Summary Background Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are ...no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. Methods In our observational, prospective study we enrolled previously untreated adults (≥18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR -α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. Findings We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio HR per allele 3·57, 1·75–7·30; punadjusted =0·00049, padjusted =0·0079) and rs307821 (3·31, 1·64–6·68; punadjusted =0·00085, padjusted =0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67–8·41; punadjusted =0·0014, padjusted =0·022). No other SNPs were associated with sunitinib response or toxicity. Interpretation Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. Funding Pfizer.
The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response.
This was a ...phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease.
Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-α, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-β1 and CCL5 were significantly decreased. TNF-α, endoglin, and PD-L1 expression are correlated with the response after treatment initiation.
The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.
Phase I/II translational trial evaluating the molecular determinants of pazopanib plus interferon alpha efficacy in advanced renal cell carcinoma. The expression levels of TNF-α, endoglin and PD-L1 correlated with response at eight weeks after treatment initiation. This suggests a crucial role of vascular remodelling and inflammatory-mediated immune cell infiltration for an optimal response to pazopanib plus interferon alpha combination.
Several agents have demonstrated an overall survival (OS) benefit in metastatic castration-resistant prostate cancer (mCRPC); however, optimal sequencing is unknown. Retrospective analysis of data ...from 574 mCRPC patients showed increasing OS with the number of therapies provided; a sequence including docetaxel, cabazitaxel (CABA), and an androgen receptor–targeted agent (ART) provided the greatest benefit. Prior administration of ART did not appear to influence CABA activity. These findings will help guide treatment decisions in daily practice.
Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).
Records of 574 consecutive patients treated (2012−2016) at 44 centers in 6 countries were retrospectively examined.
A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.
OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.
The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic ...drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (
values from 6 × 10
to 3 × 10
). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (
= 4.6 × 10
, 6.5 × 10
, and 3.4 × 10
, respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85;
= 1.3 × 10
) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (
= 6.8 × 10
and 7.8 × 10
for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.
At the Advanced Prostate Cancer Consensus Conference 2022, expert panellists discussed clinically significant topics in advanced prostate cancer and voted beforehand on 82 predefined multiple-choice ...consensus questions on intermediate- and high-risk and locally advanced disease, biochemical recurrence after local treatment (including the incorporation of next-generation imaging), and side effects from hormonal therapies. The results are summarised here. The remaining 116 consensus questions from the conference pertain to other aspects of advanced prostate cancer and are discussed in a separate report.
Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management.
To present consensus voting results for select questions from APCCC 2022.
Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members (“panellists”) who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1–3.
Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement.
The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis.
These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.
The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.
Purpose
This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis
®
) 3 mg/m
2
1 h every 3-week intravenous infusion in ...patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy.
Methods
The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors.
Results
In a first stage (
n
= 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (
C
max
= 48.57 μg/l and area under the curve (AUC) = 154.97 h μg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or
C
max
.
Conclusions
No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.
Nitrogen fertilization is critical to optimize short-term crop yield, but its long-term effect on soil organic C (SOC) is uncertain. Here, we clarify the impact of N fertilization on SOC in typical ...maize-based (Zea mays L.) Midwest U.S. cropping systems by accounting for site-to-site variability in maize yield response to N fertilization. Within continuous maize and maize-soybean Glycine max (L.) Merr. systems at four Iowa locations, we evaluated changes in surface SOC over 14 to 16 years across a range of N fertilizer rates empirically determined to be insufficient, optimum, or excessive for maximum maize yield. Soil organic C balances were negative where no N was applied but neutral (maize-soybean) or positive (continuous maize) at the agronomic optimum N rate (AONR). For continuous maize, the rate of SOC storage increased with increasing N rate, reaching a maximum at the AONR and decreasing above the AONR. Greater SOC storage in the optimally fertilized continuous maize system than in the optimally fertilized maize-soybean system was attributed to greater crop residue production and greater SOC storage efficiency in the continuous maize system. Mean annual crop residue production at the AONR was 22% greater in the continuous maize system than in the maize-soybean system and the rate of SOC storage per unit residue C input was 58% greater in the monocrop system. Our results demonstrate that agronomic optimum N fertilization is critical to maintain or increase SOC of Midwest U.S. cropland.
Labile, ‘high‐quality’, plant litters are hypothesized to promote soil organic matter (SOM) stabilization in mineral soil fractions that are physicochemically protected from rapid mineralization. ...However, the effect of litter quality on SOM stabilization is inconsistent. High‐quality litters, characterized by high N concentrations, low C/N ratios, and low phenol/lignin concentrations, are not consistently stabilized in SOM with greater efficiency than ‘low‐quality’ litters characterized by low N concentrations, high C/N ratios, and high phenol/lignin concentrations. Here, we attempt to resolve these inconsistent results by developing a new conceptual model that links litter quality to the soil C saturation concept. Our model builds on the Microbial Efficiency‐Matrix Stabilization framework (Cotrufo et al., 2013) by suggesting the effect of litter quality on SOM stabilization is modulated by the extent of soil C saturation such that high‐quality litters are not always stabilized in SOM with greater efficiency than low‐quality litters.
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, ...an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
Abstract Background Causal mediation analysis plays a crucial role in examining causal effects and causal mechanisms. Yet, limited work has taken into consideration the use of sampling weights in ...causal mediation analysis. In this study, we compared different strategies of incorporating sampling weights into causal mediation analysis. Methods We conducted a simulation study to assess 4 different sampling weighting strategies-1) not using sampling weights, 2) incorporating sampling weights into mediation “cross-world” weights, 3) using sampling weights when estimating the outcome model, and 4) using sampling weights in both stages. We generated 8 simulated population scenarios comprising an exposure ( A ), an outcome ( Y ), a mediator ( M ), and six covariates ( C ), all of which were binary. The data were generated so that the true model of A given C and the true model of A given M and C were both logit models. We crossed these 8 population scenarios with 4 different sampling methods to obtain 32 total simulation conditions. For each simulation condition, we assessed the performance of 4 sampling weighting strategies when calculating sample-based estimates of the total, direct, and indirect effects. We also applied the four sampling weighting strategies to a case study using data from the National Survey on Drug Use and Health (NSDUH). Results Using sampling weights in both stages (mediation weight estimation and outcome models) had the lowest bias under most simulation conditions examined. Using sampling weights in only one stage led to greater bias for multiple simulation conditions. Discussion Using sampling weights in both stages is an effective approach to reduce bias in causal mediation analyses under a variety of conditions regarding the structure of the population data and sampling methods.
PDF
