The present study found that the hypotensive of egg white protein hydrolysate in female spontaneously hypertensive rats was executed via regulating the competing endogenous RNA regulatory network, which provides novel insights into the mechanisms of food protein-derived antihypertensive peptides.
291 Background: Unexplained leukocytosis, thought to be associated with paraneoplastic GCSF, has been described in several malignancies and is linked to a poor prognosis. We sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated WBC. Methods: We queried a prospectively maintained database at the University of Washington. Patients were included if they had a histological diagnosis of urothelial carcinoma of the bladder and a WBC of >20 x 10 3 cells/µl. Patient charts were reviewed and were excluded from analysis if the leukocytosis was not persistent in duration or if an underlying cause for the leukocystosis could be identified. Clinical, histological and laboratory data were then collected from the remaining patient cohort. Results: We identified a total of 44 patients who met the inclusion criteria of having urothelial carcinoma of the bladder with a WBC of >20 x 10 3 cells/µl. Of these patients, 7 (16%) patients with a median age of 61.9 (range 34 - 80) yrs at diagnosis had persistent, unexplained leukocytosis. Mixed histologies were present in 3 patients (extensive squamous differentiation in 2 and sarcomatoid differentiation in 1). At the time of presentation with leukocytosis, 5 of 7 had muscle invasive disease and 3 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n = 5), thrombocytosis (n = 5) and anemia (n = 6). All patients died from their disease with the exception of one who is currently alive with locally advanced and unresectable disease 8 months after presentation. Median time from leukocytosis until death was 55 (range 8 - 139) days. Chemotherapy was able to achieve a WBC response in 2 of 4 patients although neither demonstrated a substantial reduction in tumor volume. Both patients ultimately developed a recurrence of their leukocytosis after chemotherapy and progression of their disease. Conclusions: The presence of leukocytosis conveys a poor prognosis. To our knowledge this represents the largest case series of patients with paraneoplastic leukocytosis secondary to urothelial carcinoma.
Appendix for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients
131 Background: The phase 3, randomized KEYLYNK-010 trial (NCT03834519) of pembro + ola vs next-generation hormonal agent (NHA) abi or enza did not significantly improve rPFS or OS in molecularly unselected pts with mCRPC treated with prior NHA and docetaxel. The study was stopped for futility after the second prespecified interim analysis. PROs for pembro + ola vs NHA in KEYLYNK-010 are presented. Methods: Pts were randomly assigned 2:1 to receive pembro 200 mg IV Q3W for ≤35 cycles (~2 y) + ola 300 mg orally BID or NHA (either abi 1000 mg orally QD + prednisone 5 mg orally BID, if pt previously received enza, or enza 160 mg orally QD if pt previously received abi). PROs were evaluated in pts who received ≥1 dose of study treatment and had ≥1 PRO assessment. FACT-P and BPI-SF were administered at baseline, Q3W until wk 24, Q6W until wk 72, and Q12W thereafter for ≤2 y. Time to pain progression (TTPP) based on BPI-SF was a prespecified secondary end point. Prespecified exploratory end points included least squares mean (LSM) change from baseline to wk 15 for FACT-P total and subscales scores (FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS) and BPI-SF scores (pain interference, pain severity, and worst pain), and time to deterioration (TTD) and overall improvement rate in FACT-P total and subscale scores. Differences were evaluated using 2-sided nominal P values not controlled for multiplicity. Results: A total of 793 pts were randomly assigned to pembro + ola (n = 529) or NHA (n = 264). As of January 18, 2022, median follow-up was 18.7 mo (range, 6.1-31.7). In all randomized pts, completion rate for FACT-P and BPI-SF at baseline and wk 15 was >84% and >57%, respectively. No differences were observed in the median TTPP for pembro + ola (13.5 mo [95% CI, 9.7-NR]) vs NHA (12.0 mo [95% CI, 10.1-NR]; HR, 0.95 [0.72-1.26]). No LSM differences were observed in FACT-P total scores (pembro + ola, –4.62 [95% CI, –6.47 to –2.77] vs NHA, –5.86 [95% CI, –8.58 to –3.13]) or BPI-SF scores (Table). There were no differences in TTD in FACT-P total, FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS scores between groups. A numerically higher proportion of pts had improved + stable FACT-P total scores for pembro + ola (44.0%) vs NHA (39.0%). FACT-P and BPI-SF scores were generally maintained across all evaluated time points up to wk 81. Conclusions: No clinically meaningful changes from baseline were observed in HRQoL or disease-related symptom scores with either pembro + ola or NHA. PRO scores were generally similar between pembro + ola and NHA at all analyzed time points, suggesting HRQoL was maintained in heavily pretreated pts receiving pembro + ola. Clinical trial information: NCT03834519 . [Table: see text]
