Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

Computed Tomography Texture Analysis for Predicting Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors.

BACKGROUND: The treatment responses of immune checkpoint inhibitors in metastatic renal cell carcinoma (mRCC) vary, requiring reliable prognostic biomarkers. We assessed the prognostic ability of computed tomography (CT) texture analysis in patients with mRCC treated with programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. MATERIALS AND METHODS: Sixty-eight patients with mRCC treated with PD-1/PD-L1 inhibitors between 2012 and 2019 were revaluated. Using baseline and first follow-up CT, baseline and follow-up texture models were developed to predict overall survival (OS) and progression-free survival (PFS) using least absolute shrinkage and selection operator Cox-proportional hazards analysis. Patients were divided into high-risk or low-risk group, and the survival difference was assessed using Kaplan-Meier and log-rank test. Multivariable Cox models were constructed by including only the clinical variables (clinical models) and by combining the clinical variables and the texture models (combined clinical-texture models), and their predictive performance was evaluated using Harrell's C-index. RESULTS: The baseline texture models distinguished longer- and shorter-term survivors for both OS (median, 60.1 vs. 17.0 months; P = .048) and PFS (5.2 vs. 2.8 months; P = .003). The follow-up texture models distinguished longer- and shorter-term overall survivors (40.3 vs. 15.2 months; P = .008) but not for PFS (5.0 vs. 3.6 months; P = .25). The combined clinical-texture model outperformed the clinical model in both predicting the OS (C-index, 0.70 vs. 0.63; P = .03) and PFS (C-index, 0.63 vs. 0.55; P = .04). CONCLUSION: CT texture analysis performed at baseline and early after starting PD-1/PD-L1 inhibitors is associated with clinical outcomes of patients with mRCC.

Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. METHODS: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. CONCLUSION: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Alterations of 3D acetabular and lower limb parameters in adolescent idiopathic scoliosis.

PURPOSE: To evaluate the 3D deformity of the acetabula and lower limbs in subjects with adolescent idiopathic scoliosis (AIS) and their relationship with spino-pelvic alignment. METHODS: Two hundred and seventy-four subjects with AIS (frontal Cobb: 33.5° ± 18° [10°-110°]) and 84 controls were enrolled. All subjects underwent full-body biplanar X-rays with subsequent 3D reconstructions. Classic spino-pelvic and lower limb parameters were collected as well as acetabular parameters: acetabular orientation in the 3 planes (tilt, anteversion and abduction), center-edge angle (CEA) and anterior and posterior sector angles. Subjects with AIS were represented by both lower limb sides and classified by elevated (ES) or lowered (LS), depending on the frontal pelvic obliquity. Parameters were then compared between groups. Determinants of acetabular and lower limb alterations were investigated among spino-pelvic parameters. RESULTS: Acetabular abduction was higher on the ES in AIS (59.2° ± 6°) when compared to both LS (55.6° ± 6°) and controls (57.5° ± 3.9°, p < 0.001). CEA and acetabular anteversion were higher on the LS in AIS (32° ± 6.1°, 20.5° ± 5.7°) when compared to both ES (28.7° ± 5.1°, 19.8° ± 5.1°) and controls (29.8° ± 4.8°, 19.1° ± 4°, respectively, p < 0.001). Anterior sector angle was lower on both ES and LS in AIS when compared to controls. CEA, acetabular abduction and acetabular anteversion were found to be mostly determined (adjusted R2: 0.08-0.32) by pelvic tilt and less by frontal pelvic obliquity, frontal Cobb and T1T12. CONCLUSIONS: Subjects with AIS had a more abducted acetabulum at the lowered side, more anteverted acetabulum and a lack of anterior coverage of both acetabula. These alterations were strongly related to pelvic tilt.

The relationships between bone variables and physical fitness across the BMI spectrum in young adult women.

In this cross-sectional study we aimed to evaluate the relationship between physical fitness and bone variables across the body mass index (BMI) spectrum in women aged 20-35 years. The study included 13 underweight women (BMI < 18.5 kg/m2), 24 normal weight women (BMI 18.5-24.9 kg/m2), and 20 overweight/obese women (BMI ≥ 25 kg/m2) aged between 20 and 35 years. Bone mineral density (BMD) and content (BMC) at the whole body, lumbar spine, and femoral neck, lumbar spine trabecular bone score, femoral neck geometry were assessed using dual-energy X-ray absorptiometry. Cardiorespiratory fitness and lower limb muscle power were estimated using the 20-m shuttle run test and the Sargent jump test, respectively. The associations between bone variables and physical fitness were different according to BMI categories. Correlations between physical fitness and bone parameters are particularly significant in normal BMI and less significant in low and high BMI. Multivariate ANCOVA regression models demonstrated that absolute VO2max (L/min) is a strong determinant of all the bone parameters regardless of BMI. Implementing strategies for increasing VO2max (L/min) by increasing lean mass and promoting resistance and/or high-intensity interval training could be effective to optimize bone health in underweight and overweight young adult women.

