Publications by authors named "Maxine G B Tran"

28 Publications

  • Page 1 of 1

TCR Gene Therapy: Challenges, Opportunities, and Future Directions.

Cells 2020 Dec 1;9(12). Epub 2020 Dec 1.

Division of Surgery and Interventional Science, University College London, Royal Free Hospital, London NW3 2PF, UK.

Adoptive immunotherapy with gene-engineered T cells has provided new treatment options for cancer patients [...].
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http://dx.doi.org/10.3390/cells9122567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760667PMC
December 2020

Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development.

Nat Immunol 2020 11 31;21(11):1408-1420. Epub 2020 Aug 31.

Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell-activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.
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http://dx.doi.org/10.1038/s41590-020-0772-8DOI Listing
November 2020

Oncocytoma: risk of promoting unnecessary surgery.

World J Urol 2020 Jul 9. Epub 2020 Jul 9.

Division of Surgery and Interventional Science, University College London, London, UK.

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http://dx.doi.org/10.1007/s00345-020-03347-0DOI Listing
July 2020

Independence of HIF1a and androgen signaling pathways in prostate cancer.

BMC Cancer 2020 May 25;20(1):469. Epub 2020 May 25.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK.

Background: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated.

Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq.

Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic.

Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.
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http://dx.doi.org/10.1186/s12885-020-06890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249645PMC
May 2020

Outcomes of Renal Tumors Treated by Image-Guided Percutaneous Cryoablation: Immediate and 3- and 5-Year Outcomes at a Regional Center.

AJR Am J Roentgenol 2020 07 14;215(1):242-247. Epub 2020 Apr 14.

Imaging Department, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

The purpose of this study was to evaluate the immediate and 3- and 5-year outcomes of patients with clinical stage T1 (cT1) biopsy-proven renal cell carcinoma (RCC) treated by image-guided percutaneous cryoablation at a regional interventional oncology center. A prospectively maintained local interventional radiology database identified patients with cT1 RCC lesions that were treated by percutaneous cryoablation. Technical success, procedural complications (graded using the Clavien-Dindo classification system), and the residual unablated tumor rate were collated. Local tumor progression-free survival was estimated using Kaplan-Meier estimates. A total of 180 patients with 185 separate cT1 RCC lesions were identified. Mean patient age was 68.4 years (range, 34.1-88.9 years) and 52 patients (28.9%) were women. There were 168 (90.8%) and 17 (9.2%) cT1a and cT1b lesions, respectively, with a mean lesion size of 28.5 mm (range, 11-58 mm). Technical success was achieved in 183 of 185 (98.9%) patients. The major complication rate (Clavien-Dindo classification ≥ grade III) was 2.2% (four out of 185). Residual unablated tumor on the first follow-up scan was identified in four of 183 tumors (2.2%). Estimated local tumor progression-free survival at 3 and 5 years was 98.3% and 94.9%, respectively. No distant metastases or deaths attributable to RCC occurred. Mean estimated glomerular filtration rate (eGFR) before the procedure was 72.4 ± 18.5 (SD) mL/min/1.73 m and this was not statistically significantly different after the procedure (69.7 ± 18.8 mL/min/1.73 m), at 1 year (70.7 ± 16.4 mL/min/1.73 m), or at 2 years (69.8 ± 18.9 mL/min/1.73 m) ( > 0.05). These data add to the accumulating evidence that image-guided cryoablation is an efficacious treatment for selected cT1 RCC with a low complication rate and ro bust 3- and 5-year outcomes.
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http://dx.doi.org/10.2214/AJR.19.22213DOI Listing
July 2020

Acceptability and feasibility study of patient-specific 'tumouroids' as personalised treatment screening tools: Protocol for prospective tissue and data collection of participants with confirmed or suspected renal cell carcinoma.

Int J Surg Protoc 2019 2;14:24-29. Epub 2019 Apr 2.

Faculty of Medical Science, University College London, UK.

Introduction: 'Personalised medicine' aims to tailor interventions to the individual, and has become one of the fastest growing areas of cancer research. One of these approaches is to harvest cancer cells from patients and grow them in the laboratory, which can then be subjected to treatments and the response assessed. We have developed a 3D tumour model with a complex protein matrix that mimics the tumour stroma, cell to cell and cell-matrix interactions seen , called a tumouroid. In this study, we test the acceptability and feasibility of using this model to establish patient-derived tumouroids.

