Publications by authors named "Sarah J Welsh"

31 Publications

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

N Engl J Med 2021 11;385(22):2036-2046

From the University of Texas M.D. Anderson Cancer Center, Houston (E.J.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (O.I.); Vanderbilt University Medical Center, Nashville (W.K.R.); University of Pennsylvania, Philadelphia (V.K.N.); the University of Utah, Salt Lake City (B.L.M.); Hôpital Européen Georges-Pompidou, University of Paris, Paris (S.O.); the University of Michigan, Ann Arbor (T.E.); the University of Pittsburgh, Pittsburgh (J.K.M.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (S.J.W.); Merck, Kenilworth, NJ (S.T., E.K.P., R.F.P.); and the Center for Cancer Research, National Cancer Institute, Bethesda, MD (W.M.L., R.S.).

Background: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).

Methods: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.

Results: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).

Conclusions: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
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http://dx.doi.org/10.1056/NEJMoa2103425DOI Listing
November 2021

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BMC Cancer 2021 Nov 18;21(1):1238. Epub 2021 Nov 18.

CRUK Cambridge Centre, University of Cambridge, Cambridge, UK.

Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7 commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE).

Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by K on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging.

Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda.

Trial Registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .
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http://dx.doi.org/10.1186/s12885-021-08965-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600815PMC
November 2021

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials.

Br J Cancer 2021 Nov 8. Epub 2021 Nov 8.

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

Background: Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment.

Methods: Motivated by the WIRE trial in renal cell carcinoma (NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms.

Results: The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick.

Conclusions: We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.
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http://dx.doi.org/10.1038/s41416-021-01613-5DOI Listing
November 2021

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

PLoS One 2021 26;16(10):e0258988. Epub 2021 Oct 26.

University of Cambridge, Cambridge, United Kingdom.

Purpose: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI.

Method: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival.

Results: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001).

Conclusions: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS.

Trial Registration: EudraCtNo: 2005-004502-82.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258988PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547646PMC
October 2021

Early detection of kidney cancer using urinary proteins: a truly non-invasive strategy.

BJU Int 2021 Sep 27. Epub 2021 Sep 27.

Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.

Objectives: To review urinary protein biomarkers as potential non-invasive, easily obtainable, early diagnostic tools in renal cell carcinoma (RCC).

Methods: A PubMed database search was performed up to the year 2020 to identify primary studies reporting potential urinary protein biomarkers for RCC. Separate searches were conducted to identify studies describing appropriate methods of developing cancer screening programmes and detection of cancer biomarkers.

Results: Several urinary protein biomarkers are under validation for RCC diagnostics, e.g. aquaporin-1, perilipin-2, carbonic anhydrase-9, Raf-kinase inhibitory protein, nuclear matrix protein-22, 14-3-3 Protein β/α and neutrophil gelatinase-associated lipocalin. However, none has yet been validated or approved for clinical use due to low sensitivity or specificity, inconsistencies in appropriate study design, or lack of external validation.

Conclusions: Evaluation of biomarkers' feasibility, sample preparation and storage, biomarker validation, and the application of novel technologies may provide a solution that maximises the potential for a truly non-invasive biomarker in early RCC diagnostics.
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http://dx.doi.org/10.1111/bju.15601DOI Listing
September 2021

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

BJU Int 2021 Sep 22. Epub 2021 Sep 22.

Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Objective: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial.

Patients And Methods: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory.

Results: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (K , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03).

Conclusion: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.
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http://dx.doi.org/10.1111/bju.15600DOI Listing
September 2021

Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth.

Nat Commun 2021 01 29;12(1):683. Epub 2021 Jan 29.

MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, England.

Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
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http://dx.doi.org/10.1038/s41467-021-20982-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846803PMC
January 2021

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Nat Commun 2020 08 27;11(1):4306. Epub 2020 Aug 27.

