Total neoadjuvant treatment in locally advanced rectal cancer

Locally advanced rectal cancer requires a multidisciplinary management, traditionally based on neo-adjuvant (chemo) radiotherapy, conservative surgery with total mesorectal excision and adjuvant chemotherapy. Despite effective in term of local control, this strategy is linked to a high risk of distant metastasis (up to 30%). In this context, recent published randomized phase III clinical trials have tested the potential benefits with a different sequencing and/or intensification of the standard components of the trimodal therapy.Here, we briefly assess the efficacy and discuss the clinical relevance of total neoadjuvant treatment with a focus on indications and results in the short-course radiotherapy followed by chemotherapy use for this setting of patients. Long term results and additional prospective studies are necessary to more accurately estimate the clinical benefit and further establish the role of total neoadjuvant therapy in locally advanced rectal cancer disease.     

Involvement of the insulin-like growth factor binding proteins in the cancer cell response to DNA damage

The complex mechanisms that cells have evolved to meet the challenge of constant exposure to DNA-damaging stimuli, also serve to protect cancer cells from the cytotoxic effects of chemo- and radiotherapy. IGFBPs appear to be involved, directly or indirectly, in some of these protective mechanisms. Activation of p53 is an early response to genotoxic stress, and all six human IGFBP genes have predicted p53 response elements in their promoter and/or intronic regions, at least some of which are functional. IGFBP3 has been extensively characterized as a p53-inducible gene, but in some cases it is suppressed by mutant p53 forms. DNA double-strand breaks (DSBs), induced by radiotherapy and some chemotherapies, potentially lead to apoptotic cell death, senescence, or repair and recovery. DSB damage can be repaired by homologous recombination or non-homologous end-joining (NHEJ), depending on the cell cycle stage, availability of key repair proteins, and other factors. The epidermal growth factor receptor (EGFR) has been implicated in the NHEJ pathway, and EGFR inhibition may inhibit repair, promoting apoptosis and thus improving sensitivity to chemotherapy or radiotherapy. Both IGFBP-3 and IGFBP-6 interact with components of the NHEJ pathway, and IGFBP-3 can facilitate this process through direct interaction with both EGFR and the catalytic subunit of DNA-PK. Cell fate after DNA damage may in part be regulated by the balance between the sphingolipids ceramide and sphingosine-1-phosphate, and IGFBPs can influence the production of both lipids. A better understanding of the involvement of IGFBPs in the DNA damage response in cancer cells may lead to improved methods of sensitizing cancers to DNA-damaging therapies.     

Synchronous primary mammary osteosarcoma and invasive breast cancer. A case report – Pathohistological and immunohistochemical analysis

Primary osteogenic sarcoma of the breast is a rare neoplasm, diagnosed mainly by pathohistological and immunohistochemical analysis.We hereby present a case of primary osteogenic sarcoma in the right breast of a 62-year-old woman with synchronous appearance of an invasive ductal carcinoma. Clinical findings are manifested with two separate painless formations 2.5 cm/2 cm and 1.5 cm/1 cm in size, located on the border of the upper and lower lateral quadrant of the right breast. No axillary lymphadenopathy was diagnosed. The pathohistological and immunohistochemistry findings of both tumors revealed a synchronous manifestation of two distinct neoplasms – epithelial and non-epithelial. Multimodality treatment consisted of Patey''s radical mastectomy; 3 cycles of adjuvant chemotherapy; postoperative 50 Gy radiotherapy to the chest wall followed by additional 3 cycles of chemotherapy and anti-estrogen hormonotherapy.Due to the rarity of osteogenic mammary sarcoma, even more so in a combination with epithelial breast tumors, its clinical features are unclear and optimal treatment remains controversial. Considering the poor prognosis of the combination of both malignomas, we discuss a number of diagnostic and therapeutic issues.     