Second-line Treatments of Advanced Hepatocellular Carcinoma: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) constitutes the second leading cause of cancer-related deaths. First-line therapy is either sorafenib or lenvatinib. Several treatment options have been recently added to the second-line treatment of advanced HCC. The aim of this network meta-analysis of randomized controlled trials was to compare the second-line treatments of advanced HCC. METHODS: Network meta-analyses were computed for overall survival (OS), progression-free survival, rates of grade 3 to 5 adverse events, and for treatment discontinuation due to adverse events. OS was considered to be the primary outcome of this study, and everolimus was chosen to be the common comparator for efficacy analyses and placebo for safety analyses. Subgroup analyses were computed for OS in patients with hepatitis B, patients with hepatitis C, Asian patients, patients with macrovascular invasion, and patients with extrahepatic metastases. RESULTS: Thirteen randomized controlled trials including 5076 patients and evaluating 11 agents were found to be eligible. Regorafenib [hazard ratio (HR)=0.60, 95% confidence interval (CI)=0.44-0.81] and cabozantinib (HR=0.72, 95% CI=0.55-0.95) were found to significantly prolong OS compared with everolimus. The effect of regorafenib on OS tended to be conserved across patient subgroups. Regorafenib was also found to significantly prolong progression-free survival (HR=0.46, 95% CI=0.35-0.62) and significantly increase the rates of grade 3 to 5 adverse events (odds ratios=3.18, 95% CI=2.22-4.54) and treatment discontinuation due to adverse events (odds ratios=2.67, 95% CI=1.21-5.87). CONCLUSIONS: This network meta-analysis concludes that, based on current evidence, regorafenib could be the agent of choice in the second-line treatment of HCC, with cabozantinib as a possible alternative for sorafenib-intolerant patients.

Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials.

INTRODUCTION: There is a lack of studies on the optimal anti-tumor necrosis factor (anti-TNF) agent for postoperative prophylaxis of Crohn's disease (CD) recurrence. Therefore, we conducted a network meta-analysis (NMA) of prospective trials to compare the efficacy of anti-TNF agents in the prevention of postoperative endoscopic and clinical recurrence of CD following ileocolonic resection. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and recent American gastroenterology association (AGA) meeting abstracts through August 2017. We selected prospective studies comparing anti-TNF agents among each other or to other agents in the setting of postoperative prevention of CD recurrence. We performed a NMA using a frequentist approach with generalized pairwise modeling and inverse variance heterogeneity method. RESULTS: We identified 9 studies, including 571 patients and 5 treatment agents, among which 2 anti-TNF drugs (adalimumab and infliximab). Compared with infliximab, our NMA yielded the following results for endoscopic recurrence: adalimumab [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.18-4.75], thiopurines (OR, 4.11; 95% CI, 0.68-24.78), placebo (OR, 4.39; 95% CI, 0.70-27.68), and Mesalamine (OR, 37.84; 95% CI, 3.77-379.42). For clinical recurrence: adalimumab (OR, 1.03; 95% CI, 0.17-6.03), thiopurines (OR, 1.40; 95% CI, 0.20-10.02), placebo (OR, 1.77; 95% CI, 1.01-3.10), and mesalamine (OR, 16.54; 95% CI, 1.55-176.24). CONCLUSIONS: On the basis of a NMA combining direct and indirect evidence either adalimumab or infliximab may be used in the postoperative prophylaxis of CD recurrence. There is currently a lack of evidence on the use of other anti-TNF agents in this setting.

Comparison of second-line treatments of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

AIM: The literature lacks direct evidence comparing the different regimens evaluated in the second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: We conducted a network meta-analysis (NMA) of the randomized controlled Phase III trials reporting on the second-line drug treatment options in R/M SCCHN. RESULTS: The eligible trials included 11 regimens among which six targeted therapies, two immune checkpoint inhibitors and three chemotherapy regimens. Only nivolumab has shown statistically significant superiority over methotrexate in terms of overall survival (HR: 0.64; 95% CI: 0.43-0.96) and objective response rate (OR: 2.51; 95% CI: 1.07-5.86). CONCLUSION: Based on the efficacy and safety outcomes of this network meta-analysis, nivolumab seems the most favorable regimen inthe management of R/M SCCHN.

Factors associated with the time to first palliative care consultation in Lebanese cancer patients.