Methods And Analysis: This is a first in-human study using prospective tissue and data collection of adult participants with confirmed or suspected renal cell carcinoma. The goals of the study are to assess patient acceptability to the use of patient-derived tumour models for future treatment decisions, and to assess the feasibility of generating patient-specific renal cancer tumouroids that can be challenged with drugs. These goals will be realised through the collection of tumour samples (expected n = 10), participant-completed questionnaires (expected n = 10), and in-depth semi-structured interviews with patients (expected n = 5). Collected multiregional tumour samples will be dissociated to isolate primary cells which are then expanded and incorporated into tumouroids. Drug challenge will ensue and the response will be categorised into "responder", "weak responder", and "non-responder". Statistical analysis will be descriptive.

Ethics And Dissemination: The study has ethical approval (REC reference 17/LO/1744). Findings will be made available to patients, clinicians, funders, and the National Health Service (NHS) through presentations at national and international meetings, peer-reviewed publications, social media and patient support groups.

Trial Registration: Registered on ClinicalTrials.gov (NCT03300102).
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http://dx.doi.org/10.1016/j.isjp.2019.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913561PMC
April 2019

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Re: Selecting Patients with Small Renal Masses for Active Surveillance: A Domain Based Score from a Prospective Cohort Study.

J Urol 2020 01 3;203(1):206-207. Epub 2019 Sep 3.

Division of Surgery and Interventional Science, University College London, and Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1097/JU.0000000000000519DOI Listing
January 2020

Qualitative exploration of the renal stone patients' experience and development of the renal stone-specific patient-reported outcome measure.

BJU Int 2020 01 1;125(1):123-132. Epub 2019 Aug 1.

Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Objectives: To investigate the experience of patients living with renal calculi via a qualitative methodology, aiming to develop and validate a disease-specific patient-reported outcome measure (PROM) for renal stones, the Cambridge Renal Stone PROM (CReSP).

Patients, Subjects And Methods: Patients with radiologically confirmed renal calculi who had undergone a range of management options were invited to focus groups or semi-structured interviews to elicit patient input and generate the PROM content. The developed renal stone PROM underwent validity studies included Cronbach's α for internal consistency, Spearman's and Pearson's correlation coefficients for test-retest reliability. Discriminant validity was assessed by Pearson's correlation coefficients vs the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Our project has Health and Social Care Research Ethics Committee approval.

Results: A total of 106 subjects participated in creating the newly developed PROM. In all, 36 patients were invited to 22 semi-structured interviews and four focus groups, until reaching saturation. Major issues reported, and themes selected for the renal stone PROM included pain, anxiety, limitations to social life and tiredness, urinary symptoms, dietary changes' impacts, and gastrointestinal tract symptoms. Reliability analysis for 30 patients to determine internal consistency using Cronbach's α with a mean (range) of 0.91 (0.90-0.93) within domains and Cronbach's α between domains was 0.92. Average inter-item Pearson's and Spearman's correlation within domains was performed, with a Pearson's correlation mean (range) of 0.77 (0.73-0.85) and Spearman's correlation mean (range) of 0.72 (0.63-0.77). The test-retest Pearson's correlation mean (range) was 0.85 (0.57-0.95). Validity assessment was performed for 20 patients vs 20 controls. Pearson's correlation with EQ-5D-5L was -0.74, showing the newly developed PROM successfully discriminated patients with kidney stones. Our final renal stone PROM consists of 14 questions that are rated on a Likert scale; the higher the score, the worse the effect on a patient's quality of life.

Conclusions: Although pain was the most frequent symptom, other health-related and social well-being issues significantly impacted patients' lives. Our validated patient-derived CReSP is a new instrument, specifically tailored to measure renal stone disease health outcomes from the patient's point of view.
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http://dx.doi.org/10.1111/bju.14873DOI Listing
January 2020

Guideline adherence for the surgical treatment of T1 renal tumours correlates with hospital volume: an analysis from the British Association of Urological Surgeons Nephrectomy Audit.

BJU Int 2020 01 18;125(1):73-81. Epub 2019 Aug 18.

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objective: To assess European Association of Urology guideline adherence on the surgical management of patients with T1 renal tumours and the effects of centralisation of care.

Patients And Methods: Retrospective data from all kidney tumours that underwent radical nephrectomy (RN) or partial nephrectomy (PN) in the period 2012-2016 from the British Association of Urological Surgeons Nephrectomy Audit were retrieved and analysed. We assessed total surgical hospital volume (HV; RN and PN performed) per centre, PN rates, complication rates, and completeness of data. Descriptive analyses were performed, and confidence intervals were used to illustrate the association between hospital volume and proportion of PN. Chi- squared and Cochran-Armitage trend tests were used to evaluate differences and trends.

