Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Evaluation of the early adverse effects of radiotherapy in breast cancer patients with COVID-19: Prospective single institutional study

The COVID-19 caused by the SARS-CoV-2 coronavirus is at the origin of a global pandemic. This pandemic has prompted the current health system to reorganize and rethink the care offered by health establishments. We report the early toxicity in patients infected with COVID-19 treated at the same time for early-stage breast cancer (BC). This is a monocentric prospective study of patients treated in our hospital between March 2020 and June 2020 and were diagnosed with COVID-19 infection. The inclusion criteria were to be irradiated for early-stage BC and to have a positive COVID-19 diagnosis on a PCR test and/or a lung computed tomography (CT) scan and/or suggestive clinical symptoms. Radiotherapy (RT) consisted of breast or chest wall irradiation with or without lymph node irradiation, with protocols adapted to pandemic situation. The treatment-related toxicity was graded according to the CTCAE (version 4.03). All 350 patients treated for early-stage BC were studied. Of them, 16 were presented with clinical symptoms of COVID-19 infection and of them, 12 had clinical, CT scan, and PCR confirmation. This entire cohort of 12 pts with median age of 56 (42–72) underwent their RT. During the radiotherapy, there were 9 pts presented radiation dermatitis, 8 (66%) were grade 1 and one was (8%) grade 2. Two patients with lymph nodes irradiation presented esophagitis grade 2. This prospective COVID-19 cohort, treated for early-stage BC demonstrated an acceptable toxicity profile with few low-grade adverse events. Longer follow-up is needed to confirm these findings.     

Reproducibility and diagnostic value of a new method using ratios to diagnose anterior atlanto-axial subluxation on plain radiographs

ObjectivesMeasures on conventional radiography are used to detect, especially in rheumatoid arthritis, upper cervical spine instabilities (CSIs) with the anterior and posterior atlanto-dental intervals (AADI and PADI) measurements. Our objective was to evaluate the diagnostic performance and reliability of AADIs and PADIs extrapolated based on ratios in assessing anterior atlanto-axial subluxation (aAAS) when plain radiographs do not allow the measures.MethodsRadiographies of 119 patients were randomly selected. Two blinded observers performed two measurements of the odontoid sagittal diameter (O), axis body base sagittal diameter (C2), AADI, PADI, Clark station and Ranawat index, and the AADI/O, AADI/C2, PADI/O and PADI/C2 ratios were calculated. The diagnostic value of AADI and PADI extrapolated from the AADI/O, AADI/C2, PADI/O and PADI/C2 ratios was evaluated using ROC curves, with AADI > 2.9 mm used as the gold standard.ResultsAmong the 119 patients, 12 patients had aAAS (AADI > 2.9 mm), 6 of them had severe aAAS (AADI > 8.9 mm and/or a PADI < 14 mm), and 6 patients had vertical AAS (Clarks station = 2 or 3 and/or Ranawat index < 13 mm). The AADI extrapolated from the AADI/O and AADI/C2 ratios has excellent intra- and inter-observer reproducibility. The diagnostic value of the extrapolated AADI was high for aAAS (sensitivity 92%; specificity of 100%) and severe aAAS (sensitivity75%; specificity 100%). The diagnostic value of the extrapolated PADI was good but lower than the diagnostic value of the extrapolated AADI.ConclusionExtrapolated AADI can be used instead AADI to detect aAAS and severe aAAS.     

Is romantic partner betrayal a form of traumatic experience? A qualitative study

According to a growing body of research, betrayal by a romantic partner is increasingly considered as a form of interpersonal trauma. Between 30% and 60% of betrayed individuals experience symptoms of post-traumatic stress disorder (PTSD), depression and anxiety to clinically meaningful levels. From a clinical perspective, this constellation of symptoms can be conceptualized as a stressor-related adjustment disorder. Yet, no qualitative research has examined the association between romantic betrayal and traumatic stress from the perspective of betrayed individuals. Face-to-face semi-structured interviews were conducted with 13 participants who had completed a clinical trial for a new treatment for adjustment disorder stemming from betrayal. Data were analysed using thematic content analysis. Although betrayal was experienced as a shocking and destabilizing event, and participants used trauma or ‘feeling traumatized’ as a metaphor to describe their experience, few had constructed their reaction as traumatic stress. In fact, participants reported experiencing difficulties understanding the intensity of their experience. However, when exposed to external sources (e.g., books and interviews by psychologists and researchers) that used a trauma and PTSD framework to explain the effects of betrayal, participants reported feeling clarity, validation and relief. Findings are discussed in the light of theoretical and clinical implications.     

Amoeboid Microglial Cells and not Astrocytes Synthesize TNF-alpha in Swiss Mouse Brain Cell Cultures

The role of tumour necrosis factor (TNF-alpha) in brain physiology and pathology has been the focus of several studies. However, the source of this lymphokine in the central nervous system and the regulation of its synthesis is still poorly understood. We have therefore used purified astrocytes and brain macrophages in culture to compare the abilities of these two cell types to synthesize TNF-alpha and its mRNA. We find that, in the Swiss mouse, no significant TNF activity or TNF-alpha mRNA are produced by astrocytes, even following activation with lipopolysaccharides (LPS). On the other hand, purified microglial cells express a cytotoxic activity able to kill TNF-sensitive LM cells. Part of this activity is released into the culture medium and part remains bound to the membrane after mild paraformaldehyde treatment, demonstrating the existence in the culture of the soluble and membrane-bound forms of TNF activity. The fact that amoeboid microglial cells, and not astrocytes, are the actual source of TNF in brain cultures was further demonstrated by Northern blot analysis and in situ hybridization using a TNF-alpha specific oligonucleotide probe. The definition of the cell type which, in the CNS, is responsible for TNF synthesis will allow the regulation of this lymphokine to be analysed and opens the way for a better understanding of the interactions between amoeboid microglial cells and the other cell types which make up the nervous system.