Immunogenicity of radiotherapy on bone metastases from prostate adenocarcinoma: What is the future for the combination with radiotherapy/immunotherapy?

Bone metastatic prostate cancers (PCa) are resistant to usual immunotherapies such as checkpoint inhibitors. The main hypothesis related to this immunoresistance is the lack of antigens to stimulate anti-tumor immunity. External radiation is a potential inducer antigens presentation and thus to immunotherapy proprieties. The aim of this review is to describe the tumor microenvironment specificities, especially in bone metastasis and the immune modifications after radiation therapy on a metastatic castration-resistant PCa population. PCa microenvironment is immunosuppressive because of many tumor factors. The complex interplay between PCa cells and bone microenvironment leads to a 'vicious circle' promoting bone metastasis. Furthermore, the immune and bone systems, are connected through an osteoclastogenic cytokine: the Receptor Activator Nuclear Factor Kappa B ligand. Adapted doses of ionizing radiation play a dual role on the tumor. Indeed, radiotherapy leads to immunogenicity by inducing damage associated with molecular patterns. However, it also induces an immunosuppressive effect by increasing the number of immunosuppressive cells. Interestingly, the abscopal effect could be used to optimize immunotherapy potential, especially on bone metastasis. Radiotherapy and immunotherapy combination is a promising strategy, however further studies are necessary to determine the more efficient types of radiation and to control the abscopal effect.

PSA outcomes and late toxicity of single-fraction HDR brachytherapy and LDR brachytherapy as monotherapy in localized prostate cancer: A phase 2 randomized pilot study.

PURPOSE: To evaluate the PSA outcomes and the late patient's reported health related quality of life (HRQOL) and toxicity after single-fraction High-Dose-Rate brachytherapy (HDRB) and Low-Dose-Rate brachytherapy (LDRB) for prostate cancer. METHODS: Men with low and favorable intermediate-risk prostate cancer across 3 centres were randomized between monotherapy brachytherapy with either Iodine-125 LDRB or 19 Gy single-fraction HDRB. Biochemical outcomes were evaluated using the Phoenix definition, PSA nadir and absolute PSA value <0.4 ng/mL. Toxicities and HRQOL were recorded at 24 and 36 months. RESULTS: A total of 31 patients were randomized, 15 in the LDRB arm and 16 patients in the HDRB arm. After a median follow-up of 45(36-53) months, 3 patients in the HDRB arm experienced biochemical failure (p = 0.092). Nineteen Gy single-fraction HDRB was associated with significantly higher PSA nadir compared to LDRB (1.02 ± 0.66vs 0.25 ± 0.39, p < 0.0001). Moreover, a significantly larger proportion of patients in the LDRB group had a PSA <0.4 ng/mL (13/15 vs 2/16, p < 0.0001). For late Genito-Urinary, Gastro-Intestinal, and sexual toxicities at 24 and 36 months, no significant differences were found between the 2 arms. As for HRQOL, the IPSS and EPIC-26 urinary irritative score were significantly better for patients treated with HDRB over the first 36 months post-treatment (p = 0.001 and p = 0.01, respectively), reflecting superior HRQOL. CONCLUSION: HDRB resulted in superior HRQOL in the irritative urinary domain compared to LDRB. PSA nadir was significantly lower in the LDRB group and a higher proportion of patients in the LDRB group reached PSA <0.4 ng/mL.

Pretreatment with glucose-insulin-potassium improves ventricular performances after coronary artery bypass surgery: a randomized controlled trial.

Heart failure is the main cause of poor outcome following open heart surgery and experimental studies have demonstrated that glucose-insulin-potassium (GIK) infusion exerts cardioprotective effects by reducing myocardial ischemia-reperfusion injuries. This randomized controlled trial was designed to assess the effects of GIK on left ventricular function in moderate-to-high risk patients undergoing on-pump isolated coronary artery bypass surgery (CABGS), or combined with aortic valve replacement. The primary outcomes were the effects of GIK on two- and three-dimensional left ventricular ejection fraction (2D and 3D-LVEF), and on transmitral flow propagation velocity (Vp), that occurred between the pre- and post-CPB periods. GIK administration was associated with favorable interaction effects (p < 0.001) on 2D-LVEF, 3D-LVEF and Vp changes over the study periods. In GIK pretreated patients (N = 54), 2-D and 3D-LVEF and Vp increased slightly during surgery (mean difference [MD] + 3.5%, 95% confidence interval [95% CI] - 0.2 to 7.1%, MD + 4.0%, 95% CI 0.6-7.4%, and MD + 22.2%, 95% CI 16.0-28.4%, respectively). In contrast, in the Placebo group (N = 46), 2D-and 3D-LVEF, as well as Vp all decreased after CPB (MD - 7.5% [- 11.6 to - 3.4%], MD - 12.0% [- 15.2 to - 8.8%] and MD - 21.3% [- 25.7 to - 16.9%], respectively). In conclusion, the administration of GIK resulted in better preservation of systolic and diastolic ventricular function in the early period following weaning from CPB.