姜黄素对晚期宫颈癌患者Bcl-xL、Bcl-2、EphA2及EphrinA1表达的影响

目的:探究姜黄素对宫颈癌晚期放疗患者Bcl-x L、Bcl-2、Eph A2与Ephrin A1表达的影响。方法:收集160例晚期宫颈癌放疗患者的宫颈癌石蜡标本,分为姜黄素组与对照组,均给予放射治疗,姜黄素组放疗期间加服姜黄素片剂,采用免疫组化等实验方法,观察两组病例标本Bcl-x L、Bcl-2、Eph A2与Ephrin A1的表达情况,比较两组病理标本化疗前后的凋亡细胞指数(AI)与微血管密度(MVD)。结果:姜黄素组的Bcl-x L、Bcl-2、Eph A2与Ephrin A1的表达阳性率分别为8.3%、43.33%、46.67%、15.0%,均显著低于对照组(P0.05);放疗后姜黄素组的AI显著高于对照组(P0.05),MVD显著低于对照组(P0.05)。结论:姜黄素可抑制Bcl-x L、Bcl-2的表达以促进肿瘤细胞凋亡,同时降低Eph A2与Ephrin A1的表达以减少肿瘤微血管形成,有显著的抗肿瘤与放疗增敏作用。     

Dosimetric characterization of a small-scale (Zn,Cd)S:Ag inorganic scintillating detector to be used in radiotherapy

PurposeIn modern radiotherapy techniques, to ensure an accurate beam modeling process, dosimeters with high accuracy and spatial resolution are required. Therefore, this work aims to propose a simple, robust, and a small-scale fiber-integrated X-ray inorganic detector and investigate the dosimetric characteristics used in radiotherapy.MethodsThe detector is based on red-emitting silver-activated zinc-cadmium sulfide (Zn,Cd)S:Ag nanoclusters and the proposed system has been tested under 6 MV photons with standard dose rate used in the patient treatment protocol. The article presents the performances of the detector in terms of dose linearity, repeatability, reproducibility, percentage depth dose distribution, and field output factor. A comparative study is shown using a microdiamond dosimeter and considering data from recent literature.ResultsWe accurately measured a small field beam profile of 0.5 × 0.5 cm² at a spatial resolution of 100 µm using a LINAC system. The dose linearity at 400 MU/min has shown less than 0.53% and 1.10% deviations from perfect linearity for the regular and smallest field. Percentage depth dose measurement agrees with microdiamond measurements within 1.30% and 2.94%, respectively for regular to small field beams. Besides, the stem effect analysis shows a negligible contribution in the measurements for fields smaller than 3x3 cm². This study highlights the drastic decrease of the convolution effect using a point-like detector, especially in small dimension beam characterization. Field output factor has shown a good agreement while comparing it with the microdiamond dosimeter.ConclusionAll the results presented here anticipated that the developed detector can accurately measure delivered dose to the region of interest, claim accurate depth dose distribution hence it can be a suitable candidate for beam characterization and quality assurance of LINAC system.     

Artificial Intelligence in magnetic Resonance guided Radiotherapy: Medical and physical considerations on state of art and future perspectives

Over the last years, technological innovation in Radiotherapy (RT) led to the introduction of Magnetic Resonance-guided RT (MRgRT) systems.Due to the higher soft tissue contrast compared to on-board CT-based systems, MRgRT is expected to significantly improve the treatment in many situations. MRgRT systems may extend the management of inter- and intra-fraction anatomical changes, offering the possibility of online adaptation of the dose distribution according to daily patient anatomy and to directly monitor tumor motion during treatment delivery by means of a continuous cine MR acquisition.Online adaptive treatments require a multidisciplinary and well-trained team, able to perform a series of operations in a safe, precise and fast manner while the patient is waiting on the treatment couch.Artificial Intelligence (AI) is expected to rapidly contribute to MRgRT, primarily by safely and efficiently automatising the various manual operations characterizing online adaptive treatments. Furthermore, AI is finding relevant applications in MRgRT in the fields of image segmentation, synthetic CT reconstruction, automatic (on-line) planning and the development of predictive models based on daily MRI.This review provides a comprehensive overview of the current AI integration in MRgRT from a medical physicist’s perspective. Medical physicists are expected to be major actors in solving new tasks and in taking new responsibilities: their traditional role of guardians of the new technology implementation will change with increasing emphasis on the managing of AI tools, processes and advanced systems for imaging and data analysis, gradually replacing many repetitive manual tasks.     