Experimental Cancer Genetics, The Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
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http://dx.doi.org/10.1038/s41467-020-18060-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453196PMC
August 2020

Biomarkers Predicting for Response and Relapse with Melanoma Systemic Therapy.

Acta Derm Venereol 2020 Jun;100(11):adv00142

For all primary cutaneous squamous cell carcinomas (cSCCs), physical examination should include full skin examination, recording of tumour diameter and regional lymph-node-basin status. Surgery is the treatment of choice, with a minimal 5-mm margin. For elderly patients with well-differentiated tumours, other surgical modalities can be explored. Surgery for organ-transplant recipients should not be delayed. The issue with cSCC is identifying high-risk tumours with staging, as this may alter treatment and follow-up schedules. Adjuvant radiation therapy should be considered for incomplete resection, when re-excision is impossible or there are poor-prognosis histological findings. Recommendations are at least biannual dermatological surveillance for 2 years, but in elderly patients with small, well-differentiated tumours long-term follow-up is not always necessary. In case of positive lymph nodes, radical dissection is needed, with regional postoperative adjuvant radiation. Advanced cSCCs are defined as unresectable local, regional or distant disease requiring systemic treatment. Their only approved treat-ment is the PD-1 inhibitor, cemiplimab. Trials evaluating adjuvant or neo-adjuvant anti-PD-1 are ongoing. Platin-based chemo or anti-epidermal growth-factor-receptor therapies are possible second-line treatments. For transplant patients, minimizing immunosuppression and switching to sirolimus must be considered at first appearance of cSCC.
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http://dx.doi.org/10.2340/00015555-3497DOI Listing
June 2020

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

Biology (Basel) 2020 Apr 7;9(4). Epub 2020 Apr 7.

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
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http://dx.doi.org/10.3390/biology9040074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236799PMC
April 2020

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.

Genome Med 2020 02 28;12(1):23. Epub 2020 Feb 28.

Hutchison/MRC Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK.

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established.

Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine.

Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings.

Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
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http://dx.doi.org/10.1186/s13073-020-00723-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048087PMC
February 2020

Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor-targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data.

Eur Urol Oncol 2020 04 16;3(2):168-173. Epub 2020 Jan 16.

Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK. Electronic address:

Background: Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting.

Objective: The aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN).

Design, Setting, And Participants: Pooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN.

Outcome Measurements And Statistical Analysis: Overall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group.

Results And Limitations: Patients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0-51.0) compared with 22.8 mo (95% CI 17.9-30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52-0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort.

Conclusions: In MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients.

Patient Summary: In this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.
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http://dx.doi.org/10.1016/j.euo.2019.12.004DOI Listing
April 2020

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound.

Eur Urol Focus 2021 03 14;7(2):407-419. Epub 2019 Sep 14.

Cambridge Centre for Health Services Research, University of Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge, UK; Health Economics Group, Norwich Medical School, University of East Anglia, Norwich, UK. Electronic address:

Background: Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value.

Objective: To determine (1) whether current evidence suggests that screening is potentially cost-effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps.

Design, Setting, And Participants: A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted.

Intervention: A single focused renal ultrasound scan compared with standard of care (no screening).

Outcome Measurements And Statistical Analysis: Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum.

Results And Limitations: Given a prevalence of RCC of 0.34% (0.18-0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08-0.25%), screening 60-yr-old women resulted in an ICER of £37327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60yr. Given the willingness to pay a threshold of £30000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities.

Conclusions: Current evidence suggests that one-off screening of 60-yr-old men is potentially cost-effective and that further research into this topic would be of value to society.

Patient Summary: Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed.
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http://dx.doi.org/10.1016/j.euf.2019.09.002DOI Listing
March 2021

Prognostic effect of cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: a comparative study using inverse probability of treatment weighting.

World J Urol 2018 Mar 18;36(3):417-425. Epub 2017 Dec 18.

Department of Urology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.

Purpose: To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT).

Methods: We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses.

Results: Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01).