Hypofractionated Stereotactic Radiotherapy as a Salvage Therapy for Recurrent High-Grade Gliomas: Single-Center Experience.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the survival outcomes and safety of hypofractioned stereotactic radiotherapy as a salvage treatment for recurrent high-grade glioma. PATIENTS AND METHODS: Between March 2012 and March 2017, 32 consecutive patients (12 women, 20 men) treated in a single center were retrospectively included in this study. Grade III gliomas were diagnosed in 14 patients and grade IV in 18 patients. Thirty-four lesions were treated with hypofractionated stereotactic radiotherapy on a linear accelerator. Hypofractionated stereotactic radiotherapy delivered a median dose of 30 Gy (27-30) in 6 fractions (3-6) of 5 Gy (5-9). The treatment plans were normalized to 100% at the isocenter and prescribed to the 80% isodose line. Clinical outcomes and prognostic factors were analyzed. RESULTS: Median follow-up was 20.9 months. Median overall survival following hypofractionated stereotactic radiotherapy was 15.6 months (median overall survival for patients with glioblastoma and grade III glioma was 8.2 and 19.5 months, respectively; P = .0496) and progression-free survival was 3.7 months (median progression-free survival for patients with glioblastoma and grade III glioma was 3.6 and 4.5 months, respectively; P = .2424). In multivariate analysis, tumor grade III ( P = .0027), an Eastern Cooperative Oncology Group status <2 at the time of reirradiation ( P = .0023), and a mean dose >35 Gy ( P = .0055) significantly improved overall survival. A maximum reirradiation dose above 38 Gy ( P = .0179) was significantly associated with longer progression-free survival. CONCLUSION: Hypofractionated stereotactic radiotherapy is well tolerated and offers an effective salvage option for the treatment of recurrent high-grade gliomas with encouraging overall survival. Our results suggest that the dose distribution had an impact on survival.

Patient and procedural features predicting early and mid-term outcome after radical surgery for non-small cell lung cancer.

BACKGROUND: Postoperative cardiovascular and pulmonary complications (PCVCs and PPCs) are frequent and result in prolonged hospital stay. The aim of this study was to update the risk factors associated with major complications and survival after lung cancer surgery. METHODS: This is a post-hoc analysis of a randomized controlled trial that was designed to assess the benefits of preoperative physical training. After enrollment, clinical, biological and functional data as well as intraoperative details were collected. In-hospital PCVCs and PPCs were recorded and survival data were adjudicated up to 4 years after surgery. RESULTS: Data from 151 patients were analyzed. Thirty-day mortality rate was 2.6% and the incidence of PCVCs and PPCs was 15% and 33%, respectively. Stepwise logistic regression analysis showed that, PCVCs were mainly related to elevated plasma levels of brain natriuretic peptides [odds ratios (ORs) =6.0; 95% confidence interval (CI), 1.3-27.3] and performance of a pneumonectomy (OR =9.6; 95% CI, 2.9-31.5) whereas PPCs were associated with the presence of COPD (OR =5.9; 95% CI, 2.4-14.8), current smoking (OR =2.6; 95% CI, 1.1-6.5) and the need for blood transfusion (OR =5.2; 95% CI, 1.2-23.3). Preoperative physical training was a protective factor regarding PPCs (OR =0.13; 95% CI, 0.05-0.34). Cox proportional hazards regression analysis showed that ventilatory inefficiency during exercise (expressed by a ratio >40 of ventilation to carbon dioxide elimination), coronary artery disease, elevated plasma levels of brain natriuretic peptides and the occurrence of PPCs were all predictive of poor survival after surgery. CONCLUSIONS: Besides smoking and the extent of lung resection, preexisting cardiopulmonary disease as evidence by elevated levels of brain natriuretic peptides and inefficient ventilation are associated with poor clinical outcome after lung cancer surgery.