Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas.

Post-radiation sarcomas are rare secondary cancers arising from radiation therapies. To date, few genetic specificities have been described for such malignancies and the oncogenesis of sarcomas with complex genetics (both sporadic and post-radiation) remains largely misunderstood. We performed genomic and transcriptomic analyses on 77 post-radiation sarcomas using DNA-array and RNA sequencing. Consequently, we were able to investigate changes in copy number variations, transcriptome profiling, fusion gene expression, and mutational landscapes. We compare these data to a reference cohort of 93 sporadic sarcomas. At genomic level, similar chromosomal complexity was observed both in post-radiation and sporadic sarcomas with complex genetics. We found more frequent CDKN2A and CDKN2B (coding for p14/p16 and p15 proteins, respectively; at 9p21.3) losses in post-radiation (71%) than in sporadic tumors (39%; P = 6.92e-3). Among all detected fusion genes and punctual variations, few specificities were observed between these groups and such alterations are not able to drive a strong and specific oncogenesis. Recurrent MYC amplifications (96%) and KDR variants (8%) were detected in post-radiation angiosarcomas, in agreement with the literature. Transcriptomic analysis of such angiosarcomas revealed two distinct groups harboring different genomic imbalances (in particular gains of 17q24.2-17qter) with different clinical courses according to patient's vital status. Differential gene expression analysis permitted to focus on the immune response as a potential actor to tumor aggressiveness. Histochemistry validated a lower inflammation and lower immune infiltrate at tumor periphery for highly aggressive angiosarcomas. Our results provide new genomic and transcriptomic information about post-radiation sarcomas. The techniques we used (RNA-seq and DNA-arrays) did not highlight major differences in sarcomas with complex genetics depending on the radiation context, revealing similar patterns of transcriptomic profiles and chromosomal copy number variations. Additional characterizations, particularly whole genome sequencing, could measure changes in DNA following radiation therapy in such malignancies and may precise their oncogenesis.

Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard of care (SoC) in locally advanced (LA) head and neck squamous cell carcinomas (HNSCC). This trial was designed to test whether dose-escalated IMRT and cisplatin could improve locoregional control without increasing complications over 3D-radiotherapy. METHODS: Patients were randomized between 70 Gy/35F in 7 weeks with 3D-RT (Arm A) versus 75 Gy/35F with IMRT (Arm B). Both arms received 50 Gy in 25 fractions followed by a sequential boost of 20 Gy/10F in Arm A and 25 Gy/10F to gross tumor volume in Arm B, as well as 3 cycles of cisplatin at 100 mg/m2 during RT. The primary endpoint was locoregional progression (LRP). RESULTS: 188 patients were randomized: 85% oropharynx and 73% stage IVa. P16 status was documented for 137 oropharyngeal tumors with P16+ in 53 (39%) patients; and 90% were smokers. Median follow-up was 60.5 months. Xerostomia was markedly decreased in arm B (p < 0.0001). The 1-year grade ≥2 xerostomia (RTOG criteria) was 63% vs 23% and 3-year 45% vs 11% in arms A and B, respectively. Xerostomia LENT-SOMA scale was also reduced in arm B. Dose-escalated IMRT did not reduce LRP with an adjusted HR of 1.13 [95%CI = 0.64-1.98] (p = 0.68). Survival was not different (adjusted HR: 1.19 [95%CI = 0.78-1.81], p = 0.42). No interaction between p16 and treatment effect was found. CONCLUSION: Dose-escalated IMRT did not improve LRC in LA-HNSCC patients treated with concomitant CRT over standard 3D-RT. This trial reinforces the evidence showing IMRT reduces xerostomia in LA-HNSCC treated with radiotherapy. Clinicaltrial.gov: NCT00158678.

Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.

