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Enhanced DNA double-strand break repair of microbeam targeted A549 lung carcinoma cells by adjacent WI38 normal lung fibroblast cells via bi-directional signaling

Kobayashi A, Tengku Ahmad TAF, Autsavapromporn N, Oikawa M, Homma-Takeda S, Furusawa Y, et al.

Mutat Res, 2017 10;803-805:1-8.
PMID: 28689138 DOI: 10.1016/j.mrfmmm.2017.06.006

Understanding the mechanisms underlying the radiation-induced bystander effect (RIBE) and bi-directional signaling between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to cancer radiotherapy. The present study investigated propagation of RIBE signals between human lung carcinoma A549 cells and normal lung fibroblast WI38 cells in bystander cells, either directly or indirectly contacting irradiated A549 cells. We prepared A549-GFP/WI38 co-cultures and A549-GFP/A549 co-cultures, in which A549-GFP cells stably expressing H2BGFP were co-cultured with either A549 cells or WI38 cells, respectively. Using the SPICE-NIRS microbeam, only the A549-GFP cells were irradiated with 500 protons per cell. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured for up to 24h post-irradiation in three categories of cells: (1) "targeted"/irradiated A549-GFP cells; (2) "neighboring"/non-irradiated cells directly contacting the "targeted" cells; and (3) "distant"/non-irradiated cells, which were not in direct contact with the "targeted" cells. We found that DSB repair in targeted A549-GFP cells was enhanced by co-cultured WI38 cells. The bystander response in A549-GFP/A549 cell co-cultures, as marked by γ-H2AX levels at 8h post-irradiation, showed a decrease to non-irradiated control level when approaching 24h, while the neighboring/distant bystander WI38 cells in A549-GFP/WI38 co-cultures was maintained at a similar level until 24h post-irradiation. Surprisingly, distant A549-GFP cells in A549-GFP/WI38 co-cultures showed time dependency similar to bystander WI38 cells, but not to distant cells in A549-GFP/A549 co-cultures. These observations indicate that γ-H2AX was induced in WI38 cells as a result of RIBE. WI38 cells were not only involved in rescue of targeted A549, but also in the modification of RIBE against distant A549-GFP cells. The present results demonstrate that radiation-induced bi-directional signaling had extended a profound influence on cellular sensitivity to radiation as well as the sensitivity to RIBE.

Matched MeSH terms: Lung Neoplasms/radiotherapy
Systematic investigation on the validity of partition model dosimetry for90Y radioembolization using Monte Carlo simulation

Hashikin NAA, Yeong CH, Guatelli S, Abdullah BJJ, Ng KH, Malaroda A, et al.

Phys Med Biol, 2017 Aug 22;62(18):7342-7356.
PMID: 28686171 DOI: 10.1088/1361-6560/aa7e5b

We aimed to investigate the validity of the partition model (PM) in estimating the absorbed doses to liver tumour ([Formula: see text]), normal liver tissue ([Formula: see text]) and lungs ([Formula: see text]), when cross-fire irradiations between these compartments are being considered. MIRD-5 phantom incorporated with various treatment parameters, i.e. tumour involvement (TI), tumour-to-normal liver uptake ratio (T/N) and lung shunting (LS), were simulated using the Geant4 Monte Carlo (MC) toolkit. 108track histories were generated for each combination of the three parameters to obtain the absorbed dose per activity uptake in each compartment ([Formula: see text], [Formula: see text], and [Formula: see text]). The administered activities, A were estimated using PM, so as to achieve either limiting doses to normal liver, [Formula: see text] or lungs, [Formula: see text] (70 or 30 Gy, respectively). Using these administered activities, the activity uptake in each compartment ([Formula: see text], [Formula: see text], and [Formula: see text]) was estimated and multiplied with the absorbed dose per activity uptake attained using the MC simulations, to obtain the actual dose received by each compartment. PM overestimated [Formula: see text] by 11.7% in all cases, due to the escaped particles from the lungs. [Formula: see text] and [Formula: see text] by MC were largely affected by T/N, which were not considered by PM due to cross-fire exclusion at the tumour-normal liver boundary. These have resulted in the overestimation of [Formula: see text] by up to 8% and underestimation of [Formula: see text] by as high as -78%, by PM. When [Formula: see text] was estimated via PM, the MC simulations showed significantly higher [Formula: see text] for cases with higher T/N, and LS ⩽ 10%. All [Formula: see text] and [Formula: see text] by MC were overestimated by PM, thus [Formula: see text] were never exceeded. PM leads to inaccurate dose estimations due to the exclusion of cross-fire irradiation, i.e. between the tumour and normal liver tissue. Caution should be taken for cases with higher TI and T/N, and lower LS, as they contribute to major underestimation of [Formula: see text]. For [Formula: see text], a different correction factor for dose calculation may be used for improved accuracy.

