Publications by authors named "W Marston Linehan"

690 Publications

Intravitreous treatment of severe ocular von Hippel-Lindau disease using a combination of the VEGF inhibitor, ranibizumab, and PDGF inhibitor, E10030: Results from a phase 1/2 clinical trial.

Clin Exp Ophthalmol 2021 Sep 21. Epub 2021 Sep 21.

Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Treatment options for severe ocular VHL disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a VEGF inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation.

Methods: This was a prospective, single-arm, open-label phase 1/2 study, comprised of 3 adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation, and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52.

Results: Three participants each received 9 injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12, and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52.

Conclusions: Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.
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http://dx.doi.org/10.1111/ceo.14001DOI Listing
September 2021

MicroRNA Profiling of Morphologically Heterogeneous Clear Cell Renal Cell Carcinoma.

J Cancer 2021 6;12(18):5375-5384. Epub 2021 Jul 6.

Translational Surgical Pathology, Laboratory of Pathology, National Institutes of health, Bethesda, MD.

Intratumoral heterogeneity (IH) has been recently described as an important contributor to tumor growth through a branched rather than a linear pattern of tumor evolution for renal cell carcinoma. As to whether the miRNA profiling of the different and heterogeneous areas is the same or not, it is not known. This study analyzed the differences and similarities of the miRNA profiles in histologically distinct regions within several RCC tumors. The observed differences may have great implications for the development of predictive biomarkers and the identification of druggable targets with improvement of combinatorial therapeutic approaches for the effective treatment of kidney cancer, as well as for the identification of circulating malignant cells that can be useful to detect tumor recurrences.
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http://dx.doi.org/10.7150/jca.52310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364632PMC
July 2021

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Nat Struct Mol Biol 2021 08 11;28(8):662-670. Epub 2021 Aug 11.

Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
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http://dx.doi.org/10.1038/s41594-021-00633-2DOI Listing
August 2021

Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement.

Cancer 2021 Nov 3;127(21):3957-3966. Epub 2021 Aug 3.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions.

Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions.

Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC.

Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment.

Lay Summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
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http://dx.doi.org/10.1002/cncr.33679DOI Listing
November 2021

A deep-learning based artificial intelligence (AI) approach for differentiation of clear cell renal cell carcinoma from oncocytoma on multi-phasic MRI.

Clin Imaging 2021 Sep 18;77:291-298. Epub 2021 Jun 18.

Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Purpose: To investigate the diagnostic performance of a deep convolutional neural network for differentiation of clear cell renal cell carcinoma (ccRCC) from renal oncocytoma.

Methods: In this retrospective study, 74 patients (49 male, mean age 59.3) with 243 renal masses (203 ccRCC and 40 oncocytoma) that had undergone MR imaging 6 months prior to pathologic confirmation of the lesions were included. Segmentation using seed placement and bounding box selection was used to extract the lesion patches from T2-WI, and T1-WI pre-contrast, post-contrast arterial and venous phases. Then, a deep convolutional neural network (AlexNet) was fine-tuned to distinguish the ccRCC from oncocytoma. Five-fold cross validation was used to evaluate the AI algorithm performance. A subset of 80 lesions (40 ccRCC, 40 oncocytoma) were randomly selected to be classified by two radiologists and their performance was compared to the AI algorithm. Intra-class correlation coefficient was calculated using the Shrout-Fleiss method.

Results: Overall accuracy of the AI system was 91% for differentiation of ccRCC from oncocytoma with an area under the curve of 0.9. For the observer study on 80 randomly selected lesions, there was moderate agreement between the two radiologists and AI algorithm. In the comparison sub-dataset, classification accuracies were 81%, 78%, and 70% for AI, radiologist 1, and radiologist 2, respectively.

Conclusion: The developed AI system in this study showed high diagnostic performance in differentiation of ccRCC versus oncocytoma on multi-phasic MRIs.
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http://dx.doi.org/10.1016/j.clinimag.2021.06.016DOI Listing
September 2021
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