Conclusions: IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials.
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http://dx.doi.org/10.1007/s00345-017-2154-xDOI Listing
March 2018

Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients.

Biomark Res 2017 10;5:32. Epub 2017 Nov 10.

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.

Background: Selective kinase and immune checkpoint inhibitors, and their combinations, have significantly improved the survival of patients with advanced metastatic melanoma. Not all patients will respond to treatment however, and some patients will present with significant toxicities. Hence, the identification of biomarkers is critical for the selection and management of patients receiving treatment. Biomarker discovery often involves proteomic techniques that simultaneously profile multiple proteins but few studies have compared these platforms.

Methods: In this study, we used the multiplex bead-based Eve Technologies Discovery assay and the aptamer-based SomaLogic SOMAscan assay to identify circulating proteins predictive of response to immunotherapy in melanoma patients treated with combination immune checkpoint inhibitors. Expression of four plasma proteins were further validated using the bead-based Millipore Milliplex assay.

Results: Both the Discovery and the SOMAscan assays detected circulating plasma proteins in immunotherapy-treated melanoma patients. However, these widely used assays showed limited correlation in relative protein quantification, due to differences in specificity and the dynamic range of protein detection. Protein data derived from the Discovery and Milliplex bead-based assays were highly correlated.

Conclusions: Our study highlights significant limitations imposed by inconsistent sensitivity and specificity due to differences in the detection antibodies or aptamers of these widespread biomarker discovery approaches. Our findings emphasize the need to improve these technologies for the accurate identification of biomarkers.
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http://dx.doi.org/10.1186/s40364-017-0112-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681837PMC
November 2017

Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?

Eur J Cancer 2016 07 24;62:76-85. Epub 2016 May 24.

Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

Treatment of BRAF-mutant metastatic melanoma with mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors has revolutionised management and improved outcomes for patients with advanced stage disease. However, acquired resistance to MAPK inhibitor therapy develops in the majority of patients at approximately 12 months and multiple mechanisms lead to resistance. Understanding the mechanisms of resistance is therefore critical for the development of more effective therapeutic strategies in BRAF-mutant melanoma. Recently, several distinct mechanisms of resistance to BRAF-inhibition have been proposed based on data obtained in experimental melanoma cell models and small series of human tumour samples. These include reactivation of the MAPK pathway resulting in continued extracellular signal-regulated kinase activation and activation of parallel signalling pathways including the PI3K-mTOR (phosphoinositide 3-kinase-mammalian target of rapamycin) pathway. Alterations in how the cells of the immune system respond to melanoma cells treated with targeted therapy may also influence response and progression. In this review, we discuss these mechanisms and identify potential therapeutic strategies to overcome resistance which, in turn, will lead to improved outcomes for patients with metastatic melanoma.
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http://dx.doi.org/10.1016/j.ejca.2016.04.005DOI Listing
July 2016

Melanocyte reprogramming requires chromatin and transcription remodelling.

Pigment Cell Melanoma Res 2016 May 3;29(3):260-1. Epub 2016 Mar 3.

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http://dx.doi.org/10.1111/pcmr.12457DOI Listing
May 2016

Pazopanib for the treatment of renal cell carcinoma.

Future Oncol 2015 ;11(8):1169-79

Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.

The incidence and mortality from renal cell cancer (RCC) is increasing. RCC tumors are particularly vascular in nature as a result of disruption of the VHL gene and/or its upstream pathway leading to upregulation of the hypoxia-inducible factor transcription factor. The hypoxia-inducible factor pathway drives angiogenesis by upregulating VEGF and bFGF, amongst other proangiogenic downstream target genes. Therapies which target angiogenesis have been successful in treating metastatic RCC (mRCC) and the receptor tyrosine kinase inhibitor, pazopanib, is licensed for first line treatment of mRCC. This review details the past, current and future roles of pazopanib in the treatment of mRCC.
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http://dx.doi.org/10.2217/fon.14.274DOI Listing
February 2016

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma.

Ther Adv Med Oncol 2015 Mar;7(2):122-36

Cambridge Cancer Centre Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.

Following the discovery that nearly half of all cutaneous melanomas harbour a mutation in the BRAF gene, molecular targeted kinase inhibitors have been developed for the treatment of metastatic melanoma and have dramatically improved outcomes for those patients with BRAF mutant disease, achieving high levels of objective response and prolonging survival. Since 2011, the specific BRAF targeted agents, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been licensed for the treatment of patients with unresectable or metastatic BRAF mutant melanoma. As with other biological targeted agents, these drugs are associated with predictable patterns of adverse events. Proactive toxicity management is important to ensure maximum treatment benefit and avoid unnecessary treatment discontinuation. We review the most common and serious adverse events associated with BRAF targeted agents and suggest management algorithms to guide practitioners in using these drugs effectively in the clinic.
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http://dx.doi.org/10.1177/1758834014566428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346212PMC
March 2015

The clinical use of granulocyte-colony stimulating factor.

Br J Hosp Med (Lond) 2014 Feb;75(2):C29-32

Academic Clinical Lecturer in Medical Oncology in the Department of Oncology, Cambridge University Health Partners, Addenbrooke’s Hospital, Cambridge.

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http://dx.doi.org/10.12968/hmed.2014.75.Sup2.C29DOI Listing
February 2014

Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.

Sci Rep 2013 Sep 30;3:2799. Epub 2013 Sep 30.

UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.

The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression.
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http://dx.doi.org/10.1038/srep02799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810677PMC
September 2013

Adjuvant therapy in renal cell carcinoma-past, present, and future.

Semin Oncol 2013 Aug;40(4):482-91

Department of Oncology, Cambridge University Biomedical Research Campus, Addenbrooke's Hospital, Cambridge, United Kingdom.

To date, no effective adjuvant treatment for renal cell carcinoma (RCC) has been described, but research in this area is important since the 5-year relapse rate for intermediate- and high-risk early-stage RCC is 30%-40%. Metastatic RCC can be treated successfully with immune therapy and targeted therapy. Adjuvant trials with immune therapy have been conducted, but they reported no benefit in disease-free survival, and clinical trials with targeted agents have not yet reported results. Further advances in our understanding of the molecular pathogenesis of RCC will identify additional potential targets for adjuvant treatment trials. Future challenges will consequently include target identification, as well as trial design to answer multiple trial questions concurrently, comprehensively, and economically. We review the past efforts, summarize the current adjuvant clinical trial landscape, and consider the challenges in adjuvant trials for RCC. Additionally, we identify potential future adjuvant trial treatments and propose an alternative design for future adjuvant clinical trials.
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http://dx.doi.org/10.1053/j.seminoncol.2013.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765962PMC
August 2013

A novel series of G-quadruplex ligands with selectivity for HIF-expressing osteosarcoma and renal cancer cell lines.

Bioorg Med Chem Lett 2012 Sep 14;22(18):5984-8. Epub 2012 Jul 14.

UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.

A series of naphthalene derivatives with disubstituted triazole side-arms have been assembled by click chemistry. Lead compounds show a high level of selectivity for renal, osteo- and Ewing's sarcomas that express the HIF-1α transcription factor. They also interact selectively with the quadruplex DNAs located in the promoter of the HIF genes and it is suggested that the mechanism of action involves inhibition of transcription by drug-mediated quadruplex stabilization in these regions.
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http://dx.doi.org/10.1016/j.bmcl.2012.07.009DOI Listing
September 2012

Management of the patient with neutropenic sepsis.

Br J Hosp Med (Lond) 2012 Jul;73(7):C101-3

Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.12968/hmed.2012.73.sup7.c101DOI Listing
July 2012

Assessment of the patient with neutropenic sepsis.

Br J Hosp Med (Lond) 2012 Jun;73(6):C89-92

Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.12968/hmed.2012.73.sup6.c89DOI Listing
June 2012

68Ga-DOTA-TATE PET vs. 123I-MIBG in identifying malignant neural crest tumours.

