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KMT2a-rearranged acute leukaemias — insights and potential therapeutic options
Get PDFThe lysine methyltransferase 2A (KMT2A) protein is a histone lysine 4 (H3K4) methyltransferase that is involved innormal development through supporting certain gene transcriptions. On the other hand, it is rather a ‘promiscuous’protein that is involved in fusion with a variety of partner proteins creating an altered mixed lineage leukaemiacomplex that is not expressed in normal cells and is involved in the transformation of normal haematopoietic cells toleukaemic ones. To date, more than 120 fusion partners have been identified. They account for 5–10% of all acuteleukaemias. Of these, infants account for more than 70% of the total cases. Another subgroup of acute leukaemiapatients with the KMT2A-rearrangement develops it as a result of exposure to certain types of chemotherapeuticagents. The outcome of KMT2A-rearranged acute leukaemia is usually very poor especially when compared to otherpatients without the KMT2A-rearrangement. They are often chemo-resistant and display cell plasticity. This hasprompted a search for better therapies. At the same time, more research has led to elucidation of the KMT2A fusionprotein complexes and its involvement in leukaemic transformation.This article reviews the biology of the KMT2A protein and the role played by some of the partner proteins in the developmentof acute leukaemias. It also considers cell plasticity in KMT2A-rearranged leukaemia, and finally somepromising therapeutics that could impact upon the management landscape of KMT2A-rearranged acute leukaemias
Application of 3D printing for personalized boluses in radiotherapy: a systematic review
No full textThe goal of this study was to evaluate the current literature covering the topic of 3D-printed radiotherapy boluses in the context of fabrication methods, materials, and clinical outcomes.
This systematic review followed the PRISMA 2020 guidelines. Data were extracted for authors, publication details, application type, printing technique and materials, study type, radiation type, reported outcomes and implementation difficulties.
The search yielded 161 articles, 52 of which met the inclusion criteria. Publications on 3D printing for customized boluses have increased since 2014, with the most articles from the United States (21%). Most studies (80.8%) focused on manufacturing custom boluses and testing 3D printing materials, whereas 19.2% explored creating molds for boluses. CT scans were the primary method for defining the bolus area (88.6%). The publications included three study types: dosimetric evaluations, evaluations with anthropomorphic phantoms, and clinical case studies. Fused Deposition Modeling (FDM) was the most common printing technique (88.1%), with Polylactic Acid (PLA) being the most frequently used material (57.1%). Challenges included ensuring proper fit, assessing material properties, and managing printing time.
The outcomes of this review suggest that 3D printing technology holds significant promise for improving radiotherapy by creating custom-fit boluses. 3D-printed boluses demonstrated notable advantages, such as improved dose distribution, better bolus conformity, and reduced setup times. However, several limitations have been identified, including considerable variability in study designs, making it challenging to draw generalized conclusions. Some studies had small sample sizes or did not clearly report methodological details. Addressing these issues will help to optimize technology's implementation
Carcinoma lung with cutaneous metastasis: experience from an Indian institute
No full textBackground: Majority of lung cancer patients are presented with metastatic disease. However, cutaneous metastasis (CM) from lung carcinoma is a rare entity with very few case reports published in the Indian background. Moreover, outcome in these patients is dismal and no standard therapeutic approaches are there. Thus, a long-term analysis from a single institute in this infrequent occurrence holds scientific importance. The purpose of this study was to describe the clinico-demographic profile of patients having CM with lung primary and also to evaluate the survival outcomes in these patients.
Materials and methods: This was a retro-prospective study conducted over 5-year time period in an academic institute of India. Records of all histopathologically confirmed lung cancer patients were reviewed and patients having biopsy-proven CM were included in this analysis. Permission from Institutional Ethics Committee and informed consent from all the patients were taken. Data of these patients were collected and analysed using standard statistical software.
