Markerless liver online adaptive stereotactic radiotherapy: feasibility analysisCervantes.

Objective. Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in thisin-silicostudy the feasibility of cone-beam computed tomography-guided stereotactic online-adaptive radiotherapy (CBCT-STAR) to propagate the target volumes without implanting radio-opaque markers and assess its consequence on the margin that should be used in that context.Approach. An emulator of a CBCT-STAR-dedicated treatment planning system was used to generate plans for 32 liver SABR patients. Three target volume propagation strategies were compared, analysing the volume difference between the GTVPropagatedand the GTVConventional, the vector lengths between their centres of mass (lCoM), and the 95th percentile of the Hausdorff distance between these two volumes (HD95). These propagation strategies were: (1) structure-guided deformable registration with deformable GTV propagation; (2) rigid registration with rigid GTV propagation; and (3) image-guided deformable registration with rigid GTV propagation. Adaptive margin calculation integrated propagation errors, while interfraction position errors were removed. Scheduled plans (PlanNon-adaptive) and daily-adapted plans (PlanAdaptive) were compared for each treatment fraction.Main results.The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding tolCoM(mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTVPropagatedand GTVConventional. This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (PlanAdaptive) reduced the violation rate of the most important dose constraints ('priority 1 constraints', 4.2 versus 0.9%, respectively;p< 0.001) and even improved target volume coverage compared to non-adaptive plans (PlanNon-adaptive).Significance. Markerless CBCT-STAR for liver tumours is feasible using Image-guided deformable registration with rigid GTV propagation. Despite the cost in terms of PTV volumes, daily adaptation reduces constraints violation and restores target volumes coverage.

Cone-beam computed tomography-guided online-adaptive radiotherapy for inoperable right colon cancer: First in human.

We report the case of a medically inoperable patient with localised colon cancer. Due to symptomatic bleeding, definitive radiotherapy (5 daily fractions of 5 Gy) has been performed using cone-beam computed tomography-based online-adaptive radiotherapy (ART). Online-ART enables compensation of interfraction motion of abdominal organs by performing daily delineation of organs at risk (OARs) and target volumes. Daily treatment replanning maximised target volume coverage while lowering the dose to OARs. Intrafraction variation of the tumour was still significant and had to be incorporated in the planning target volume margin computation. After the treatment, the patient did not develop any acute radiotherapy-induced adverse events and had no further rectal bleeding either at the end of the radiotherapy or at oncological follow-up 4 months later. Online-ART for colon cancer is feasible and is a valuable alternative when surgery is not an option.

Regression of a melanoma brain metastasis that had appeared after immune checkpoint inhibitor discontinuation: a hypothesis-generating case.

We present the case of a 50-year-old woman previously treated with nivolumab-ipilimumab combination therapy for a metastatic melanoma. Despite premature discontinuation of these immune checkpoint inhibitors (ICIs) after 2 cycles due to severe immune-related hepatitis, the patient achieved a complete response. Nine months later, brain magnetic resonance imaging (MRI) showed progression of a single cerebral lesion, and the patient was referred for stereotactic radiosurgery. Unexpectedly, the brain MRI acquired one month later as part of radiosurgery planning showed a spontaneous regression of this lesion, allowing for radiosurgery cancellation. Follow-up imaging showed a sustained response, although the patient did not receive any other oncological treatment. We discuss here the potential immune mechanisms involved in this unusual course and the importance of better understanding the behaviour of tumours in the era of ICIs.

Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting.

With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.

Global management of brain metastasis from renal cell carcinoma.

During the last decade, major improvements have been made in the treatment of renal cell carcinoma (RCC) with the development and use of multiple tyrosine kinase inhibitors and immune checkpoint inhibitors. Brain metastases in RCC patients (BM-RCC) is associated with poor outcome and their management represents a challenge for clinicians. In most of case, brain metastases in this context require local intervention such as radiotherapy, stereotactic radiotherapy/stereotactic radiosurgery and whole brain radiation therapy. Despite efficacy in extracranial metastases, systemic therapies have modest antitumoral effect on cerebral lesions. In this review, we highlight the benefits and pitfalls of the available therapies in BM-RCC.

Future Strategies Involving Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma.

OPINION STATEMENT: Immune checkpoint inhibitors have importantly improved the outcome of patients with urothelial carcinoma. Different immune checkpoint inhibitors are currently approved and used in first- and second-line setting. The multiple agents currently approved in these setting make the choice sometimes difficult for clinicians. Furthermore, only a minority of patients present drastic response and long-term benefit with current immunotherapy. In this review, we describe the current use of immunotherapy in urothelial carcinoma but we also highlight the new strategies of treatment involving immune checkpoint inhibitors; we describe the place of immunotherapy with chemotherapy, targeted agents, and anti-angiogenic agents, incorporating the recent results presented at ASCO 2020. This review explores also the different action mechanisms of immune checkpoint inhibitors and the molecular rational to evaluate these agents in other strategies, such as maintenance and salvage strategies. The new advances in biomarker development are also presented.

c-MET as a Potential Resistance Mechanism to Everolimus in Breast Cancer: From a Case Report to Patient Cohort Analysis.