Mol Imaging Biol 2011 Aug;13(4):769-75

Department of Nuclear Medicine, Imperial College Healthcare Trust, London, UK.

Purpose: We aimed to compare imaging with (123)I-MIBG and (68)Ga-DOTA-TATE in neural crest tumours (NCT) to see if the latter could offer more advantage in detecting extra lesions and have higher sensitivity for malignant lesions.

Procedures: We retrospectively reviewed 12 patients (M = 10, F = 2; age range 20-71 years) with NCT (phaeochromocytomas = 7, paragangliomas = 4, medullary thyroid cancer = 1) who underwent both (68)Ga-DOTA-TATE positron emission tomography (PET) or PET/computed tomography (CT) and (123)I-MIBG single-photon emission computed tomography within 6 months. Visual assessment of all lesions and measurement of target/non-target (T/N) ratio in selected lesions were performed. Five patients (aged 50 or less) had SDHB screening results correlated with imaging results of both radiopharmaceuticals. All patients had contrast-enhanced CT and/or other cross-sectional imaging.

Results: (68)Ga-DOTA-TATE PET showed tumour lesions in ten out of 12 patients with confirmed disease, while (123)I-MIBG showed lesions in five out of 12 patients. In one patient, both (68)Ga-DOTA-TATE PET and (123)I-MIBG were negative, but CT, magnetic resonance imaging, and 2-deoxy-2-[(18)F]fluoro-D-glucose PET scans identified a lesion in the thorax. (68)Ga-DOTA-TATE and (123)I-MIBG detected a total of 30 lesions, of which 29/30 were positive with (68)Ga-DOTA-TATE and 7/30 with (123)I-MIBG. We also found higher incidence of SDHB positive results in patients with positive (68)Ga-DOTA-TATE.

Conclusion: Our limited data suggest that (68)Ga-DOTA-TATE is a better imaging agent for NCT and detects significantly more lesions with higher T/N ratio compared to (123)I-MIBG. (68)Ga-DOTA-TATE was more likely to detect malignant lesions as indicated by correlating imaging results with SDHB screening.
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http://dx.doi.org/10.1007/s11307-010-0396-8DOI Listing
August 2011

The hypoxic inducible stress response as a target for cancer drug discovery.

Semin Oncol 2006 Aug;33(4):486-97

Oxford Medical School, University of Oxford, Oxford, UK.

All solid tumors experience some degree of hypoxia. The response to the stress of hypoxia is mediated in large part by the hypoxia inducible factor-1 (HIF-1) transcription factor that increases the expression of a variety of genes that allow the tumor to survive and grow in the hostile hypoxic environment. Increased tumor HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis. This has lead to the current interest in HIF-1 as a cancer drug target. HIF-1 activity in tumors depends on the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions or through the activation of oncogenes and/or inactivation of tumor-suppressor genes. HIF-1alpha level and HIF-1 activity are regulated by multiple pathways involving transcription, translation, post-translational modification, and the interaction with other transcription factors. A number of agents have been reported to block HIF-1 activity, acting on all of these mechanisms. Not all of the agents have been shown to block tumor HIF-1 activity in vivo. Some have shown marked HIF-1 inhibition and anti-tumor activity. There are agents already, or soon to be, tested in the clinic as anti-tumor inhibitors of HIF-1. The challenges will be to determine whether the effects of these agents that are seen is due to HIF-1 inhibition and to identify which patients are most likely to benefit from treatment with HIF-1 inhibitors.
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http://dx.doi.org/10.1053/j.seminoncol.2006.04.011DOI Listing
August 2006

Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors.

Neoplasia 2005 Apr;7(4):324-30

Department of Biochemistry and Molecular Biophysics, University of Arizona Cancer Center, Tucson, AZ 85724, USA.