INTRODUCTION: Early palliative care is recommended for cancer patients. However, palliative care consults (PCC) are often delayed in Lebanon. The aim of this study was to identify the factors associated with timing of PCC and their impact on the place of death. METHODS: This is a retrospective, single institution, study conducted at Hotel Dieu de France University Hospital in Lebanon. The clinical and demographic characteristics of oncology patients who received PCC were obtained. Cox and logistic regression models were used to evaluate the factors determining the time to first PCC and location of death, respectively. RESULTS: Two hundred and ten patients were included in our analyses with a median age of 69 years (range 22-92 years). The median survival times were: overall survival 18.7 months, time to first PCC 17.9 months, and survival post-PCC 0.6 months. Among patients who were followed-up at home, the median time spent at home was 0.6 months. Late PCC were associated with a childless status (HR = 0.57, 95%CI = 0.37-0.86, p = 0.007), awareness of the diagnosis (HR = 0.64, 95%CI = 0.45-0.91, p = 0.013), and lack of palliative home care (HR = 0.42, 95%CI = 0.25-0.65, p < 0.001). Older patients (OR = 1.03, 95%CI = 1.01-1.05, p = 0.026) and those who had been followed up at home during the PCC (OR = 160.56, 95%CI = 21.39-1205.50, p < 0.001) were significantly more likely to have died at home as opposed to the hospital. DISCUSSION: Cancer patients often receive PCC only shortly before their death. PCC for Lebanese cancer patients were found to be significantly delayed in patients that are childless, knowledgeable of their diagnosis, and lack home palliative care.

Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication. CONCLUSION: In the absence of direct comparative evidence, the results of this network meta-analysis represent the best available evidence for decision making in the first-line treatment of metastatic luminal breast cancer.

The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis.

AIM: As no meta-analyses have evaluated tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma (RCC), the aim was to evaluate the benefit of sunitinib and pazopanib in the adjuvant setting. METHODS: This meta-analysis included all Phase III randomized controlled trials evaluating adjuvant sunitinib and pazopanib in high-risk RCC. Primary outcome was the comparison of disease-free survival (DFS) between tyrosine kinase inhibitors and placebo. RESULTS: There was a tendency for significant overall effect of both sunitinib and pazopanib on DFS (hazard ratio: 0.85; 95% confidence interval: 0.72-1.01; p = 0.06). There was no significant difference between the effect of sunitinib and pazopanib on DFS (p = 0.51;  I2 = 0%). CONCLUSION: Pazopanib and sunitinib could prolong DFS in the adjuvant treatment of high-risk RCC and seem equally effective in this setting.

Cervical and postural strategies for maintaining horizontal gaze in asymptomatic adults.

PURPOSE: To investigate the different cervical strategies for maintaining horizontal gaze in asymptomatic subjects. METHODS: One hundred and forty-four asymptomatic adults filled the SF-36 quality of life questionnaire and underwent full-body biplanar radiographs. Chin brow vertical angle (CBVA) and postural and cervical parameters were measured. Subjects were grouped according to cervical spine curvature (C2-C7 angle): kyphotic (< - 5°), straight [- 5°, 5°], lordotic (> 5°). Demographics, SF-36 component scores and CBVA were compared between groups. All other parameters were compared between groups, while controlling for confounding factors (ANCOVA). A correlation test was conducted between all cervical parameters. RESULTS: 32% of subjects had kyphotic (- 12° ± 7°), 27% straight (0° ± 3°) and 41% lordotic (12° ± 7°) cervical spines. While demographic and SF-36 data did not differ between groups, CBVA differed between lordotic and kyphotic groups (2° vs. 6.5°, p = 0.002). Sagittal vertical axis (SVA) and thoracic kyphosis (TK) were lower in the kyphotic group (SVA: K = - 26 ± 20 mm vs. L = - 2 ± 21 mm, p < 0.001; TK: K = 40° ± 6° vs. L = 51° ± 8°, p < 0.001). C2 slope (K = 29° ± 6° vs. L = 18° ± 6°, p < 0.001), C0-C2 (K = 42° ± 8° vs. L = 30° ± 8°, p < 0.001) and C1-C2 (K = 33° ± 6° vs. L = 28° ± 6°, p = 0.004) were higher in the kyphotic group. Significant correlations were found between almost all cervical parameters and C2-C7 angle. CONCLUSIONS: Subjects with cervical kyphosis presented with more posterior global alignment and lower TK than subjects with lordosis. In order to maintain horizontal gaze, subjects with cervical kyphosis presented with a more lordotic upper cervical spine than subjects with cervical lordosis. Subjects with straight cervical curvature presented with an intermediate sagittal alignment. These slides can be retrieved under Electronic Supplementary Material.

Influence of patient axial malpositioning on the trueness and precision of pelvic parameters obtained from 3D reconstructions based on biplanar radiographs.