BACKGROUND: We describe in a patient with breast cancer the change in c-MET expression during everolimus treatment, opening a better understanding of the resistance to everolimus and a role for cabozantinib. OBJECTIVE: The objective of this study was to evaluate c-MET as a potential predictive biomarker for everolimus efficacy in breast cancer. METHODS: We first selected a patient with breast cancer with a long-lasting response to everolimus and retrospectively profiled biopsies that were taken before everolimus initiation (Biopsy 1) and at progression on everolimus (Biopsy 2) using amplicon sequencing and immunohistochemistry. We then retrospectively evaluated c-MET expression in a cohort of patients with breast cancer treated with everolimus. RESULTS: While not expressed in Biopsy 1, c-MET was highly expressed in Biopsy 2, suggesting a role for c-MET in breast cancer progression. Cabozantinib resulted in a rapid radiological response in this patient. Twenty-nine patients were included (12 c-MET-positive and 17 c-MET-negative patients) in the second part of the study. Baseline c-MET expression was associated with higher tumor grade, higher frequency of visceral metastases, and lower endocrine sensitivity. The c-MET-positive patients presented with a shorter progression-free survival (6.1 vs 10.5 months, respectively; p = 0.002) and a lower response rate (0% vs 12%) to everolimus, compared with c-MET-negative patients. CONCLUSIONS: c-MET could play a role in the resistance to everolimus and its inhibition should be evaluated in breast cancer.

Isolated adrenocorticotropic hormone (ACTH) deficiency and Guillain-Barré syndrome occurring in a patient treated with nivolumab.

The increased use of immune checkpoint inhibitors (ICIs) has led to the observation of a variety of immune-related adverse events (irAEs). These irAEs occur usually within the first months after ICIs onset and can involve theorically all organs. We describe two rare irAEs occurring in a 70-year-old caucasian man who was treated with nivolumab for an advanced urothelial cancer of the left kidney. He developed an isolated adrenocorticotropic hormone deficiency that was diagnosed at week 19 and a neurological complication that appeared at week 79 and initially confounded with a lumbar spinal stenosis. Diagnosis of Guillain-Barré syndrome was finally confirmed with the complete resolution of symptoms after 5 days of intravenous immunoglobulin and corticosteroids. We highlight the importance of quickly recognising these potential life-threatening irAEs such as cortisol insufficiency and neurologic adverse events whose initially presentation could be non-specific.

Comparative Cohort Study of Percutaneous Pedicle Screw Implantation without Versus with Navigation in Patients Undergoing Surgery for Degenerative Lumbar Disc Disease.

BACKGROUND: The major limitation of computer-based three-dimensional fluoroscopy is increased radiation exposure of patients and operating room staff. Combining spine navigation with intraoperative three-dimensional fluoroscopy (io3DF) can likely overcome this shortcoming, while increasing pedicle screw accuracy rate. We compared data from a cohort of patients undergoing lumbar percutaneous pedicle screw placement using io3DF alone or in combination with spine navigation. METHODS: This study consisted of 168 patients who underwent percutaneous pedicle screw implantation between 2009 and 2016. The primary endpoint was to compare pedicle screw accuracy between the 2 groups. Secondary endpoints were to compare radiation exposure of patients and operating room staff, duration of surgery, and postoperative complications. RESULTS: In group 1, 438 screws were placed without navigation guidance; in group 2, 276 screws were placed with spine navigation. Mean patient age in both groups was 58.6 ± 14.1 years. The final pedicle accuracy rate was 97.9% in group 1 and 99.6% in group 2. Average radiation dose per patient was significantly larger in group 1 (571.9 mGym2) than in group 2 (365.6 mGym2) (P = 0.000088). Surgery duration and complication rate were not significantly different between the 2 groups (P > 0.05). CONCLUSIONS: io3DF with spine navigation minimized radiation exposure of patients and operating room staff and provided an excellent percutaneous pedicle screw accuracy rate with no permanent complications compared with io3DF alone. This setup is recommended, especially for patients with a complex degenerative spine condition.

An Unusual Case of Ureteral Perforation in Minimally Invasive Pedicle Screw Instrumentation: Case Report and Review of the Literature.

BACKGROUND: Injury of the ureter is a potentially devastating complication most often reported in gynecologic, colorectal, or vascular pelvic surgery or endoscopic procedures for ureteric diseases. We report a rare case of ureteral rupture occurring as a complication of percutaneous pedicle screw placement. CASE DESCRIPTION: A 60-year-old man reported unbearable abdominal pain on the day after right L4-L5 transforaminal intervertebral fusion and percutaneous pedicle screw placement. A computer tomography workup showed contrast media extravasation outside the excretory system consistent with a left ureteral traumatic perforation. The patient underwent left nephrostomy and a double-J stent insertion and subsequently fully recovered. The ureter completely healed, enabling stent removal 5 months later. METHODS: PubMed and EMBASE were screened for ureteral injury caused by posterior lumbar surgery. RESULTS: We found 27 other reports with only 1 other case after minimally invasive transforaminal lumbar interbody. CONCLUSIONS: Complications of minimally invasive pedicle screw placement are often described as dural tear of neurologic impairment. This report shows that unexpected side effects are still possible and spine surgeons should be aware especially when performing minimally invasive procedures, in which, by definition, pedicles are concealed from direct visualization.