Metastatic tumors generally exhibit aerobic glycolysis (the Warburg effect). The advent of [18F]fluorodeoxyglucose positron emission tomography imaging, coupled with recent findings linking hypoxia-inducible factor (HIF-1alpha) overexpression to aggressive cancers, has rekindled an interest in this aspect of tumor metabolism. These studies explore the role of HIF-1alpha in human breast cancer lines and its relationship to glycolytic regulation. Here we demonstrate that, under normal oxygen conditions, nonmetastatic cells consume less glucose and express low HIF-1alpha, whereas metastatic cells constitutively express high glycolysis and HIF-1alpha, suggesting that dysregulation of HIF-1alpha may induce the Warburg effect. This hypothesis was tested by renormalizing HIF-1alpha levels in renal carcinoma cells, leading to inhibition of aerobic glycolysis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1501147PMC
http://dx.doi.org/10.1593/neo.04430DOI Listing
April 2005

Hypoxia inducible factor as a cancer drug target.

Curr Cancer Drug Targets 2003 Dec;3(6):391-405

Arizona Cancer Center, 1515 N Campbell Avenue, Tucson, Arizona 85724, USA.

Solid tumors with areas of hypoxia are the most aggressive and difficult tumors to treat and are a major reason for treatment failure. Previous attempts to treat hypoxic tumors have been largely unsuccessful and new agents are needed. The cellular response to hypoxia is controlled by the hypoxia inducible factor-1 (HIF-1) transcription factor. HIF-1 consists of an oxygen regulated alpha subunit and a constitutively expressed beta subunit, which bind and translocate to the nucleus to activate transcription of a range of genes involved in increasing glycolysis, inhibition of apoptosis and promotion of angiogenesis and metastasis. The activity of the HIF-1 complex is primarily controlled by levels of the alpha subunit and a series of mechanisms exist to control activation of the HIF-1 pathway. HIF-1alpha is over-expressed in a large number of human tumors and its over-expression correlates with poor prognosis and treatment failure. HIF-1 is therefore an important target for cancer chemotherapy. This review summarizes the literature surrounding the control of HIF-1, its role in cancer and potential drugs to target the pathway for cancer therapy.
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http://dx.doi.org/10.2174/1568009033481732DOI Listing
December 2003

The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation.

Mol Cancer Ther 2003 Mar;2(3):235-43

Arizona Cancer Center, Tucson, Arizona 85724, USA.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in tumor growth by increasing resistance to apoptosis and the production of angiogenic factors such as vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer comprised of oxygen-regulated HIF-1alpha and constitutively expressed HIF-1beta subunits. The redox protein thioredoxin-1 (Trx-1), which is found at high levels in many human cancers, increases both aerobic and hypoxia-induced HIF-1alpha protein in cells leading to increased expression of HIF-regulated genes. We have investigated whether two cancer drugs that inhibit Trx-1 signaling, PX-12 (1-methylpropyl 2-imidazolyl disulfide) and pleurotin, decrease HIF-1alpha protein levels and the expression of downstream target genes. Treatment of MCF-7 human breast cancer and HT-29 human colon carcinoma cells with PX-12 and pleurotin prevented the hypoxia (1% oxygen)-induced increase in HIF-1alpha protein. HIF-1-trans-activating activity, VEGF formation, and inducible nitric oxide synthase were also decreased by treatment with PX-12 and pleurotin under hypoxic conditions. PX-12 and pleurotin also decreased HIF-1alpha protein levels and HIF-1 trans-activation in RCC4 renal cell carcinoma cells that constitutively overexpress HIF-1alpha protein because of loss of the pVHL gene, indicating that HIF-1alpha is inhibited independently of the pVHL pathway. HIF-1alpha and VEGF protein levels in MCF-7 tumor xenografts in vivo were decreased by PX-12 treatment of mice. The results suggest that inhibition of HIF-1alpha by Trx-1 inhibitors may contribute to the growth inhibitory and antitumor activity of these agents.
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March 2003
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