcinoma of oral cavity (34 pts), oropharynx (11 pts) and larynx (3) in stage T1-4N0-1 have been treated at Centre of Oncology in Gliwice, between the years 1988–92. There were four patients with T1 primary tumour, 27 with T2, 11 with T3 and 2 with T4; in 4 patients the tumour stage remains unknown (TX). All the patients were treated by radiation therapy alone, using the technique of two opposed parallel fields and hyperfractionation with escalation of the dose per fraction during the second part of the treatment schedule. The total dose ranged between 62,2 and 74 Gy. The median follow-up was 62 months.ResultsDespite of the relative high proportion of complete local regressions (75%), the 5-year LTC rate of 54% was noted in the whole group of patients. Stage-related LTC rates were as follows: 100% for TX tumours, 50% for T1, 55% for T2, 45% for T3 and 0% for T4. Acute radiation reactions were more intensive than those usually observed during conventional radiotherapy; all patients experienced a confluent mucositis and two waves of acute mucosal reaction because of treatment gap were observed during the radiation course. Severe late radiation toxicity (grade IV) was noted in two patients (4%).ConclusionsLong-term tumour control results of escalated hyperfractionation radiotherapy may suggest that there is no benefit of a such regimen. However, in the majority of patients the treatment course differed markedly from protocol assumptions.     

Should the management of radiation therapy for breast cancer be standardized? Results of a survey on current French practices in breast radiotherapy

BackgroundBreast cancer is the most frequent cancer in women in France. Its management has evolved considerably in recent years with a focus on reducing iatrogenic toxicity. The radiotherapy indications are validated in multidisciplinary consultation meetings; however, questions remain outstanding, particularly regarding hypofractionated radiotherapy, partial breast irradiation, and irradiation of the internal mammary chain and axillary lymph node area.Materials and methodsAn online survey was sent to 47 heads of radiotherapy departments in France. The survey consisted of 22 questions concerning indications for irradiation of the supraclavicular, internal mammary and axillary lymph node areas; irradiation techniques and modalities; prescribed doses; and fractionation.ResultsTwenty-four out of 47 centers responded (response rate of 51%). This survey demonstrated a wide variation in the prescribed dose regimen, monoisocentric radiotherapy, and indications of irradiation of the lymph node areas.ConclusionThis survey provides insight into the current radiotherapy practice for breast cancer in France. It shows the need to standardize practices.     

Molecular dynamics of interaction of Sesamin and related compounds with the cancer marker β-catenin: an in silico study

By virtue of their regulatory role in the biological process, certain protein–protein complexes form potential targets for designing and discovery of drugs. Alteration set in the controlled formation of such complexes results in dysregulation of several metabolic processes, leading to diseased condition. β-catenin/Tcf4 complex is one such protein–protein complex found altered in colorectal epithelial cells resulting in activation of target genes leading to cancer. Recently, certain lignans from seeds of the oil crop sesame were found inhibiting initiation and progression of this type of cancer. Molecular mechanism involved in the process, however, is not yet known. By an in silico study, we present here a possible mechanism of interaction between the sesame lignans and β-catenin leading to inhibition of formation of the said complex, thereby elevating some of these ligands as potential lead molecules in the development of drugs for treatment of colon cancer. To achieve this objective, we performed docking, molecular dynamics simulation, and binding free energy analysis of target–ligand complexes. Using computational alanine scanning approach, the key pocket residues of β-catenin that interact with Tcf4 in the formation of complex were identified. The test molecules were initially evaluated for their drug-like properties by application of Lipinski’s rule of five. Results of this study revealed that Sesamin, a furofuran lignan from sesame, has the highest affinity for β-catenin particularly with its residues that interact with Tcf4 and thus serving as a potential lead molecule for development of a drug for colon cancer.     

