Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits ...multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial.
MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).
MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD.
High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition.
Summary Background Although childhood trauma and violence against women are global public health issues, few population-based data from low-income and middle-income countries exist about the links ...between them. We present data from the UN Multi-country Study on Men and Violence in Asia and the Pacific, exploring the pathways between different forms of childhood trauma and violence against women. Methods In this multicountry study, we interviewed multistage representative samples of men and women, aged 18–49 years, in Asia and the Pacific, using standardised population-based household surveys. Men were interviewed in six countries, and women in four. Respondents were asked questions about their perpetration or experience of intimate partner violence or non-partner sexual violence, childhood trauma, and harsh parenting (smacking their children as a form of discipline). We used maximum likelihood multivariate logit models to explore associations between childhood trauma and violence against women, and fitted path models to explore associations between experience and perpetration of child maltreatment. Findings Between Jan 1, 2011, and Dec 1, 2012, 10 178 men and 3106 women completed interviews in this study, with between 815 and 1812 men per site and 477 and 1103 women per site. The proportion of men who experienced any childhood trauma varied between 59% (n=478, 95% CI 54·0–63·3; Indonesia rural site) and 92% (n=791, 89·4–93·8; Bougainville, Papua New Guinea). For women, the results ranged from 44% (n=272, 37·7–50·8; Sri Lanka) to 84% (n=725, 80·7–86·8; Bougainville, Papua New Guinea). For men, all forms of childhood trauma were associated with all forms of intimate partner violence perpetration. For women, all forms of childhood trauma were associated with physical intimate partner violence, and both physical and sexual intimate partner violence. There were significant, often gendered, pathways between men's and women's perpetration and experiences of childhood trauma, physical intimate partner violence, harsh parenting, and other factors. Interpretation The data point to both a co-occurrence and a cycle of abuse, with childhood trauma leading to violence against women and further child maltreatment, which in turn increases the risk of experience or perpetration of violence during adulthood. Efforts to prevent both forms of violence would benefit from a meaningful integrated approach. Interventions should promote positive parenting, address inequality and the normalisation of violence across the life course, and transform men's power over women and children. Funding Partners for Prevention. National studies were funded by the UN Population Fund in Bangladesh and China, UN Women in Cambodia and Indonesia, UN Develoment Programme in Papua New Guinea, and CARE in Sri Lanka.
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Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the ...mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.
Airway management is a critical component of the management of emergency department (ED) patients. The ED airway literature primarily focuses upon endotracheal intubation; relatively less is known ...about the ED use of extraglottic devices (EGDs). The goal of this study was to describe the frequency of use, success, and complications for EGDs among ED patients.
The National Emergency Airway Registry (NEAR) is a prospective, multi-center, observational registry. It captures data on all ED patients at participating sites requiring airway management. Intubating clinicians entered all data into an online system as soon as practical after each encounter. We conducted a secondary analysis of these data for all ED encounters in which EGD placement occurred. We used descriptive statistics to characterize these encounters.
Of 19,071 patients undergoing intubation attempts, 56 (0.3%) underwent EGD placement. Of 25 participating sites, 13 reported no cases undergoing EGD placement; the median number of EGDs placed per site was 2 (interquartile range 1–2.5, range 1–31). Twenty-nine (54%) patients had either hypotension or hypoxia prior to the start of airway management. Clinicians reported anticipation of a difficult airway in 55% and at least one difficult airway characteristic in 93% of these patients. Forty-one encounters entailed placement of a laryngeal mask airway (LMA®) Fastrach™, 33 of whom underwent subsequent successful intubation through the EGD and 7 of whom underwent intubation by alternative methods. An additional 10 encounters utilized a standard LMA® device. Providers placed 34 (61%) EGDs during the first intubation attempt. Seventeen EGD patients (30%) experienced peri-procedure adverse events, including 14 (25%) experiencing hypoxemia. None of these patients expired due to failed airways.
EGD use was rare in this multi-center ED registry. EGD occurred predominantly in patients with difficult airway characteristics with favorable airway management outcomes. Clinicians should consider this emergency airway device for patients with a suspected difficult airway.
Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in ...metastatic RCC, but its effect on brain metastases remains unclear.
To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC.
This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy.
Receipt of cabozantinib monotherapy at any line of treatment.
Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib.
Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed.
In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
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Background: Patients with rare genitourinary malignancies (Bladder cancer of variant histologies (BCVH), adrenal tumors, chemotherapy refractory germ cell tumors (CRGCT), penile ...carcinoma and prostate cancer of variant histology (PCVH)) have poor outcomes. Nivolumab and ipilimumab has demonstrated safety and efficacy in genitourinary malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluated the efficacy of nivolumab and ipilimumab in pts with advanced rare genitourinary cancers (NCT 03333616). Herein, we report the results of the fully accrued BCVH, adrenal and other cohorts. Methods: Eligible pts had a metastatic rare genitourinary malignancy, ECOG performance status of 0-2 and no prior immune checkpoint inhibitor exposure; aside from CRGCT pts could be treatment naïve. Eligible pts received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses with continued nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 56 pts were enrolled at 6 institutions between 4/2018 and 7/2019 in 3 cohorts: BCVH (N = 19), adrenal tumors (n = 18) and other tumors (n = 19). Median follow-up was 9.9 (range < 1~21) months. 28(50%) pts received all 4 doses of nivolumab and ipilimumab. 25 pts received nivolumab maintenance at a median of 4 (range 1-18) cycles. ORR in entire cohort was 16% (n = 9: 2 CR 7 PR, Table); 67% of responders (6/9) maintained response greater than 9 months. Median PFS was 2.8 (2.7-5.2) months. 22 pts (39%) developed treatment-related ≥ grade 3 toxicity; 23% required high dose steroids (≥40 mg prednisone or equivalent) and 15 (27%) pts discontinued treatment due to an AE. Grade 5 toxicity occurred in 3 pts; 1 death was treatment related. Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of pts with rare GU malignancies, especially in BCVH. Biomarkers are being evaluated and an additional cohort exploring the activity in genitourinary tumors with neuroendocrine differentiation is ongoing. This combination warrants further investigation in these pts with substantial unmet needs. Clinical trial information: NCT 03333616 . Table: see text
This study aims to determine the age of first infection of pulmonary tuberculosis in Dhaka, the capital of Bangladesh. Registered cases at an arbitrarily selected chest disease clinic in Dhaka under ...the National Tuberculosis Control Program (NTP) of Bangladesh was considered for this study. From the study of the sample of 303 cases, it was revealed that women are more likely to be affected by Tuberculosis bacilli at earlier ages as compared to men in Dhaka. Mann Whitney Median test showed a significant difference between the median age of first infection of male and female (p-value < 0.001). In addition it is also observed that there is a significant difference (p-value<0.05) between the median age of first infection between people with in-house occupational activities and individuals with outgoing occupational activities where outgoing people are infected by Tuberculosis bacilli at later ages than in-house workers. An exponential regression model shows significant effect of the variables sex and place of occupational activities on the age of first infection (p-value < 0.05). DOI: http://dx.doi.org/10.3329/dujs.v62i1.21961 Dhaka Univ. J. Sci. 62(1): 49-53, 2014 (January)
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Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We ...retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. Table: see text
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