Results: Total of 25 cases of biopsy-proven CM were found in the stipulated time period. Mean age of patients was 57.6 years with high male predominance. Anterior chest wall was the most common site of skin involvement and squamous cell carcinoma was the most common primary histopathology. Overall, median survival was 4.9 months.
Conclusion: Once CM developed, survival of lung carcinoma patients become dismal. Goal of the treatment will be to palliate and to improve quality of life in these patients. Understanding the clinical pattern and demographic profile of these patients will guide a standard treatment approach
A comprehensive site-specific analysis of patient-specific quality assurance based on dose volume histogram of RapidArc treatment delivery
No full textBackground: The current study aims to evaluate the use of dose-volume histogram (DVH) metrics as part of a comprehensive pre-treatment quality assurance (PSQA) protocol for RapidArc treatment delivery.
Materials and methods: A total of ninety patients were included in this study, with the patient population divided into four groups: Brain (n = 15), Head and Neck (H & N) (n = 30), Thorax (n = 15), and Pelvis (n = 30) RapidArc plans. The delivered dose was assessed using the Octavius 4D 1500 detector array and the Verisoft DVH application, focusing on DVH-related errors pertaining to targets and organ-at-risk (OARs). Additionally, three-dimensional local and global gamma passing rates were analyzed in the axial, coronal, and sagittal planes using various gamma criteria, including 3 mm/3%, 3 mm/2%, 2 mm/3%, and 2 mm/2%.
Results: All treatment plans met the action level requirement, achieving a gamma acceptance rate exceeding 95% with a 3%/3 mm criterion. Among the anatomical planes, the transverse plane consistently exhibited the highest passing rates for various global gamma criteria across all treatment sites. Local gamma analysis revealed that the coronal plane had the highest passing rates for thorax and pelvis sites compared to other planes. DVH analysis indicated that doses to target volumes remained within specified tolerances for all cases. The most significant OAR dose discrepancies were observed in the H&N region.
Conclusion: Integrating DVH metrics into the RapidArc PSQA protocol can yield clinically significant results closely aligned with the gamma index. It was observed that a single action-level approach cannot be universally applied to DVH metrics across different anatomical sites
Can the daily position of bolus material influence radiotherapy treatment?
No full textBackground: Daily bolus positioning implies a high degree of variability, which can affect the dose distribution within the planning target volume (PTV) and the organs at risk (OAR). We carried out a retrospective study to evaluate bolus positioning in patients with breast cancer.
Materials and methods: We evaluated 7 cases with left and 5 cases with right chest-wall with comprehensive nodal region irradiation in which bolus material was used to obtain better skin surface coverage. The bolus positioning on the daily cone-beam computed tomography images was compared to the reference image from the treatment planning system. Deviations from the reference position of the bolus were categorized as positive shifts (PosS) or negative shifts (NegS), depending on the material’s overlapping with its planned position. Subsequently, a second plan was calculated using the information from the CBCT images for comparison with the original treatment plan. We performed a statistical and dosimetric analysis on the results.
Results: For both the 95% dose coverage for the PTV for the chest wall and for the lymph node regions, about 2% variation between initial and recalculated plans was seen, with a shift of the hotspots’ position in some cases. The average mean heart dose was 4.1 ± 0.3 Gy, whereas the values for PosS and NegS mean heart doses were 3.8 ± 0.4 Gy and 4.0 ± 0.6 Gy, respectively. In contrast to the original values for the ipsilateral lung V5 (57.1 ± 12.9%), V20 (30.2 ± 2.7%), and Dmean (15.0 ± 1.7 Gy), the values for PosS were 56.1 ± 4.2% for V5:, 30.1 ± 3.3% for V20, and 14.9 ± 1.2 Gy for Dmean while for NegS we obtained 56.9 ± 8.9% for V5, 30.0 ± 2.3% for V20, and 15.2 ± 1.8 Gy for Dmean.