4515 Background: A majority of mUC patients (pts) treated with chemo ultimately progress, and subsequent therapy is often accompanied by low ORRs and short OS. Atezo (MPDL3280A) has been found to be safe and effective in plat treated pts. Here we report updated efficacy in pts with > 1-y median follow up. Methods: IMvigor210 (NCT02108652) cohort 2 mUC pts who progressed during/following plat received atezo 1200 mg IV q3w until loss of clinical benefit. PD-L1 status was centrally scored on tumor-infiltrating immune cells (IC; SP142 IHC assay): IC2/3, 1, 0. Confirmed RECIST v1.1 ORR (RECIST, central review) and modified (m)RECIST ORR (investigator) were co-primary endpoints. DOR, OS and safety were secondary (data cut Nov 27, 2015). Results: 310 efficacy/safety evaluable pts had median age 66 y; 37% had prior cystectomy; 41% had ≥ 2 prior regimens for mUC; 39% had chemo within past 3 mo. Responses were consistent in IC2/3 pts (26% RECIST ORR; 29% mRECIST) as well as across all IC subgroups, and enriched in pts with higher IC status (Table). RECIST responses were seen in pts with ECOG PS1 (8% ORR; 16/193), CrCl < 60 mL/min (13%; 14/110), Hb < 10 g/dL (7%; 5/69), visceral mets (10%; 24/243) and ≥ 4 prior mUC regimens (8%; 2/24). Responses were ongoing in 37/46 pts (80%) per RECIST and 46/60 (77%) per mRECIST. mDOR was not reached in IC2/3, IC1/2/3 and all comers. With longer follow up (median 14.4 mo [range 0.2-17.1]) an evolution of responses including additional CRs was seen. mOS and 1-y OS were notable in all IC subgroups (Table). Atezo remains well tolerated. Conclusions: Atezois an efficacious monotherapy in heavily pretreated mUC pts. Durable responses occurred across predefined IC subgroups, including pts with poor prognostic factors. Clinically meaningful OS was seen. With sustained efficacy coupled with favorable safety, atezo shows promise as a new standard of care in plat treated mUC (expanded access study: NCT02589717). Clinical trial information: NCT02108652. n RECIST mRECIST OS ORR, % 95% CI CR, n ORR, % 95% CI CR, n mOS, mo 95% CI 1-y OS, % 95% CI IC2/3 100 26 18, 36 12 29 20, 39 8 11.9 9.0, NEa 50 40, 60 IC1/2/3 207 18 13, 24 14 23 17, 29 16 9.0 7.1, 10.9 40 33, 47 Allb 310 15 11, 19 17 19 15, 24 18 7.9 6.7, 9.3 37 31, 42 aNot estimable; b IC0, 1, 2/3
Abstract Evidence on the effects of meat consumption from different sources on the risk of bladder cancer (BC) is limited and controversial. Therefore, this study aimed to evaluate the associations between meat consumption and BC risk using a pooled data approach. Individual data from 11 prospective cohorts comprising 2848 BC cases and 515,697 non-cases with a total of 5,498,025 person-years of follow-up was pooled and analysed to investigate the potential associations between total red meat and products, red meat, processed meat, poultry and total fish and BC risk. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox regression models stratified on cohort. Overall, an increased BC risk was found for high intake of organ meat (HR comparing highest with lowest tertile: 1.18, 95% CI: 1.03, 1.36, p-trend = 0.03). On the contrary, a marginally inverse association was observed for total fish intake and BC risk among men (HR comparing highest with lowest tertile: 0.79, 95% CI 0.65, 0.97, p-trend = 0.04). No associations were observed for other meat sources. Results of this prospective study suggest that organ meat consumption may be associated with BC development. Replication in large-scale prospective studies and investigation of possible causal mechanisms is needed.
Background and objectiveAbiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC.MethodsIn cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3–modified RECIST v1.1 by BICR and overall survival (OS).Key findings and limitationsFor the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26–31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1–measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2–22) and median OS was 30 mo (95% confidence interval 23–not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3–5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design.ConclusionsPembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents.Patient summaryFor patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.
Additional file 1: Table S1. Information of included metabolite measures. Table S2. Components and scaling methods of dietary patterns used in The Maastricht Study. Table S3. Association of metabolite measures with dietary patterns. Table S4. Association of metabolite measures with glucose metabolism status, HOMA-IR and HbA1c. Table S5. Metabolite measures mediated between MED and GMS. Table S6. Metabolite measures mediated between DASH and GMS. Table S7. Metabolite measures mediated between DHD and GMS. Table S8. Associations of dietary patterns with glucose metabolism status in The Maastricht Study excluding participants with incomplete data on covariates and newly type 2 diabetes diagnoses. Table S9. Associations of dietary patterns with HOMA-IR and HbA1c in The Maastricht Study excluding participants with incomplete data on covariates and newly type 2 diabetes diagnoses. Table S10. Associations of dietary patterns with identified metabolite measures in The Maastricht Study excluding participants with incomplete data on covariates and newly type 2 diabetes diagnoses. Table S11. Associations of dietary patterns with identified metabolite measures in The Maastricht Study excluding participants with incomplete data on covariates and newly type 2 diabetes diagnoses. Table S12. Metabolite measures mediated between dietary patterns and GMS in The Maastricht Study excluding participants with incomplete data on covariates and newly type 2 diabetes diagnoses.
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