Matched MeSH terms: Lung Neoplasms/radiotherapy
Dosimetric evaluation near lung and soft tissue interface region during respiratory-gated and non-gated radiotherapy: A moving phantom study

Jong WL, Ung NM, Vannyat A, Rosenfeld AB, Wong JHD

Phys Med, 2017 Oct;42:39-46.
PMID: 29173919 DOI: 10.1016/j.ejmp.2017.08.011

Challenges in treating lung tumours are related to the respiratory-induced tumour motion and the accuracy of dose calculation in charged particle disequilibrium condition. The dosimetric characteristics near the interface of lung and Perspex media in a moving phantom during respiratory-gated and non-gated radiotherapy were investigated using Gafchromic EBT2 and the MOSkin detector. The MOSkin detectors showed good agreement with the EBT2 films during static and gated radiotherapy. In static radiotherapy, the penumbral widths were found to be 3.66mm and 7.22mm in Perspex and lung media, respectively. In non-gated (moving) radiotherapy with 40mm respiratory amplitude, dose smearing effect was observed and the penumbral widths were increased to 28.81mm and 26.40mm, respectively. This has been reduced to 6.85mm and 9.81mm, respectively, in gated radiotherapy with 25% gating window. There were still some dose discrepancies as compared to static radiotherapy due to the residual motion. This should be taken into account in the margin generation for the target tumour.

Matched MeSH terms: Lung Neoplasms/radiotherapy
Palliative radiotherapy for advanced Cancer: Are we giving it to the right patient at the right time?

Syadwa AS, Anita ZB

Med J Malaysia, 2018 08;73(4):190-196.
PMID: 30121680 MyJurnal

AIM: Symptomatic relief following palliative radiotherapy for advanced cancers may take a few weeks up to a few months to achieve. Thus, accurate prognostication is important to avoid harm to these patients with limited lifespan. We conducted a retrospective cohort study to determine the median survival and 30-day mortality (30-DM) and factors associated with these parameters in our centre.
METHODS: Data from 585 eligible patients who received palliative radiotherapy between January 2012 and December 2014 were analysed. Median overall survival was calculated from the commencement of first fraction of the last course of radiotherapy to date of death or when censored. 30-DM was calculated as the proportion of patients who died within 30 days from treatment start date. Kaplan-Meier survival analysis was used to estimate survival. Chi-square test and logistic regression was used to assess the impact of potential prognostic factors on median survival and 30-DM.
RESULTS: The most common diagnoses were lung and breast cancers and most common irradiated sites were bone and brain. Median survival and 30-DM were 97 days and 22.7% respectively. Primary cancer, age, treatment course, performance status, systemic treatment post radiotherapy and intended radiotherapy treatment completed had an impact on median survival whereas mainly the latter three factors had an impact on 30-DM.
CONCLUSION: Median survival and factors affecting both survival and 30-DM in our study are comparable to others. However, a 30-DM rate of 22.7% is significantly higher compared to the literature. We need to better select patients who will benefit from palliative radiotherapy in our centre.