Conclusion: We observed dosimetric differences between the initial and given treatment plans depending on the position of the bolus for all cases, indifferent of the shift direction. Although the differences were not statistically significant, we identified a few specific instances where the variations might cause uncertainties regarding doses to the OAR. We suggest therefore that strategies for correct daily reproducibility of the bolus need to be implemented on a departmental level
Dosimetric advantage of ipsilateral lung and cardiac sparing of left breast cancer prone position compared with supine free breathing in the COVID-19 era and personalized medicine
No full textBackground: As coronavirus disease 19 (COVID-19) run unabated across the globe, its potential survival detrimental effects on lung function may be potentiated by systemic therapy and/or radiotherapy. Limiting lung exposure to high radiation dose in addition to sparing the heart may be critical for left-sided breast cancer patients. Deep inspiration breath-hold allows heart sparing. However, a minority of patients cannot hold breath for radiotherapy. We aim to evaluate whether a prone setup can be advantageous in these patients.
Materials and methods: Left breast cancer patients who had dual supine and prone planning, both in free-breathing, were retrospectively identified. A multiple-structures penalty score was computed from the mean absolute dose deviation (MADD) to heart, lungs, breasts, and tumor bed for each supine and prone plan. Dosimetric advantage of prone was assessed by the reduction of penalty score compared with supine. Patients' characteristics effect on the reduction of penalty was analyzed using robust linear regression.
Results: The prone vs. supine MADD for 27 patients demonstrated significant sparing for the ipsilateral lung and was 0.6 vs. 3 Gy, respectively, without differences regarding heart and target volumes. The average penalty ± standard deviation was 0.90 ± 0.28 Gy prone, vs. 1.13 ± 0.38 Gy supine, p = 0.024. Overall, 70.4% (19/27) patients had a reduction of penalty with prone setup, as compared with 29.6% (8/27) supine, p = 0.0065. Pre-dosimetry characteristics could not predict the reduction of penalty.
Conclusion: Prone conferred substantial lung sparing without dose-deterioration to other structures, providing a significant advantage as compared with supine free-breathing radiotherapy in left-breast cancer patients
Trastuzumab derukstekan — nowy standard leczenia zaawansowanego raka piersi
No full textRak HER2-dodatni stanowi około 15-20% wszystkich przypadków nowotworów piersi. Złe rokowanie chorych z tym podtypem nowotworu uległo znacznej poprawie od czasu odkrycia trastuzumabu ponad 20 lat temu i wykorzystaniu go w leczeniu zaawansowanego raka piersi. W kolejnych latach standardem terapii pierwszej linii leczenia zaawansowanego raka piersi stało się skojarzenie docetakselu, trastuzumabu i pertuzumabu. Po progresji choroby w kolejnych liniach leczenia stosowano trastuzumab-emtanzynę (T-DM1), inhibitory kinaz tyrozynowych (lapatynib) oraz trastuzumab w skojarzeniu z chemio- i hormonoterapią. Pomimo znacznego postępu istnieje jednak nadal znaczna niezaspokojona potrzeba poprawy wyników leczenia w tym wskazaniu.
W niniejszym artykule omówiono doniesienia na temat trastuzumabu derukstekanu (T-DXd), który jest koniugatem złożonym z przeciwciała monoklonalnego anty-HER2 połączonego z derukstekanem- aktywnym metabolitem irynotekanu. Przedstawiono budowę oraz mechanizm działania leku, a także wyniki badań klinicznych z T-DXd u chorych na raka piersi, w tym w przerzutowym raku piersi z niską eksperesją HER2 (HER2-low). Wyniki badań Destiny-Breast02 i Destiny-Breast03 spowodowały zmianę obowiązujących standardów leczenia i ugruntowanie miejsca trastuzumabu derukstekanu w drugiej linii leczenia zaawansowanego HER2-dodatniego raka piersi. W badaniu Destiny-Breast04 trastuzumab derukstekan wykazał wyższą aktywność niż standardowe opcje chemioterapii u pacjentek z zaawansowanym rakiem piersi z niską ekspresją HER2, co zmienia diametralnie nasze dotychczasowe postrzeganie klasycznych podtypów raka piersi oraz podkreśla potrzebę ponownego zdefiniowania tego podziału.