Metaplastic breast cancer: Treatment and prognosis by molecular subtype

BackgroundMetaplastic breast cancer (MBC) is a rare and aggressive subtype of breast. However, the effect of molecular subtype on treatment and prognosis of MBC remains unclear.Patients and methodsThe Surveillance, Epidemiology, and End Results database was used to analyze patients with MBC between 2010 and 2016. Molecular subtype was stratified to TN group (ER and PR-/HER2-), HER2 group (ER and PR-/HER2+, ER/PR+ and HER2+), and HR group (ER/PR+ and HER2-). The breast cancer-specific survival (BCSS) differences were estimated using multivariate Cox regression model and Kaplan-Meier curves.ResultsWe included 1665 patients with median follow-up time of 27 months (range 0–83 months). 1154 (69.3%), 65 (3.9%), and 446 (26.8%) patients presented in TN group, HER2 group, and HR group, respectively. On multivariate Cox analysis, the prognosis was related to age, tumor size, regional node metastasis, and surgery. Molecular subtype remained no impact on BCSS. Radiotherapy (RT) was associated with better prognosis. Patients cannot benefit from chemotherapy. In Kaplan-Meier curve, triple-negative (P = 0.047) and HR-positive (P = 0.006) patients receiving RT had a superior BCSS than that not RT. HER2-positive patients cannot benefit from RT. However, adjusted Kaplan-Meier survival model showed that triple-negative (P = 0.019) but not HER2-positive (P = 0.575) or HR-positive (P = 0.574) patients receiving RT had a superior BCSS than that not RT.ConclusionsMolecular subtype is not associated with the better prognosis of MBC. Patients could benefit from RT. However, triple-negative but not HR-positive or HER2-positive patients have superior survival after receiving RT.     

Photons – Radiobiological issues related to the risk of second malignancies

Photons are widely used in radiotherapy and while they are low LET radiation, can still pose a risk in developing second malignant neoplasms (SMN). Due to the physics of photons that allow distribution of energy outside the target volume, out-of-field irradiation is an important component of SMN risk assessment. The epidemiological evidence supporting this risk should be augmented with radiobiological justifications for a better understanding of the underlying processes.There are several factors that impact second cancer risk which can be analysed from a radiobiological perspective: age at irradiation, type of irradiated tissue, irradiated volume, treatment technique, previous irradiation/radiological investigations. Age-dependence has a radiobiological foundation given by the higher radiosensitivity of children as compared to adult patients. However, in its 2013 report, UNSCEAR advises against generalisation of the effects of childhood radiation exposure, given the fact that these effects are strongly organ dependent. Furthermore, the age-dependent radiation sensitivity has a bimodal distribution, since aging cells present an increase in the oxidative stress, which can promote premalignant cells.Non-targeted effects such as radiation-induced genomic instability, bystander or abscopal effects could also impact on the risk of SMN. Recent studies show that beside the known cellular changes, bystander effects can be manifested through increased cell proliferation, which could be a culprit for SMN development. Furthermore, new evidence on the existence of tumour-specific cancer stem cells that are long-lived and more quiescent and radioresistant than non-stem cancer cells can raise questions about their association with SMN risk.     

The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer

PurposeTo investigate the use of dual isocenters for VMAT planning in patients with lymph node positive synchronous bilateral breast cancer (BBC) compared to a single isocenter option.MethodsTreatment plans of 11 patients with lymph node positive BBC were retrospectively analyzed using two different VMAT planning techniques: dual-isocenter split-arc VMAT plans (Iso2) were compared with mono-isocenter VMAT plans (Iso1). For Iso2 plans, PTV dose was investigated after introducing ±2 and ±5 mm couch shift errors between the two isocenters in the lateral, longitudinal and vertical direction.ResultsFor both techniques the planning aims for PTV coverage and OARs were met. The mean dose for the bilateral lungs and heart was reduced from 11.3 Gy and 3.8 Gy to 10.9 Gy (p < .05) and 3.6 Gy (p < .05), respectively, for Iso2 plans when compared to Iso1 plans. Positive statistically significant correlation (rho = 0.76, p = .006) was found between PTV volume and D2cc_PTV for Iso1 plans. No clinically significant change was seen in the D98_CTV or D2cc_PTV after the 2 and 5 mm errors were introduced between isocenters for Iso2 plans.ConclusionsThe split arc method was shown to be a feasible treatment technique in the case of synchronous BBC for both mono and dual isocenter techniques. The dose parameters were slightly favoring dual-isocenter option instead of mono-isocenter. The dual-isocenter method was shown to be a robust treatment option in the presence of ≤5 mm errors in the shifts between the two isocenters.