Matched MeSH terms: Lung Neoplasms/radiotherapy
Fulltext Feasibility, safety and outcomes of stereotactic radiotherapy for ultra-central thoracic oligometastatic disease guided by linear endobronchial ultrasound-inserted fiducials

Sidhu C, Tang C, Scott A, Yamini Ramamurty H, Yagnik L, Morey S, et al.

Radiother Oncol, 2024 Dec;201:110547.
PMID: 39332638 DOI: 10.1016/j.radonc.2024.110547

BACKGROUND & PURPOSE: Local treatment of oligometastases has been found to improve survival and prognosis. Stereotactic body radiotherapy (SBRT) has emerged as a treatment option for oligometastases but its use in ultra-central (UC) areas can cause significant toxicity and mortality. Fiducial markers (FM) can be used to improve SBRT accuracy, and can be inserted in the central thorax using linear endobronchial ultrasound (EBUS) bronchoscopy. Outcomes of FM-guided SBRT for UC thoracic oligometastases is unknown.
METHODS: A single-centre retrospective study investigating the feasibility, safety and outcomes of both linear EBUS-inserted FMs and subsequent FM-guided SBRT for UC-oligometastatic disease. Motion analyses of FMs were also performed.
RESULTS: Thirty outpatients underwent 32 EBUS-FM insertion procedures with 100 % success, and no major procedural mortality or morbidity. Minor complications were 4.8 % incidence of delayed FM-displacement. UC FM-guided SBRT was completed in 20 patients with 99.9 % fractions delivered. Median SBRT dose delivered was 40 Gy over a median of 8 fractions. Majority of adverse events were Grade 1 and there was no SBRT-related mortality. Local control with SBRT was 95 %, with overall survival at 1-year and 3-years of 90 % and 56.3 % respectively. Median overall survival after SBRT was 43.6 months. FM movements in UC areas were recorded being greatest in the superior-inferior axis.
CONCLUSION: Combined linear EBUS sampling and FM-insertion in UC thoracic oligometastatic disease is feasible and safe. UC-SBRT to oligometastases using FM guidance was found to have minimal complications and associated with moderate survival up to 3 years post-treatment.

Matched MeSH terms: Lung Neoplasms/radiotherapy
Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience

Toh YF, Cheah PL, Looi LM, Teoh KH, Tan PH

Malays J Pathol, 2016 Apr;38(1):19-24.
PMID: 27126660

Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed a radiologically-diagnosed lung nodule 26 months after mastectomy, was given a course of radiotherapy and remained well 8-months following identification of the lung nodule.

Matched MeSH terms: Lung Neoplasms/radiotherapy
BYSTANDER WI-38 CELLS MODULATE DNA DOUBLE-STRAND BREAK REPAIR IN MICROBEAM-TARGETED A549 CELLS THROUGH GAP JUNCTION INTERCELLULAR COMMUNICATION

Kobayashi A, Autsavapromporn N, Ahmad TAFT, Oikawa M, Homma-Takeda S, Furusawa Y, et al.

Radiat Prot Dosimetry, 2019 May 01;183(1-2):142-146.
PMID: 30535060 DOI: 10.1093/rpd/ncy249

Bi-directional signaling involved in radiation-induced bystander effect (RIBE) between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to radiation cancer therapy. Using the SPICE-NIRS microbeam, we delivered 500 protons to A549-GFP lung carcinoma cells, stably expressing H2B-GFP, which were co-cultured with normal WI-38 cells. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured up to 24-h post-irradiation in both targeted and bystander cells. As a result, inhibition of gap junction intercellular communication (GJIC) attenuated DSB repair in targeted A549-GFP cells, and suppressed RIBE in bystander WI-38 cells but not in distant A549-GFP cells. This suggests that GJIC plays a two-way role through propagating DNA damage effect between carcinoma to normal cells and reversing the bystander signaling, also called 'rescue effect' from bystander cells to irradiated cells, to enhance the DSB repair in targeted cells.

Matched MeSH terms: Lung Neoplasms/radiotherapy*