Obecnie trwają liczne badania mające na celu ocenę aktywności przeciwnowotworowej T-DXd we wczesnym raku piersi, nowotworach z niską ekspresją HER2, a także terapii skojarzonych T-DXd z klasyczną chemioterapią.Rak HER2-dodatni stanowi około 15–20% wszystkich przypadków raka piersi. Wprowadzenie trastuzumabu do leczenia tego podtypu raka znacząco wpłynęło na poprawę wyników przeżycia. W kolejnych latach standardem terapii pierwszej linii leczenia zaawansowanego raka piersi stało się skojarzenie docetakselu, trastuzumabu i pertuzumabu. Po progresji choroby w kolejnych liniach leczenia stosowano trastuzumab emtanzynę (T-DM1), inhibitory kinaz tyrozynowych (lapatynib) oraz trastuzumab w skojarzeniu z chemio- i hormonoterapią. Pomimo znacznego postępu istnieje jednak nadal niezaspokojona potrzeba poprawy wyników leczenia w tym wskazaniu. W niniejszym artykule omówiono doniesienia na temat trastuzumabu derukstekanu (T-DXd). Przedstawiono budowę oraz mechanizm działania leku, a także wyniki badań klinicznych u chorych na raka piersi, w tym w przerzutowym raku piersi z niską ekspresją HER2 (HER2-low). Wyniki badań DESTINY-Breast02 i DESTINY-Breast03 spowodowały zmianę obowiązujących standardów leczenia i ugruntowanie miejsca trastuzumabu derukstekanu w drugiej linii leczenia zaawansowanego HER2-dodatniego raka piersi. W badaniu DESTINY-Breast04 trastuzumab derukstekan wykazał wyższą aktywność niż standardowe opcje chemioterapii u pacjentek z zaawansowanym rakiem piersi z niską ekspresją HER2, co zmienia diametralnie nasze dotychczasowe postrzeganie klasycznych podtypów raka piersi oraz podkreśla potrzebę ponownego zdefiniowania tego podziału.
Obecnie trwają liczne badania mające na celu ocenę aktywności przeciwnowotworowej T-DXd we wczesnym raku piersi, nowotworach z niską ekspresją HER2, a także terapii skojarzonych T-DXd z klasyczną chemioterapią.
Role of epithelial-to-mesenchymal transition and cancer stem cells in colorectal cancer
Get PDFColorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths. To properly investigate the biology of the tumor and the molecular mechanisms leading to cancer progression or treatment resistance, it seems imperative to explore the key pathways like epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs). This review aimed to collect up-to-date knowledge on the subject of EMT and CSC in colorectal malignancies. In CRC, both EMT and CSC are associated with aggressive tumor behavior, metastases, cancer recurrence, and chemotherapy resistance. Due to their close relationship, the potential for targeting these pathways as therapeutic interventions is promising. However, direct usage of EMT and CSCs as therapeutic targets requires further investigation. Future studies should focus on unraveling the complex mechanisms underlying EMT and CSC involvement in CRC progression and developing tailored therapeutic strategies with acceptable toxicity profiles and minimal adverse events.
Mechanisms of neoplastic cell survival using melanoma as an example
Get PDFWe discuss various mechanisms of carcinogenesis using melanoma as an example. The article presents the cellular mechanism inducing pathological angiogenesis in neoplastic cells and the significance of the inflammatory process in carcinogenesis. A good understanding of the pathophysiology of tumors is key to creating new drugs and new forms of treatment. Exploring the mechanisms of tumor formation contributes to improving new therapies (new drugs, immunotherapy) and achieving higher survival rates in patients suffering from melanoma and other cancers. The article allows for a better understanding of the mechanisms of carcinogenesis.
