Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Analysis of instability mechanisms of a high rock prism standing on a cliff face

The analysis of possible failure mechanisms of a 50-m-high rock prism is presented. The case well represents a situation typical of many rock cliffs. The reconstruction of the geometry through remote and direct surveys and the mechanical characterization through laboratory and in-situ tests allowed to build a geotechnical 3D model. Analyses were conducted with the finite difference code FLAC3D where discontinuities are reproduced by interface elements. Under different hypotheses, the severity of the state of stress was evaluated to investigate which mechanism, between the failure of the rock sustaining the prism at its base or shearing along discontinuities, is more critical. The results of the numerical analyses address a more realistic evaluation of safety margins and criteria for design of stabilization measures

Buckling of high natural slopes: The case of Lavini di Marco (Trento-Italy)

Layered limestones with marly–clayey interbeds are widespread in mountain regions. Where tectonics has not changed the original structure they frequently form homocline slopes, that since the last deglaciation have evolved through planar block slides along bedding joints. A typical dip slope showing this evolution is represented by the left flank of the Adige River valley south of Rovereto (North-Eastern Italy). Even though layers never daylight at the slope toe, the exceptional persistence and weakness of bedding joints allows buckling of layers, which occasionally collapse causing rock avalanches. Before monitoring started, deformations were believed to be no longer active, this conviction being strengthened by the high safety factors provided by limit equilibrium analyses. SAR satellite interferometry performed between 1990 and 2002 and probe inclinometer measures indicate that the slabs located uphill from the buckle folds are slowly sliding. Since some doubts have been raised about rock mass behaviour, slope geometry and hydraulic conditions assumed in the analyses, buckling was back-analysed using the Distinct Element Method (DEM) and the Discontinuous Deformation Analysis (DDA). These treat the rock mass as a discontinuum and account for deformation and failure of the rock material. To perform numerical analyses, rock mass structure, strength and stiffness were determined through extensive in situ and laboratory investigations. For this purpose field surveys, borehole core logging and geophysical surveys were performed and laboratory geotechnical tests on the rock material, clayey interbeds and bedding joints were conducted. Discontinuous analyses confirmed that buckling deformations are definitely possible if some conditions are present (high water pressure, minor flexures). Modelling also indicate that buckling deformations may evolve into failures and should therefore be taken into account in evaluating long term stability of the slope

Buckling of high natural slopes: The case of Lavini di Marco (Trento-Italy)

Layered limestones with marly–clayey interbeds are widespread in mountain regions. Where tectonics has not changed the original structure they frequently form homocline slopes, that since the last deglaciation have evolved through planar block slides along bedding joints. A typical dip slope showing this evolution is represented by the left flank of the Adige River valley south of Rovereto (North-Eastern Italy). Even though layers never daylight at the slope toe, the exceptional persistence and weakness of bedding joints allows buckling of layers, which occasionally collapse causing rock avalanches. Before monitoring started, deformations were believed to be no longer active, this conviction being strengthened by the high safety factors provided by limit equilibrium analyses. SAR satellite interferometry performed between 1990 and 2002 and probe inclinometer measures indicate that the slabs located uphill from the buckle folds are slowly sliding. Since some doubts have been raised about rock mass behaviour, slope geometry and hydraulic conditions assumed in the analyses, buckling was back-analysed using the Distinct Element Method (DEM) and the Discontinuous Deformation Analysis (DDA). These treat the rock mass as a discontinuum and account for deformation and failure of the rock material. To perform numerical analyses, rock mass structure, strength and stiffness were determined through extensive in situ and laboratory investigations. For this purpose field surveys, borehole core logging and geophysical surveys were performed and laboratory geotechnical tests on the rock material, clayey interbeds and bedding joints were conducted. Discontinuous analyses confirmed that buckling deformations are definitely possible if some conditions are present (high water pressure, minor flexures). Modelling also indicate that buckling deformations may evolve into failures and should therefore be taken into account in evaluating long term stability of the slope

Reversible Tumor Progression Induced by a Dexamethasone Course for Severe COVID-19 during Immune Checkpoint Inhibitor Treatment

International audienceImmunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients

Inclusion of patients with chronic kidney disease in randomized phase 3 clinical trials in patients with prostate, breast, lung, and colorectal cancer

International audienceThe objective of this study was to determine the proportion of phase 3 clinical trials investigating a systemic therapy for patients with prostate, breast, lung, or colorectal cancer that excluded patients with Chronic Kidney Disease (CKD) and the exclusion criteria chosen, if any. A search was conducted using the ClinicalTrials.gov database to identify eligible studies. Of the 268 included trials, 185 (69%) had at least one renal exclusion criteria. Of these 185 trials, 116 (63%) had an undefined exclusion criterion. Only disease site was associated with exclusion of patients with CKD in the univariate analysis, but no factors in the multivariate analysis. There are several potential barriers to including patients with CKD in clinical trials. Nevertheless, solutions can be proposed to allow the inclusion of these patients. This would allow them to access to innovative therapeutic strategies, but also allow a better applicability of trial results to this patient population

Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets

Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets

Cytochrome P-450-mediated herb and food–drug interactions can be identified in cancer patients through patient self-reporting with a tablet application: results of a prospective observational study

International audienceBackground: Consumption of herbs, food used as medicine and dietary supplements (HFDSs) is common in cancer patients. Herbs and food-drug interactions (HFDIs) can lead to serious adverse effects and can be prevented. We previously reviewed cytochrome P-450 (CYP)-mediated HFDI for 261 HFDSs and we classified the risk of CYP inhibition and induction on a level of evidence scale from 1 (high evidence, supported by several clinical studies) to 5 (low evidence, only limited preclinical data). Patients and methods: We conducted a prospective, non-interventional study (NCT04128865) to assess whether self-assessment of patients could detect HFDI classified as ‘probable’ (i.e. level 1, 2 or 3 of the scale) in a population of cancer patients. Patients were invited through a tablet application to report their consumption of herbs, regular CYP-interacting food consumption and dietary supplements, as well as some clinical data and cancer treatments. The patient's completion of the survey could be supervised by a health care professional or not. A prespecified threshold of 5% of HFDIs classified as ‘probable’ detected with the application was deemed relevant. Results: Between 29 March 2018 and 22 June 2018, 143 patients completed the survey. Ninety-five patients (66%) reported at least one current systemic cancer treatment and were included in the analyses. Seventy-four patients reported an intake of at least one HFDS (77.9%), while 21 patients reported no HFDS (22.1%). Twenty-two HFDIs classified as ‘probable’ were found in 16 patients (16.8%) with the application, which was significantly superior to the prespecified threshold (P = 0.02). The interactions were reported with food (n = 19, 86%) more frequently than with herbs (n = 3, 14%) or with dietary supplements (no interaction reported). Conclusions: Self-assessment of HFDS interaction with cancer treatment with an application is feasible and should be considered in daily routine. Prospective interventional studies should be conducted to better assess the clinical benefits of this approach

Prognostic Impact of Stromal Immune Infiltration before and after Neoadjuvant Chemotherapy (NAC) in Triple Negative Inflammatory Breast Cancers (TNIBC) Treated with Dose-Dense Dose-Intense NAC

International audienceInflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13-3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07-3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36-3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05-3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment