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An abrupt cooling event in the North Atlantic region 8,200 years ago affected climate throughout the Northern Hemisphere. The event is well constrained in Greenland ice cores, but lack of resolution in records from other regions has challenged our understanding of the timing and nature of the associated teleconnections. Speleothem records from East Asia have suggested monsoonal changes associated with the 8,200 year event, but the nature of these changes remains controversial. Here we assess changes in East Asian precipitation during the event from a sub-annually resolved stalagmite record from central China. Using δ 18 O and Mg/Ca measurements of the speleothem carbonate, we show that climate dried significantly about 8,200 years ago. Based on our annual-layer-counted chronology, we show that the dry event lasted 150 years, with a central period of pronounced aridity that lasted 70 years. The duration and evolution of the event is indistinguishable from that observed in the Greenland ice cores. We therefore conclude that an effective and rapid atmospheric teleconnection exists between the North Atlantic and the monsoon system in warm climates similar to today's. © 2013 Macmillan Publishers Limited. All rights reserved.

Introduction: Real-world data are limited on treatment sequencing and outcomes after first-line (1L) immune checkpoint inhibitor (CPI)-based combination treatment of advanced renal cell carcinoma (aRCC)., Patients and Methods: In this real-world, UK-based, retrospective study (CARINA; NCT04957160), data were obtained from hospital and electronic prescribing records. Patients were aged ≥ 18 years at aRCC diagnosis and had received 1L CPI-CPI or tyrosine kinase inhibitor (TKI)-CPI combination therapy before second-line (2L) therapy including cabozantinib. We describe treatment outcomes including 1L and 2L durations of treatment (DoT) and overall survival (OS)., Results: Data from April 2015 to June 2022 were collected on 281 patients from nine UK centres. Median 1L DoT was 2.3 months for CPI-CPI therapy (n = 171) and 5.0 months for TKI-CPI therapy (n = 58). After 1L CPI-CPI or TKI-CPI therapy, median 2L DoT was 5.8 versus 4.2 months, respectively, for cabozantinib (n = 163), and 3.8 versus 2.4 months for other therapies (n = 118); median 2L OS was 15.2 and 15.3 months, respectively, for cabozantinib, and 14.6 and 24.2 months for other therapies., Conclusion: DoT for 2L treatment was numerically better for cabozantinib than for other therapies, and after 1L CPI-CPI therapy than after 1L TKI-CPI therapy. Median OS was similar for 2L cabozantinib and other 2L therapies, and median OS for 2L cabozantinib was similar after both 1L therapy types. These results demonstrate the antitumour effect of 2L therapies, including cabozantinib, after 1L CPI-based combination treatment, regardless of whether 1L CPI-CPI or TKI-CPI therapy is used., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Bone metastases negatively affect prognosis in patients with advanced renal cell carcinoma (aRCC). We conducted a systematic literature review to identify clinical trial publications including patients with aRCC with and without bone metastases., Methods: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42022355436). MEDLINE and Embase databases were searched (September 2, 2022) to identify publications reporting efficacy and safety outcomes for patients with/without bone metastasis from clinical trials of systemic RCC therapies. Risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Results: Of 526 publications screened, 19 were eligible: seven (from five studies) reported phase 3 trials, six reported phase 2 trials, one reported phase 1b/2 trials, and five were pooled analyses. Five publications reported moderate-quality evidence, while 14 were graded as low- or very low-quality evidence, suggesting a high potential for uncertainty. Five studies reported benefits of investigational therapies versus comparators in patients with and without bone metastases; these studies included cabozantinib, nivolumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab treatment arms. Data were also available for nivolumab plus ipilimumab. Bone metastases were consistently associated with poor prognosis in patients with aRCC. Preliminary data support the hypothesis that therapies targeting pathways implicated in the development of bone metastases may be beneficial, and warrant further investigation. However, data to support treatment decision-making are lacking., Conclusion: Our findings highlight the need for clinical data to assist in defining the optimal treatment for patients with aRCC and bone metastasis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Janet Brown: Honoraria: Novartis, Bayer, Amgen, Ipsen, MSD Oncology, Bristol Myers Squibb. Consulting or Advisory Role: Novartis, Bayer, Amgen, Ipsen, MSD Oncology, Bristol Myers Squibb. Speakers’ Bureau: Ipsen, Amgen, MSD. Research Funding: Amgen (Inst), Bayer (Inst). Travel, Accommodations, Expenses: Ipsen, MSD Oncology, Amgen, Novartis, Bayer. Daniele Santini: Honoraria: Speaker honoraria with AstraZeneca, MSD, BMS, Astellas, Janssenn, EISAI, Merck, Pfizer, Bayer, Novartis, AstraZeneca, Lilly. Consulting or Advisory Role: Advisory Board role with AstraZeneca, MSD, BMS, Astellas, Janssenn, EISAI, Merck, Pfizer, Bayer, Novartis, AstraZeneca, Lilly. Natalie Charnley: Honoraria: Lecture fees from Pfizer, Ipsen, and Janssen. Consulting or Advisory Role: Advisory boards with Pfizer, Ipsen, and Janssen. Alessia Ogareva: Employment: Employee of Ipsen. Alison Chisholm: Employee of Oxford PharmaGenesis. Robert Jones: Honoraria: Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Astellas, Janssen, MSD, Pfizer, Merck Serono. Consulting or Advisory Role: Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Novartis/AAA, Astellas, Janssen, MSD, Pfizer, Merck Serono. Research Funding: Received educational grants from Astellas, Bayer, Clovis and Exelixis., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma., Methods: TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete., Findings: Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia., Interpretation: In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MOG reports institutional research grants from Bristol Myers Squibb, Intuitive Surgical, and Bayer Vital; personal consulting fees from AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Pfizer, Astellas Pharma, EUSA Pharma, Merck Serono, Roche Pharma, Eisai, Bayer Vital, Janssen, Gilead, and Novartis; personal honoria from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, Janssen, Astellas Pharma, and Takeda; and travel expenses from Merck Serono, Bristol Myers Squibb, Bayer, Pfizer, and AstraZeneca. PB reports grants from Bristol Myers Squibb, Ipsen, MSD, Pfizer, Merck, AstraZeneca, Janssen, and Gilead; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, AAA Pharma, Novartis, Gilead, and Bayer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Suibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, Bayer, AAA Pharma, and Novartis; and travel expenses Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas Pharma. ManS reports personal consulting fees for advisory boards from Bristol Myers Squibb, MSD, Eisai, Ipsen, and Exelixis; personal honoria for lectures from Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca; and personal participation on advisory boards for Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca. JB reports an educational grant from Astellas Pharma; consulting fees from Bristol Myers Squibb, MSD, Merck, Ipsen, and Pfizer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen and Merck; travel expenses from Ipsen and Merck; and participation on a data safety monitoring board or advisory board for MSD, Pfizer, and Ipsen. BPV reports consulting fees from Bristol Myers Squibb, MSD Oncology, Astellas Pharma, AstraZeneca, Novartis, Bayer, and Advanced Accelerator Applications-Novartis; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, Roche, EUSA Pharma, Pfizer, Merck, Astellas Pharma, AstraZeneca, and Bayer; and travel expenses from Merck, Pfizer, Advanced Accelerator Applications-Novartis, and Roche. KL payment for medical writing (to their institution) for manuscript writing from Bristol Myers Squibb and Intuitive Surgical; and travel expenses from Ipsen. ID reports institutional research grants from Roche and AstraZeneca; honoria for lectures, presentations, or educational events from Bristol Myers Squibb, MSD, Ipsen, Roche Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, and Bayer; travel expenses from Merck-Pfizer, Ipsen, Janssen, Bayer, and AstraZeneca; participation on an advisory board for Bristol Myers Sqibb, MSD, Ipsen, Roche Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclics, and Gilead; is the cofounder of GO NORTE (GU cooperative group, unpaid); is Vice President of Germ Cell Spanish Group (unpaid); is an executive board member of the GUARD consortium (GU cooperative group, unpaid); has received institutional medical writing support from Roche Genentech; and has procured substances for preclinical research purposes from Jansen (institutional research group). GdV reports consulting fees from Bristol Myers Squibb, Astellas Pharma, MSD, Merck, and Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Roche, Novartis, Ipse, Pfizer, Astellas Pharma, Pierre Fabre, MSD, Merck, and Janssen; travel expenses from Roche and MSD; and participation on a data safety monitoring board or advisory board for AstraZeneca. FP reports participation on a data safety monitoring board or advisory board for Daiichi and Novartis. PM reports payment or honoria for lectures, presentation, speaker bureaus, manuscript writing or educational events from Bayer; payments for expert testimony from Amgen; travel expenses from Bayer; and reports participation on a data safety monitoring board or advisory board for Pfizer, Novartis, and Astellas Pharma. LA reports consulting fees, paid to their institution, from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. EE, NC, MarS, US, SF, and GB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Tivozanib is a licensed as first-line treatment for metastatic renal cell carcinoma (mRCC)., Objective: To evaluate the outcomes from tivozanib in a real-world mRCC population., Patients and Methods: Patients with mRCC commencing first-line tivozanib between March 2017 and May 2019 were identified across four specialist cancer centres in the UK. Data relating to response, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were collected retrospectively with censoring on 31 December 2020., Results: A total of 113 patients were identified: median age was 69 years; 78% had ECOG PS 0-1; 82% had clear cell histology; 66% had previous nephrectomy; International Metastatic RCC Database Consortium (IMDC) score was 22% favourable (F), 52% intermediate (I) and 26% poor (P). Twenty-six per cent were switched from another tyrosine kinase inhibitor (TKI) to tivozanib due to toxicity. Median follow-up was 26.6 months with 18% remaining on treatment at data censoring. Median PFS was 8.75 months. Median PFS by IMDC risk group was: F = 23.0 months; I = 10.0 months; P = 3.0 months, p value < 0.0001. Median OS was 25.0 months (F = not reached (NR) with 72% alive at data cut-off; I = 26.0 months; P = 7.0 months, p value < 0.0001). Seventy-seven per cent had an AE of any grade, and 13% had a grade ≥ 3 AE. Eighteen per cent of patients discontinued treatment due to toxicity. No patients who discontinued a prior TKI due to AEs stopped tivozanib due to AEs., Conclusions: These data suggest comparable activity of tivozanib with the pivotal trial data and other TKIs in a real-world population. Its tolerability positions tivozanib as an attractive first-line option for those unsuitable for combination therapies or unable to tolerate other TKIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: To evaluate how efficacy outcomes from real-world data (RWD) can support those from randomized controlled trials (RCTs), in the context of first-line tyrosine kinase inhibitor treatment of metastatic renal cell carcinoma. Patients & methods: PubMed, Ovid, MEDLINE and EMBASE were searched for RCTs and RWD studies with ≥50 adult patients per arm published in 2000-2017. Outcome measures were median progression-free survival, median overall survival and objective response rate. Results: A total of 13 RCTs and 22 RWD studies met eligibility criteria; 31, 28 and 25 studies, respectively, reported median progression-free survival, median overall survival and objective response rate. Summary outcome measures were similar in RWD and RCTs. Conclusion: RWD validates efficacy-based outcomes from RCTs and may provide supportive evidence to inform clinical decisions.

Background: Randomized controlled trials (RCTs) have stringent inclusion criteria and may not fully represent patients seen in everyday clinical practice. Real-world data (RWD) can provide supportive evidence for the effectiveness of medical interventions in more heterogeneous populations than RCTs. Sunitinib is a widely used first-line treatment for patients with metastatic renal cell carcinoma (mRCC)., Objective: This is the first comprehensive meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and RWD., Methods: RCTs and RWD studies published between 2000 and 2017 were identified from PubMed, Ovid, MEDLINE, and EMBASE. Eligible studies contained a cohort of ≥ 50 adult patients with mRCC receiving first-line sunitinib treatment. The meta-analysis combined RWD and RCT treatment groups, adjusting for data type (RCT or RWD). Recorded outcomes were median progression-free survival (mPFS), median overall survival (mOS), and objective response rate (ORR). Publication bias was assessed via review of funnel plots for each outcome measure. A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimates., Results: Of the 3611 studies identified through medical database searches, 22 (15 RWD studies, 7 RCTs) met eligibility criteria and were analyzed. mPFS (18 studies), mOS (19 studies), and ORR (15 studies) were reported for aggregate measures based on 4815, 5321, and 4183 patients, respectively. Reported mPFS (RWD, 7.5-11.0 months; RCTs, 5.6-15.1 months) and ORR data (RWD, 14.0-34.6%; RCTs, 18.8-46.9%) were consistent with the overall confidence estimates (95% confidence interval [CI]) of 9.3 (8.6-10.2) months and 27.9% (24.2-32.0), respectively. Reported mOS showed greater variation in RWD (6.8-33.2 months) compared with RCTs (21.8-31.5 months), with an overall confidence estimate (95% CI) of 23.0 (19.2-27.6) months. Inspection of funnel plots and sensitivity analyses indicated that there was no publication bias for any efficacy endpoint. Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS, or ORR. Interpretation of these results is limited by differences in trial design, cohort characteristics, and missing data., Conclusions: This novel, comprehensive meta-analysis validates sunitinib as an effective first-line treatment for patients with mRCC in both RCTs and everyday clinical practice. The methodology provides a framework for future analyses combining data from RCTs and RWD.

Unlabelled: The magnitude of the injected activity (A(0)) has a direct impact on the statistical quality of PET images. This study aimed to develop a generalized method for maximizing the statistical quality of dynamic PET images by optimizing A(0)., Methods: Patient-specific noise-equivalent counts (PS-NECs) were used as a metric of the statistical quality of each time frame of a dynamic PET image. Previous methodology developed to extrapolate the NEC as a function of A(0) was extended to dynamic PET, enabling the NEC to be extrapolated as a function of both A(0) and the time after injection. This method allowed A(0) to be optimized after a single scan (at a single A(0)), by maximizing the NEC within the time interval for which the parameter estimation is most sensitive. The extrapolation method was validated by a series of (15)O-H(2)O scans of the body acquired in 3-dimensional mode. Each patient (n = 6) underwent between 3 and 6 scans at 1 bed position. The injected activities were varied over a wide range (140-840 MBq). Noise-equivalent counting rate (NECR) versus A(0) curves and the optimal injected activities were calculated from each injection., Results: PS-NECR versus A(0) curves as extrapolated from different injected activities were consistent (coefficient of variation, typically <5%). The optimal injected activities for an individual, as derived from these curves, were also consistent (maximum coefficient of variation, 4.3%). For abdominal (n = 4) and chest (n = 1) scans, we found optimal injected activities of (15)O-H(2)O in the range of 220-350 MBq for estimating blood perfusion (F) and 660-1,070 MBq for estimating the volume of distribution (V(T)). Higher optimal injected activities were found in the case of a pelvic scan (n = 1; 570 MBq for F and 1,530 MBq for V(T))., Conclusion: PS-NECs are a valid and generic method for optimizing the injected activity in PET, allowing scanning protocols to be improved after the collection of an initial, single dynamic dataset. This generic method can be used to estimate the optimal injected activity, which is specific to the patient, tracer, PET scanner, and body region being scanned.

There is a need for direct imaging of effects on tumor vasculature in assessment of response to antiangiogenic drugs and vascular disrupting agents. Imaging tumor vasculature depends on differences in permeability of vasculature of tumor and normal tissue, which cause changes in penetration of contrast agents. Angiogenesis imaging may be defined in terms of measurement of tumor perfusion and direct imaging of the molecules involved in angiogenesis. In addition, assessment of tumor hypoxia will give an indication of tumor vasculature. The range of imaging techniques available for these processes includes positron emission tomography (PET), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), perfusion computed tomography (CT), and ultrasound (US).

Purpose: To compare the ability of positron emission tomography (PET) to predict response to temozolomide vs. temozolomide plus radiotherapy., Methods and Materials: Nineteen patients with high-grade glioma (HGG) were studied. Patients with recurrent glioma received temozolomide 75 mg/m2 daily for 7 weeks (n=8). Newly diagnosed patients received temozolomide 75 mg/m2 daily plus radiotherapy 60 Gy/30 fractions over 6 weeks, followed by six cycles of adjuvant temozolomide 200 mg/m2/day (Days 1-5 q28) starting 1 month after radiotherapy (n=11). [18F]Fluorodeoxyglucose ([18F]FDG) PET scan and magnetic resonance imaging (MRI) were performed at baseline, and 7 and 19 weeks after initiation of temozolomide administration. Changes in glucose metabolic rate (MRGlu) and MRI response were correlated with patient survival., Results: In the temozolomide-alone group, patients who survived>26 vs. or=25%, survived longer than nonresponders with mean survival times of 75 weeks (95% CI, 34-115 vs. 20 weeks (95% CI, 14-26) (p=0.0067). In the small group of patients studied, there was no relationship between MRI response and survival (p=0.52). For patients receiving temozolomide plus radiotherapy, there was no difference in survival between PET responders and nonresponders (p=0.32)., Conclusions: Early changes in MRGlu predict response to temozolomide, but not temozolomide plus radiotherapy.

Molecular imaging allows for the in vivo evaluation of targeted molecules and biological processes in man. Positron emission tomography (PET) is a highly sensitive and quantitative molecular imaging modality, whose utility in clinical and experimental medicine is increasing by the day. In this article, the principles of PET and its currently accepted applications in oncology, such as cancer staging, treatment response assessment and as a prognostic marker are reviewed. Further, the evolving role of PET in areas of oncology such as radiotherapy treatment planning, anti-cancer drug development and the evaluation of patho-physiological processes which drive a cell into neoplastic activity is discussed.