Results: In total, 13 045 surgically treated T1 tumours were included in the analyses. Over time, there was an increase in PN use (39.7% in 2012 to 44.9% in 2016). Registration of the Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) complexity score was included in March 2016 and documented in 39% of cases. Missing information on postoperative complications appeared constant over the years (8.5-9%).  A clear association was found between annual HV and the proportion of T1 tumours treated with PN rather than RN (from 18.1% in centres performing <25 cases/year [lowest volume] to 61.8% in centres performing ≥100 cases/year [high volume]), which persisted after adjustment for PADUA complexity. Overall and major (Clavien-Dindo grade ≥III) complication rate decreased with increasing HV (from 12.2% and 2.9% in low-volume centres to 10.7% and 2.2% in high-volume centres, respectively), for all patients including those treated with PN.

Conclusion: Closer guideline adherence was exhibited by higher surgical volume centres. Treatment of T1 tumours using PN increased with increasing HV, and was accompanied by an inverse association of HV with complication rate. These results support the centralisation of kidney cancer specialist cancer surgical services to improve patient outcomes.
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http://dx.doi.org/10.1111/bju.14862DOI Listing
January 2020

Protocol for a feasibility study of a cohort embedded randomised controlled trial comparing phron paring reatment (NEST) for small renal masses.

BMJ Open 2019 06 11;9(6):e030965. Epub 2019 Jun 11.

Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, London, UK.

Introduction: Small renal masses (SRMs; ≤4 cm) account for two-thirds of new diagnoses of kidney cancer, the majority of which are incidental findings. The natural history of the SRM seems largely indolent. There is an increasing concern regarding surgical overtreatment and the associated health burden in terms of morbidity and economy. Observational data support the safety and efficacy of percutaneous cryoablation but there is an unmet need for high-quality evidence on non-surgical management options and a head-to-head comparison with standard of care is lacking. Historical interventional trial recruitment difficulties demand novel study conduct approaches. We aim to assess if a novel trial design, the cohort embedded randomised controlled trial (RCT), will enable carrying out such a comparison.

Methods And Analysis: Single-centre prospective cohort study of adults diagnosed with SRM (n=200) with an open label embedded interventional RCT comparing nephron sparing interventions. Cohort participants will be managed at patient and clinicians' discretion and agree with longitudinal clinical data and biological sample collection, with invitation for trial interventions and participation in comparator control groups. Cohort participants with biopsy-proven renal cell carcinoma eligible for both percutaneous cryoablation and partial nephrectomy will be randomly selected (1:1) and invited to consider percutaneous cryoablation (n=25). The comparator group will be robotic partial nephrectomy (n=25). The primary outcome of this feasibility study is participant recruitment. Qualitative research techniques will assess barriers and recruitment improvement opportunities. Secondary outcomes are participant trial retention, health-related quality of life, treatment complications, blood transfusion rate, intensive care unit admission and renal replacement requirement rates, length of hospital stay, time to return to pre-treatment activities, number of work days lost, and health technologies costs.

Ethics And Dissemination: Ethical approval has been granted (UK HRA REC 19/EM/0004). Study outputs will be presented and published.

Trial Registration: ISRCTN18156881; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-030965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577353PMC
June 2019

Re: Philip S. Macklin, Mark E. Sullivan, Charles R. Tapping, et al. Tumour Seeding in the Tract of Percutaneous Renal Tumour Biopsy: A Report on Seven Cases from a UK Tertiary Referral Centre. Eur Urol 2019;75:861-7.

Eur Urol 2019 06 2;75(6):e179-e180. Epub 2019 Mar 2.

University College London, Division of Surgery and Interventional Science, Royal Free Hospital, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.eururo.2019.02.030DOI Listing
June 2019

Re: The Temporal Association of Robotic Surgical Diffusion with Overtreatment of the Small Renal Mass: P. H. Shah, M. A. Alom, B. C. Leibovich, R. H. Thompson, R. G. Uzzo, L. R. Kavoussi, L. Richstone, B. Bhindi, E. B. Habermann, V. Joshi and S. A. BoorjianJ Urol 2018; 200: 981-988.