Characterisation of phytoplasma (16SrVI) associated with little leaf disease of Portulaca grandiflora – An in silico analysis

A new severe little leaf disease was observed on P. grandiflora, popular as Moss-rose Purslane, widely grown in temperate zones. Characteristic symptoms, ultrastructural studies, antibiotic response and amplification of 16S ribosomal DNA fragments (about 1.5 kb) by polymerase chain reaction (PCR) from infected samples, suspect the involvement of phytoplasma as a pathogen. Nested PCR product, 1.2 kb, with primer pairs R16F2n/R16R2 used for cloning and sequencing. Comparision of the 16S rRNA gene sequences showed that the causal, PLL phytoplasma, is very close (98%) to Indian brinjal little leaf (EF186820) and “Candidatus Phytoplasma trifolii” (AY390261), 16SrVI group phytoplasmas, previously reported from India and Canada respectively. Here, the status of PLL (EF651786) is verified by computer-simulated restriction fragment length polymorphism analysis of 16S rRNA genes of the F2n/R2 sequences of closely related strains of the 16SrVI group using 17 restriction enzymes.     

Range optimization for target and organs at risk in dynamic adaptive passive scattering proton beam therapy – A proof of concept

PurposeThe purpose of this study was to design and develop a new range optimization for target and organs at risk (OARs) in dynamic adaptive proton beam therapy (PBT).MethodsThe new range optimization for target and OARs (RO-TO) was optimized to maintain target dose coverage but not to increase the dose exposure of OARs, while the other procedure, range optimization for target (RO-T), only focused on target dose coverage. A retrospective analysis of a patient who received PBT for abdominal lymph node metastases was performed to show the effectiveness of our new approach. The original plan (OP), which had a total dose of 60 Gy (relative biological effectiveness; RBE), was generated using six treatment fields. Bone-based registration (BR) and tumor-based registration (TR) were performed on each pretreatment daily CT image dataset acquired once every four fractions, to align the isocenter.ResultsBoth range adaptive approaches achieved better coverage (D_95%) and homogeneity (D_5%−D_95%) than BR and TR only. However, RO-T showed the greatest increases in D_2cc and D_mean values of the small intestine and stomach and exceeded the limitations of dose exposure for those OARs. RO-TO showed comparable or superior dose sparing compared with the OP for all OARs.ConclusionsOur results suggest that BR and TR alone may reduce target dose coverage, and that RO-T may increase the dose exposure to the OARs. RO-TO may achieve the planned dose delivery to the target and OARs more efficiently than the OP. The technique requires testing on a large clinical dataset.     

The SiFi-CC project – Feasibility study of a scintillation-fiber-based Compton camera for proton therapy monitoring

One of the big challenges for proton therapy is the development of tools for online monitoring of the beam range, which are suited to operate in clinical conditions and can be included in the clinical practice. A Compton camera based on stacks of heavy scintillating fibers used for prompt-gamma imaging is a promising approach for this task. It provides full, three-dimensional information on the deposited dose distribution while showing a high detection efficiency and rate capability due to its high granularity. The investigation of the rate capability and detection efficiency of such a camera under clinical conditions by means of Geant4 simulations is presented along with the event construction algorithm. The results hint towards a very low pile-up rate in the detector and a relatively high detection efficiency, so that imaging of a single proton beam spot appears to be an achievable goal.     

Aberrant DNA methylation of microRNA genes in human breast cancer – a critical appraisal

Aberrant DNA methylation of regulatory sequences is a well-documented mechanism of functional deletion of genes with anti-tumourigenic properties including microRNAs. This review discusses the publications describing aberrant methylation of microRNA genes in human breast cancer cells. Among the anti-tumourigenic properties of epigenetically inactivated microRNA genes, the inhibition of proliferation and of epithelial-to-mesenchymal transition (EMT) are the best studied. Several studies are conceptually very interesting and present a comprehensive functional characterization of anti-tumorigenic microRNAs. The link between microRNA expression and gene methylation is not addressed directly by all studies and a number of studies are limited in their strength by not including primary breast cancer specimens or by analysing very small sets of primary human specimens. The publications cover a wide range of DNA methylation detection techniques, often making direct comparison of results challenging. Despite the identification and thorough characterization of many interesting candidates and functionally important microRNA genes affected by DNA methylation, the translation of microRNA gene methylation as a new biomarker into the daily routine practice has not yet worked out.     

