Radiation nephropathy: Dose, management, and population risk

Radiation nephropathy is renal injury caused by a sufficient dose of irradiation. It can result from external beam irradiation or internal irradiation as might occur from therapeutic radioisotopes. Its usual clinical presentation is as chronic kidney disease occurring some months after irradiation, and it can evolve to end-stage-renal-disease. While the immediate cellular injury from irradiation depends on radiolysis of water and oxidative DNA damage, there is no conclusive evidence for chronic persistent oxidative stress or inflammation as the cause of the multi-tissue scarring that ensues. Antagonists of the renin-angiotensin system are effective treatments for experimental radiation nephropathy but their preferential value in human clinical medicine is unproven.

Relationship of In Vitro Toxicity of Technetium-99m to Subcellular Localisation and Absorbed Dose

Auger electron-emitters increasingly attract attention as potential radionuclides for molecular radionuclide therapy in oncology. The radionuclide technetium-99m is widely used for imaging; however, its potential as a therapeutic radionuclide has not yet been fully assessed. We used MDA-MB-231 breast cancer cells engineered to express the human sodium iodide symporter-green fluorescent protein fusion reporter (hNIS-GFP; MDA-MB-231.hNIS-GFP) as a model for controlled cellular radionuclide uptake. Uptake, efflux, and subcellular location of the NIS radiotracer [99mTc]TcO4− were characterised to calculate the nuclear-absorbed dose using Medical Internal Radiation Dose formalism. Radiotoxicity was determined using clonogenic and γ-H2AX assays. The daughter radionuclide technetium-99 or external beam irradiation therapy (EBRT) served as controls. [99mTc]TcO4− in vivo biodistribution in MDA-MB-231.hNIS-GFP tumour-bearing mice was determined by imaging and complemented by ex vivo tissue radioactivity analysis. [99mTc]TcO4− resulted in substantial DNA damage and reduction in the survival fraction (SF) following 24 h incubation in hNIS-expressing cells only. We found that 24,430 decays/cell (30 mBq/cell) were required to achieve SF0.37 (95%-confidence interval = [SF0.31; SF0.43]). Different approaches for determining the subcellular localisation of [99mTc]TcO4− led to SF0.37 nuclear-absorbed doses ranging from 0.33 to 11.7 Gy. In comparison, EBRT of MDA-MB-231.hNIS-GFP cells resulted in an SF0.37 of 2.59 Gy. In vivo retention of [99mTc]TcO4− after 24 h remained high at 28.0% ± 4.5% of the administered activity/gram tissue in MDA-MB-231.hNIS-GFP tumours. [99mTc]TcO4− caused DNA damage and reduced clonogenicity in this model, but only when the radioisotope was taken up into the cells. This data guides the safe use of technetium-99m during imaging and potential future therapeutic applications.

Potential Utility of Radiopharmaceuticals in the Battle Against SARS-Cov-2 and COVID-19 Pandemic

: Coronavirus disease 2019 (COVID-19) pandemic, which has emerged in December 2019 in the city of Wuhan, China, has significantly affected healthcare systems and economies within a short timeframe. Treatment strategies offer alleviation of symptoms in the absence of commercially available specific antiviral agents. Within this context, the introduction of innovative therapeutic approaches against the SARS-CoV-2 virus is a critical need that should be addressed urgently. The anti-inflammatory effect of low dose irradiation has been proposed as a potential therapeutic strategy for COVID-19 pneumonia. Consideration of external beam irradiation for management of COVID-19 pneumonia has prompted the investigation of alternative methods of irradiation with potentially improved toxicity profiles. Theoretically, targeted radiotherapy may have several advantages over conventional external beam radiotherapy owing to the capability to deliver effective radiation doses without adverse irradiation effects. Since radionuclides are conjugated to targeting vectors, such as antibodies and cell surface receptor binding peptides, irradiation may be focused on targeted cells with optimal sparing of surrounding normal tissues. In the context of COVID-19 management, targeted irradiation is expected to compromise SARS-CoV-2 extracellular virions. Targeted radiotherapy may offer a viable means of combating against SARS-CoV-2 virus. There is room for improvement with the need for efficacy, feasibility, and toxicity studies. Although targeted radiotherapy itself may not achieve absolute eradication of virus or virus-infected cells, it may at least serve as a supplementary therapeutic strategy that could be utilized in combination with other antiviral treatments. Further investigations focusing on nuclear medicine, radiopharmaceuticals, and targeted radiotherapy strategies may pave the way for the development of efficacious antiviral treatments which may be utilized in the battle against the current COVID-19 pandemic.

Comparative analysis of long-term results of external beam and combined radiotherapy in high-risk prostate cancer patients

Prostate cancer (PCa) of high risk is one of the crucial problems in urological oncology. Radiation therapy (RT), along with radical prostatectomy, is an important component of the complex treatment of patients with high‑risk PCa. To improve the long‑term oncological results of RT dose escalation is advocated. Currently, dose escalation can be reached via external beam irradiation and interstitial RT techniques. The study included 109 patients with high‑risk PCa who underwent either external beam RT up to 76 Gy, or combined RT (external beam + interstitial RT) using 125I sources with long‑term androgen deprivation therapy. Comparative analysis of long‑term results of patients with high‑risk PCa treatment showed an improvement in 5‑year disease‑free survival rates after combined RT compared with external beam RT. Acute rectal toxicity was decreased in combined RT group compared to patients after external beam RT: 13.2 % and 46.4 %, respectively (p < 0.01).

Advances in Hypofractionated Irradiation-Induced Immunosuppression of Tumor Microenvironment

Hypofractionated radiotherapy is external beam irradiation delivered at higher doses in fewer fractions than conventional standard radiotherapy, which can stimulate innate and adaptive immunity to enhance the body’s immune response against cancer. The enhancement effect of hypofractionated irradiation to immune response has been widely investigated, which is considered an approach to expand the benefit of immunotherapy. Meanwhile, increasing evidence suggests that hypofractionated irradiation may induce or enhance the suppression of immune microenvironments. However, the suppressive effects of hypofractionated irradiation on immunomicroenvironment and the molecular mechanisms involved in these conditions are largely unknown. In this context, we summarized the immune mechanisms associated with hypofractionated irradiation, highlighted the advances in its immunosuppressive effect, and further discussed the potential mechanism behind this effect. In our opinion, besides its immunogenic activity, hypofractionated irradiation also triggers homeostatic immunosuppressive mechanisms that may counterbalance antitumor effects. And this may suggest that a combination with immunotherapy could possibly improve the curative potential of hypofractionated radiotherapy.

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9–3.5) and median OS was 3.1 months (95% CI; 0.6–5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

Pathological Responses to Low-Dose Irradiation and Pepleomycin in Oral Squamous Cell Carcinoma are Predictive of Locoregional Control

Background The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence.Methods We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3-4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato.Results Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100% and 56.6% in patients with favorable and unfavorable pathological responses, respectively.Conclusions The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Pathological responses to low-dose irradiation and Pepleomycin in Oral squamous cell carcinoma are predictive of Locoregional control

Background The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence. Methods We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3–4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato. Results Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100 and 56.6% in patients with favorable and unfavorable pathological responses, respectively. Conclusions The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Pathological Responses to Low-Dose Irradiation and Pepleomycin in Oral Squamous Cell Carcinoma are Predictive of Locoregional Control

BackgroundThe prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence.MethodsWe retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3-4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato.ResultsEight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100% and 56.6% in patients with favorable and unfavorable pathological responses, respectively.ConclusionsThe present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.