BACKGROUND: To evaluate the MRI features of a tumor response, local control, and predictive factors of local control after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). METHODS: Thirty-five consecutive patients with 48 HCCs who were treated by SBRT were included in this retrospective study. All patients provided written informed consent to be treated by SBRT, and prior to inclusion they authorized use of the treatment data for further studies. The assessment was made using MRI, with determination of local and hepatic responses according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria during a two-year follow-up. RESULTS: The local response rate according to mRECIST was higher than with RECIST. A tumor diameter less than 20 mm at baseline was an independent predictive factor for RECIST and mRECIST responses, as was diffusion-weighted signal for RECIST. During follow-up, a tumor diameter of <20 mm (p = 0.034) and absence of a high intensity on T2-weighted (p = 0.006) and diffusion-weighted images (p = 0.039) were associated with a better response according to RECIST. Post-treatment changes include peritumoral ring-like enhanced changes with high intensity on T2-weighted images. CONCLUSIONS: SBRT is a promising technique for the treatment of inoperable HCC. Post-treatment changes on MRI images can resemble tumor progression and as such must be adequately distinguished. The regression of tumorous enhancement is variable over time, although diffusion-weighted and T2-weighted intensities are predictive factors for tumor RECIST responses on subsequent MRIs. They hence provide a way to reliably predict treatment responses.

Effect of bladder distension on doses to organs at risk in Pulsed-Dose-Rate 3D image-guided adaptive brachytherapy for locally advanced cervical cancer.

PURPOSE: To evaluate the impact of bladder distension on doses to organs at risk in patients treated with 3D image-guided adaptive pulsed-dose-rate (PDR) brachytherapy (BT) for locally advanced cervical cancer. METHODS AND MATERIALS: Twenty-two patients who had previously been treated by external beam radiation therapy (EBRT), underwent BT treatment planning to a pelvic MRI (or a CT scan in case of contraindication) after their bladder was filled with 100 cc of physiological saline (full bladder). This was immediately followed by a CT scan after emptying of the bladder. A fusion of these two examinations was conducted, and the dosimetry was duplicated for the study with an empty bladder. Equieffective doses of 2 Gy per fraction from EBRT and BT of bladder/rectum/sigmoid colon/small bowel were compared. RESULTS: A full bladder condition was found to be non-inferior in terms of the bladder D2cc (a difference of -0.9 Gy; 97.5% CI [-∞; 2.6]), and it resulted in a reduction in the bladder D0.1cc (p = 0.038). Bladder expansion resulted in a significant reduction of maximum doses received by the small bowel, both in terms of the D0.1cc (51.2 Gy vs. 63.4 Gy, p < 0.001) and the D2cc (48.5 Gy vs. 53.6 Gy, p < 0.001). A negative correlation was seen between the difference in the small bowel D2cc and the body mass index; (r = -0.55; p = 0.008). No differences were noted in regard to doses to the rectum and sigmoid colon. CONCLUSIONS: Bladder distension with 100 cc of physiological saline can reduce maximum doses received by the small bowel without the alteration of the doses received by the other organs at risk during a 3D image-guided adaptive PDR BT for locally advanced cervical cancer. However, the maintenance of a predefined bladder volume is difficult to achieve with PDR BT, whereas it could be easily managed before each session in case of high-dose-rate BT.

Comparison of the histopathological results of the radioguided percutaneous microbiopsies and the operative specimens of soft tissue tumors of limbs, trunk and retroperitoneum.

INTRODUCTION: Suspicious lesions of sarcoma require preoperative biopsies. If surgical biopsies remain the gold standard, radioguided percutaneous microbiopsies are gaining an increasing importance. The purpose of this study was to compare histopathological results of percutaneous biopsies of soft tissues, trunk and retroperitoneal tumors with the histopathological results of operative specimens. METHODS: This is a retrospective study including 84 patients treated in our institution. The concordance between the results of the microbiopsy and the operative specimen for the benign-malignant differentiation and the histological type was evaluated. The microbiopsy accuracy was calculated. The sensitivity and the specificity of the microbiopsies compared to the operative specimen were also evaluated for the benign-malignant differentiation. RESULTS: The concordance was 0.92 [0.79-1] for the benign-malignant differentiation, 0.97 [0.92-1] for the histological type. The accuracy of microbiopsies was therefore 96% (sensibility=97.0%; specificity=94.1%) for the benign-malignant detection and 97.8% for the histological type. CONCLUSION: Percutaneous microbiopsies play an important part in the diagnosis of soft tissue tumors of the limbs, trunk and retroperitoneum, in particular as a replacement to more invasive surgical biopsies. This study evidences the increasing importance of the collaboration between radiologist, surgeon and pathologist in the diagnosis of sarcoma.