An ultrastructural study of mitosis and cytokinesis in normal ‘resting’ human breast

Summary The parenchyma of the normal resting human breast was examined by electron microscopy to characterize the cells undergoing mitosis and the mechanism by which the normal tissue architecture is maintained during this process. In this study of 112 mitotic cells, it was found that the mitotic cells were luminally positioned, polarised epithelial cells with no evidence of myoepithelial cell division. Ultrastructurally, the nuclear and cytoplasmic changes were consistent with previous reports of mitosis in other tissues. However, unlike all previous reports, two specific orientations of the nuclear spindle and thus the planes of cytokinesis were observed. In a few cases the spindle formed parallel to the lumen and division resulted in two luminally positioned daughter cells. However, in the majority of mitotic cells the spindle was approximately at right angles to the lumen and this orientation resulted in a luminally and a basally positioned daughter cell. It is proposed that the abnormally positioned basal daughter cell could develop into a myoepithelial cell or undergo deletion (apoptosis). Thus the two orientations of mitosis may explain the mechanism by which the epithelial and myoepithelial cell populations were maintained by a single progenitor cell without disrupting the integrity of the tissue architecture.     

Does radiotherapy increase oxidative stress? A study with nasopharyngeal cancer patients revealing anomalies in isoprostanes measurements

Abstract

This study aimed to examine if exposure to ionizing radiation during clinical radiotherapy (RT) causes increased oxidative damage. Seven patients with nasopharyngeal cancer (NPC) who underwent RT took part in this controlled-trial study. Blood and urine samples were obtained for F₂-isoprostanes (F₂-IsoPs) measurement. Urinary F₂-IsoPs levels were elevated pre-treatment and remained high (but did not increase) during treatment, but decreased to the normal range after treatment. Plasma F₂-IsoPs decreased significantly after the start of treatment before rising midway through treatment. Levels decreased significantly to below baseline following treatment. However, the patients were observed to have substantially lower levels of plasma esterified arachidonic acid (AA) residues than controls. The data shows that NPC is associated with elevated F₂-isoprostanes in urine and in plasma after correction for decreased AA levels. RT did not increase these levels and, indeed, was associated with falls in F₂-IsoPs. The validity and usefulness of correction of plasma F₂-IsoPs for lowered AA levels is discussed.     

Characteristics and dosimetric impact of intrafraction motion during peripheral lung cancer stereotactic radiotherapy: is a second midpoint cone beam computed tomography of added value?

BackgroundIn our department, during lung stereotactic body radiation therapy (SBRT), all patients receive an intra-fractional midpoint cone beam computed tomography (CBCT). This study aimed to quantify the benefit of adding a second midpoint CBCT over a course of peripheral lung SBRT.Materials and methodsSix-hundred-sixty-four CBCTs from 166 patients were retrospectively analyzed. Treatments were based on the internal target volume (ITV) approach. An isotropic 0.5 cm margin was used to create the planning target volume (PTV) around the ITV. The prescribed dose was 48 Gy in 4 fractions to the PTV. Patients were divided into two groups: patients for whom the 3D-intra-fractional-variation (IFV) was < 0.5 cm (105 patients, low risk group) and patients with at least one 3D-IFV ≥ 0.5 cm (61 patients, high-risk group). Plans simulating the dosimetric impact of the IFV were created as follows: the original 2 arcs (ARC ) were copied into a new plan consisting of 4 times ARC 1 and 4 times ARC 2. The delivery of ARC 1 was always assumed to have occurred with the isocenter initially coordinated, whereas the positions of ARC 2 were modified for each arc by the measured the 3D-IFV.ResultsFor the PTV, we obtained: D99% (Gy) = 45.2 vs. 48.2 Gy (p < 0.0001); Dmean = 53 vs. 54 Gy (p < .0001) for the reconstructed vs. planned dose values, respectively. For the ITV, the changes are less pronounced: D99% (Gy) = 52.2 vs. 53.6 Gy (p = 0.0007); Dmean = 56 vs. 56.8 Gy (p = 0.0144). The V48 Gy(%)-ITV coverage did not statistically change between the delivered vs. planned dose (p = 0.1803). Regarding the organs at risk for both groups, dose-volume-histograms were near-identical.ConclusionWe demonstrated that a single CBCT is sufficient and reliable to manage the IFV during peripheral lung SBRT.     