J Urol 2019 03;201(3):626-627

Division of Surgery and Interventional Science, University College London and Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1016/j.juro.2018.10.011DOI Listing
March 2019

Management of Small Renal Masses.

Radiology 2018 10 4;289(1):272-273. Epub 2018 Sep 4.

Division of Surgery and Interventional Science, University College London, London, England.

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http://dx.doi.org/10.1148/radiol.2018181391DOI Listing
October 2018

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors.

Science 2018 08;361(6402):594-599

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
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http://dx.doi.org/10.1126/science.aat1699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104812PMC
August 2018

Uncoupling Diagnosis and Treatment of Incidentally Imaged Renal Masses.

JAMA Intern Med 2018 05;178(5):728

Division of Surgery and Interventional Science, University College London, London, England.

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http://dx.doi.org/10.1001/jamainternmed.2018.1186DOI Listing
May 2018

Development of a Disease-Specific Ureteral Calculus Patient Reported Outcome Measurement Instrument.

J Endourol 2018 06 9;32(6):548-558. Epub 2018 Apr 9.

1 Department of Urology, Addenbrooke's Hospital, Cambridge University , Cambridge, United Kingdom .

Introduction: Patient reported outcome measures (PROMs) are powerful instruments to assess the impact of a disease on health from the patient's perspective. We describe the process of designing, testing, and validating the Cambridge Ureteral Stone PROM (CUSP).

Materials And Methods: Patients recently diagnosed with ureteral stones were approached for participation in focus groups, structured interviews, and test-retest validation studies. Statistical tests included Cronbach's alpha for internal consistency, Spearman's and Pearson's correlation coefficients for test-retest validity, permutation tests of equality of means and Spearman's correlation coefficients for discriminant validity.

Results: Forty-three patients participated in the development of the CUSP. Twenty-two patients were involved in the focus groups and structured interviews and a further 21 participated in the prospective test-retest study. Expressed comments were grouped into seven broad health domains: pain, fatigue, sleep disturbance, work and daily activities, anxiety, gastrointestinal (GI) symptoms, and urinary symptoms. Items were selected from established PROM platforms to form the draft (dCUSP) instrument, which was then used for test-retest validation and item reduction. All domains scored highly for Cronbach's alpha (>0.8), with the exception of GI symptoms. Large Spearman's (>0.76) and Pearson's correlation estimates (>0.83) were obtained for test-retest validity, suggesting that answers were reliable through the time period tested. The estimates of the Spearman's correlation coefficient between each pair of domains ranged from 0.17 to 0.78 and the upper bounds of the corresponding 95% confidence intervals were all smaller than 0.95, suggesting that each domain measures something different. The tests of equality of the mean of scores of the control (n = 25) and patient groups were all significant, suggesting that CUSP successfully discriminated patients suffering from ureteral stones for every domain.

Conclusion: CUSP is a patient-derived ureteral stone PROM, which can be used to measure ureteral stone disease health outcomes from the patient's point of view.
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http://dx.doi.org/10.1089/end.2017.0795DOI Listing
June 2018

Contemporary surgical management of renal oncocytoma: a nation's outcome.

BJU Int 2018 06 2;121(6):893-899. Epub 2018 Mar 2.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To report on the contemporary UK experience of surgical management of renal oncocytomas.

Patients And Methods: Descriptive analysis of practice and postoperative outcomes of patients with a final histological diagnosis of oncocytoma included in The British Association of Urological Surgeons (BAUS) nephrectomy registry from 01/01/2013 to 31/12/2016. Short-term outcomes were assessed over a follow-up of 60 days.

Results: Over 4 years, 32 130 renal surgical cases were recorded in the UK, of which 1202 were oncocytomas (3.7%). Most patients were male (756; 62.9%), the median (interquartile range [IQR]) age was 66.8 (13) years. The median (IQR; range) lesion size was 4.1 (3; 1-25) cm, 43.5% were ≤4 cm and 30.3% were 4-7 cm lesions. In all, 35 patients (2.9%) had preoperative renal tumour biopsy. Most patients had minimally invasive surgery, either radical nephrectomy (683 patients; 56.8%), partial nephrectomy (483; 40.2%) or other procedures (36; 3%). One in five patients (243 patients; 20.2%) had in-hospital complications: 48 were Clavien-Dindo classification grade ≥III (4% of the total cohort), including three deaths. Two additional deaths occurred within 60 days of surgery. The analysis is limited by the study's observational nature, not capturing lesions on surveillance or ablated after biopsy, possible underreporting, short follow-up, and lack of central histology review.