OBJECTIVES: Radiographs are often performed to assess pelvic and hip parameters, but results depend upon correct pelvis positioning. Three-dimensional (3D) reconstruction from biplanar-radiographs should provide parameters that are less sensitive to pelvic orientation, but this remained to be evaluated. METHODS: Computerized-tomographic scans of six patients were used both as a reference and for generating simulated frontal and lateral radiographs. These simulated radiographs were generated while introducing axial rotations of the pelvis ranging from 0° to 20°. Simulated biplanar-radiographs were utilized by four operators, three times each, to perform pelvic 3D-reconstructions. These reconstructions were used to assess the trueness, precision and global uncertainty of radiological pelvic and hip parameters for each position. RESULTS: In the neutral position, global uncertainty ranged between ± 2° for pelvic tilt and ± 9° for acetabular posterior sector angle and was mainly related to precision errors (ranging from 1.5° to 7°). With increasing axial rotation, global uncertainty increased and ranged between ± 5° for pelvic tilt and ± 11° for pelvic incidence, sacral slope and acetabular anterior sector angle, mainly due to precision errors. CONCLUSION: Radiological parameters obtained from 3D-reconstructions, based on biplanar-radiographs, are less sensitive to axial rotation compared to plain radiographs. However, the axial rotation should nonetheless not exceed 10°. KEY POINTS: • Pelvic radiological parameters could be affected by patient malpositioning. • Biplanar radiograph-based 3D reconstructions were performed at increments of axial rotation. • Trueness, precision and global uncertainty were evaluated for pelvic and hip radiological parameters. • Hip parameters were less affected by rotation compared to pelvic parameters. • Maintaining the pelvis close to the neutral position is recommended to ensure the highest possible accuracy.

The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?

AIM: To determine whether abiraterone acetate or docetaxel should be regarded as the current standard of care for metastatic hormone-naive prostate cancer (mHNPC). METHODS & MATERIALS: A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The results of this NMA favored abiraterone acetate over docetaxel-based regimens (hazard ratio: 0.79; 95% CI: 0.64-0.99) in patients with mHNPC. The results also suggest a reconsideration of the role of prednisone in view of the absence of a survival benefit (hazard ratio: 0.98; 95% CI: 0.59-1.65) with its use. CONCLUSION: Despite the paucity of direct comparative evidence, the results of this NMA favor the use of abiraterone acetate in the first-line treatment of mHNPC.

Network meta-analysis of second-line treatment in metastatic renal cell carcinoma: efficacy and safety.

This paper aims to compare the approved second-line treatment options in metastatic renal cell carcinoma. A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed for the approved drugs in this setting. The results of this NMA showed that the combination of lenvatinib and everolimus yielded the lowest hazard ratio (HR) for progression-free survival (HR: 0.4; 95% CI: 0.21-0.75) and overall survival (HR: 0.55; 95% CI: 0.30-1.00). The great efficacy of this combination is limited by the prevalence of grade 3-4 adverse events (70.6%) leading to treatment discontinuation in 17.6%. This NMA is to the best of our knowledge, the first analysis of the approved regimens for the second-line treatment of metastatic renal cell carcinoma.

A NEW APPROACH IN THE CLINICAL DECISION-MAKING FOR CEREBRAL PALSY USING THREE-DIMENSIONAL SUBJECT-SPECIFIC MUSCULOSKELETAL RECONSTRUCTIONS.

Cerebral palsy (CP) is a neurological disorder which can cause muscular spasticity. Children with this condition suffer from a combination of gait deviations, skeletal deformities and muscular abnormalities. Precise evaluation of each of these three components is crucial for management planning in children with CP. The aim of this study is to review the latest innovative methods used for three-dimensional (3D) gait analysis and musculoskeletal modeling in children with cerebral palsy. 3D gait analysis is a quantitative objective method based on the use of infrared cameras. It allows the evaluation of dynamic joint angles, forces and moments applied on joints and is usually coupled with dynamic electromyography. Skeletal evaluation is usually based on two-dimensional X-rays and physical examination in clinical practice. However, a novel method based on stereoradiographic 3D reconstruction of biplanar low dose X-rays allows a more thorough evaluation of skeletal deformities, and in particular torsional anomalies. Muscular evaluation of children with CP is most commonly based on magnetic resonance imaging, whereby delimitation of lower limb muscles on axial slices allows 3D reconstruction of these muscles. Novel innovative techniques allow similar reconstructions by extrapolation, thus limiting the necessary quantity of axial slices that need to be manually delimitated.

Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.

Background and objective: Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types. Methods: We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events. Key findings and limitations: Clear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL. Conclusions and clinical implications: This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants. Patient summary: In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.