Phase I study of TNFα AutoVaccIne in Patients with metastatic cancer

We evaluated the safety and immunogencity of a novel vaccine directed against autologous TNF in a Phase I fixed dose escalation trial. The vaccine consisted of two recombinant TNF proteins, with specific peptides replaced by foreign immunodominant T cell epitopes from tetanus toxoid. The main objectives were to establish a safe dose and evaluate the vaccines ability to raise neutralising TNF antibodies. Secondary objectives were improvements in body weight and tumour response. Thirty-three patients were vaccinated with three doses (20, 100, or 400 g) of TNF vaccine at 2-weekly intervals adjuvanted with aluminium hydroxide. Anti-TNF antibody titres were measured by both a RIA, using soluble native TNF as the antigen, and by an ELISA using immobilized partly denatured TNF. Eleven patients (33%) had mild grade1/2 injection site reactions at the higher doses. In 10 of 20 patients, serum antibodies recognize denatured TNF in the ELISA, whereas, antibody titres against native TNF in the RIA were undetectable. This suggests that the production process had partly denatured the vaccine preventing the formation of cross-reacting antibodies to native TNF. In conclusion, TNF vaccine was able to elicit vaccine specific antibodies. However, since the antibodies were only able to cross-react with partly denatured TNF, evaluation of safety and tumour responses to the TNF vaccine was compromised.     

Shear-scaling-based approach for irreversible energy loss estimation in stenotic aortic flow – An in vitro study

Today, the functional and risk assessment of stenosed arteries is mostly based on ultrasound Doppler blood flow velocity measurements or catheter pressure measurements, which rely on several assumptions. Alternatively, blood velocity including turbulent kinetic energy (TKE) may be measured using MRI. The aim of the present study is to validate a TKE-based approach that relies on the fact that turbulence production is dominated by the flow’s shear to determine the total irreversible energy loss from MRI scans. Three-dimensional particle tracking velocimetry (3D-PTV) and phase-contrast magnetic resonance imaging (PC-MRI) simulations were performed in an anatomically accurate, compliant, silicon aortic phantom. We found that measuring only the laminar viscous losses does not reflect the true losses of stenotic flows since the contribution of the turbulent losses to the total loss become more dominant for more severe stenosis types (for example, the laminar loss is 0.0094 ± 0.0015 W and the turbulent loss is 0.0361 ± 0.0015 W for the Re_max = 13,800 case, where Re_max is the Reynolds number based on the velocity in the vena-contracta). We show that the commonly used simplified and modified Bernoulli’s approaches overestimate the total loss, while the new TKE-based method proposed here, referred to as “shear scaling” approach, results in a good agreement between 3D-PTV and simulated PC-MRI (mean error is around 10%). In addition, we validated the shear scaling approach on a geometry with post-stenotic dilatation using numerical data by Casas et al. (2016). The shear scaling-based method may hence be an interesting alternative for irreversible energy loss estimation to replace traditional approaches for clinical use. We expect that our results will evoke further research, in particular patient studies for clinical implementation of the new method.