Conclusion: We report on the largest surgical series of renal oncocytomas. In the UK, the complication rate associated with surgical removal of a renal oncocytoma was not negligible. Centralisation of specialist services and increased utilisation of biopsy may inform management, reduce overtreatment, and change patient outcomes for this benign tumour.
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http://dx.doi.org/10.1111/bju.14159DOI Listing
June 2018

Sign of the times: be careful what you say in the operating room.

Lancet 2016 Feb;387(10018):536

The Renal Cancer Center, Royal Free Hospital, Pond Street, London NW3 2QG, UK.

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http://dx.doi.org/10.1016/S0140-6736(16)00224-5DOI Listing
February 2016

Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

Mod Pathol 2011 Aug 15;24(8):1023-30. Epub 2011 Apr 15.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.
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http://dx.doi.org/10.1038/modpathol.2011.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182838PMC
August 2011

Differentiation in neuroblastoma: diffusion-limited hypoxia induces neuro-endocrine secretory protein 55 and other markers of a chromaffin phenotype.

PLoS One 2010 Sep 17;5(9). Epub 2010 Sep 17.

Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Background: Neuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiation in tumors frequently proceeds along the chromaffin lineage and that decreased oxygen (hypoxia) plays a role in this. Here we explore the utility of Neuro-Endocrine Secretory Protein 55 (NESP55), a novel member of the chromogranin family, as a marker for this process.

Methodology/principal Findings: Immunohistochemical analyses and in situ hybridizations were performed on human fetal tissues, mouse xenografts of human neuroblastoma cell lines, and on specimens of human neuroblastoma/ganglioneuroma. Effects of anaerobic exposure on gene expression by cultured neuroblastoma cells was analyzed with quantitative real-time PCR. Fetal sympathetic nervous system expression of NESP55 was shown to be specific for chromaffin cell types. In experimental and clinical neuroblastoma NESP55 immunoreactivity was specific for regions of chronic hypoxia. NESP55 expression also correlated strikingly with morphological evidence of differentiation and with other chromaffin-specific patterns of gene expression, including IGF2 and HIF2α. Anaerobic culture of five neuroblastoma cell lines resulted in an 18.9-fold mean up-regulation of NESP55.

Conclusions/significance: The data confirms that chronic tumor hypoxia is a key microenvironmental factor for neuroblastoma cell differentiation, causing induction of chromaffin features and NESP55 provides a reliable marker for this neuronal to neuroendocrine transition. The hypoxia-induced phenotype is the predominant form of differentiation in stroma-poor tumors, while in stroma-rich tumors the chromaffin phenotype coexists with ganglion cell-like differentiation. The findings provide new insights into the biological diversity which is a striking feature of this group of tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941466PMC
September 2010

Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease.

Neoplasia 2008 Oct;10(10):1146-53

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546591PMC
http://dx.doi.org/10.1593/neo.08476DOI Listing
October 2008

Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury.

J Am Soc Nephrol 2008 Jan;19(1):39-46

Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

Acute renal failure resulting from hypoperfusion and hypoxia is a significant clinical problem. Hypoxia activates the heterodimeric transcription factor hypoxia inducible factor (HIF), leading to changes in gene expression that promote tissue adaptation and survival. To determine whether HIF may protect the kidney from ischemia-reperfusion injury, we subjected hif1a(+/-) and hif2a(+/-) mice to renal ischemia-reperfusion injury. Injury was substantially more severe in hif(+/-) than in littermate controls, consistent with a protective role for HIF. Because wild-type mice exhibited submaximal HIF accumulation in response to no-flow ischemia, we tested compounds that might augment the protective HIF response following ischemia-reperfusion in these animals. We found that l-mimosine and dimethyloxalylglycine, two small molecules that activate HIF by inhibiting HIF hydroxylases, protected mouse kidneys from ischemia-reperfusion injury. Therefore, pharmacological activation of HIF may offer an effective strategy to protect the kidney from ischemic injury.
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http://dx.doi.org/10.1681/ASN.2006090998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391027PMC
January 2008

Expression of hypoxia-inducible factors in normal human lung development.

Pediatr Dev Pathol 2008 May-Jun;11(3):193-9. Epub 2007 Jul 2.

Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Pulmonary vascular development is essential for proper lung development, and its disturbance can lead to neonatal morbidity and mortality, as exemplified in congenital diaphragmatic hernia. Hypoxia-inducible factors (HIFs) appear to be key molecules in physiologic angiogenesis and in certain forms of lung pathology, such as bronchopulmonary dysplasia. Little is known about the qualitative and quantitative expression of HIFs in normal human fetal lung development. Therefore, we investigated the expression of HIF-1alpha, HIF-2alpha, and HIF-3alpha, along with their upstream regulators and downstream targets, von Hippel-Lindau protein, vascular endothelial growth factor A (VEGF-A), and its receptor, VEGFR-2, in 20 normal human fetal lungs (13.5 weeks in gestation until term) and 5 adult lungs. Quantitative polymerase chain reaction demonstrated a positive correlation between HIF-2alpha and VEGF-A expression and gestational age. Although there appeared to be a decreasing trend in HIF-3alpha expression during pregnancy, it did not reach statistical significance. Immunohistochemistry for HIF-1alpha and HIF-2alpha revealed that HIF-1alpha is expressed in the epithelium, while HIF-2alpha is expressed in both interstitium and epithelium. Our data indicate that HIFs, most notably HIF-2alpha, appear to exert an important role in angiogenesis during human fetal lung development, especially in the last phases of pregnancy, preparing the fetus for extrauterine life. As such, our results form the baseline data for the evaluation and interpretation of abnormal pulmonary vascular development.
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http://dx.doi.org/10.2350/07-04-0257.1DOI Listing
August 2008

Regulation of E-cadherin expression by VHL and hypoxia-inducible factor.

Cancer Res 2006 Apr;66(7):3567-75

Renal Laboratory, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.

Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show that VHL inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin. Moreover, in VHL-defective cell lines (RCC4 and RCC10) derived from sporadic CCRCC, reexpression of VHL was found to restore E-cadherin expression. The product of the VHL gene has multiple reported functions, the best characterized of which is its role as the recognition component of an ubiquitin E3 ligase complex responsible for mediating oxygen-dependent destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits. We show that HIF activation is necessary and sufficient to suppress E-cadherin in renal cancer cells. Given the fundamental role of E-cadherin in controlling epithelial behavior, our findings give insight into how VHL inactivation/HIF activation may lead to kidney cancer and also indicate a mechanism by which reduced oxygenation could alter E-cadherin expression in other cancers and influence normal homeostasis in other epithelia.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-2670DOI Listing
April 2006

Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia.

Cancer Res 2005 Dec;65(24):11520-8

Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, Maastricht University and University Hospital Maastricht, the Netherlands.

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-2468DOI Listing
December 2005

Effects of VHL deficiency on endolymphatic duct and sac.

Cancer Res 2005 Dec;65(23):10847-53

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892, USA.

The von Hippel-Lindau (VHL) disease is caused by VHL germ line mutation. Inactivation of the wild-type copy of the VHL gene leads to up-regulation of hypoxic response and tumor formation within central nervous system (CNS), kidneys, pancreas, adrenal glands, epididymis, broad ligament, and the endolymphatic sac/petrous bone. Endolymphatic sac tumors (ELST) have been proposed to be derived from endolymphatic sac epithelium, but other possible structures of origin have been implicated. To clarify the anatomic and cellular origin of ELSTs, we did a morphologic and molecular pathologic analysis of 16 tumors. In addition, we investigated effects of VHL deficiency on "tumor-free" endolymphatic duct and sac of VHL patients. Several tumors included in this study were <1 cm in size, and their origin could be placed in the intraosseous portion of the endolymphatic duct/sac. Furthermore, by analysis of clinically uninvolved "tumor-free" endolymphatic duct and sac tissues of VHL patients, we discovered a variety of VHL-deficient microscopic abnormalities with morphologic similarities to ELSTs. We conclude that most, if not all, ELSTs arise within the intraosseous portion of the endolymphatic duct/sac, the vestibular aqueduct. In analogy to renal parenchyma and selected topographical sites within the CNS, endolymphatic duct/sac epithelia are preferentially and multifocally targeted in VHL disease. The primary effect of VHL deficiency on human endolymphatic duct/sac epithelium seems to be the generation of multifocal sites of VHL-deficient cell proliferations from which tumorigenesis may or may not occur. Therefore, inactivation of the VHL wild-type allele seems necessary but not sufficient for the formation of tumor.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-1104DOI Listing
December 2005

Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.

Mol Cell Biol 2005 Jul;25(13):5675-86

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.
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http://dx.doi.org/10.1128/MCB.25.13.5675-5686.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1157001PMC
July 2005