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1. Technique and outcomes of transperineal prostate biopsy: The Victorian Transperineal Biopsy Collaboration.

Author

Lawrentschuk N., Grummet J., Ong W., Weerakoon M., Van Bruwaene S., Van Den Bergh R., Moon D., Frydenberg M., Murphy D., Huang S., Zargar H., Tjandra D., Lawrentschuk N., Grummet J., Ong W., Weerakoon M., Van Bruwaene S., Van Den Bergh R., Moon D., Frydenberg M., Murphy D., Huang S., Zargar H., and Tjandra D.

Abstract

INTRODUCTION & OBJECTIVES: Transperineal prostate biopsy (TPB) has been proposed as a safer more sensitive method for obtaining prostate gland biopsy. Herein we present our technique and report the outcomes and safety profile of TPB utilising our prospective Victorian Transperineal Biopsy Collaboration (VTBC) database. MATERIAL & METHODS: The VTBC is a multi-institutional registry collecting data prospectively from four contributing institutions across Melbourne, Australia. The database is ethics approved at each institution and data collected is based on the minimum dataset published by the Ginsburg Study Group. We present a video of our technique and retrospectively analyse the outcomes of men undergoing TPB. RESULT(S): Our technique for performing TPB, using the Ginsburg protocol, is demonstrated in this video. A total of 1108 men underwent TPB between June 2010 and June 2015, with 894 having adequate histological data for analysis. The indications for TPB were primary biopsy (44.4%), repeat biopsy in the setting of previous negative TRUS biopsy (19%) and confirmatory biopsy for men on active surveillance (36.6%). The mean cohort age was 63.5 (range 41 - 87) and mean pre-biopsy PSA was 9.05 (range 0.14 - 85). In 397 men undergoing TPB as initial biopsy, 328/397(82.6%) were diagnosed with prostate cancer and 215/397 (54.1%) were diagnosed with Gleason >= 7 disease. In 170 men with a prior negative TRUS biopsy, 51/170 (30%) were found to have prostate cancer and 35/170 (20.5%) were diagnosed with Gleason >= 7 disease. Of 327 patients on active surveillance, 137/327 (43%) were upstaged to Gleason >= 7 disease. Overall 230 (25.7%) men were diagnosed with an anterior tumour. The overall rate of acute urinary retention was 3.2%. Only 3(0.3%) patients in the cohort required hospital admission due to biopsy related infection. CONCLUSION(S): The VTBC is the largest reported database of patients having TPB in Australia and New Zealand. The current results show that TPB is

Published
2016

2. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Author

Dominguez-Valentin M, Crosbie EJ, Engel C, Aretz S, Macrae F, Winship I, Capella G, Thomas H, Nakken S, Hovig E, Nielsen M, Sijmons RH, Bertario L, Bonanni B, Tibiletti MG, Cavestro GM, Mints M, Gluck N, Katz L, Heinimann K, Vaccaro CA, Green K, Lalloo F, Hill J, Schmiegel W, Vangala D, Perne C, Strauß HG, Tecklenburg J, Holinski-Feder E, Steinke-Lange V, Mecklin JP, Plazzer JP, Pineda M, Navarro M, Vidal JB, Kariv R, Rosner G, Piñero TA, Gonzalez ML, Kalfayan P, Ryan N, Ten Broeke SW, Jenkins MA, Sunde L, Bernstein I, Burn J, Greenblatt M, de Vos Tot Nederveen Cappel WH, Della Valle A, Lopez-Koestner F, Alvarez K, Büttner R, Görgens H, Morak M, Holzapfel S, Hüneburg R, von Knebel Doeberitz M, Loeffler M, Rahner N, Weitz J, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Auranen A, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Therkildsen C, Okkels H, Ketabi Z, Denton OG, Rødland EA, Vasen H, Neffa F, Esperon P, Tjandra D, Möslein G, Sampson JR, Evans DG, Seppälä TT, and Møller P

Subjects
DNA Mismatch Repair genetics, Female, Heterozygote, Humans, Hysterectomy, Middle Aged, Mismatch Repair Endonuclease PMS2 genetics, MutL Protein Homolog 1 genetics, Prospective Studies, Salpingo-oophorectomy, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis prevention & control
Abstract

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants., Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages., Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively., Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021
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3. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Author

Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, and Møller P

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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4. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Author

Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, and Møller P

Subjects
Adult, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis mortality, DNA Mismatch Repair, Databases, Genetic, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Penetrance, Prospective Studies, Risk Assessment, Sex Characteristics, Survival Analysis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins economics, Mismatch Repair Endonuclease PMS2 genetics, MutL Protein Homolog 1 genetics, MutS Homolog 2 Protein genetics, Mutation
Abstract

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer., Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years., Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer., Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Published
2020
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5. Yeast Two-Hybrid Analysis for Ubiquitin Variant Inhibitors of Human Deubiquitinases.

Author

Pascoe N, Seetharaman A, Teyra J, Manczyk N, Satori MA, Tjandra D, Makhnevych T, Schwerdtfeger C, Brasher BB, Moffat J, Costanzo M, Boone C, Sicheri F, and Sidhu SS

Subjects
Deubiquitinating Enzymes antagonists & inhibitors, HEK293 Cells, Humans, Models, Molecular, Proteasome Endopeptidase Complex metabolism, Protein Binding, Two-Hybrid System Techniques, Ubiquitin Thiolesterase antagonists & inhibitors, Deubiquitinating Enzymes metabolism, Ubiquitin metabolism, Ubiquitin Thiolesterase metabolism
Abstract

We applied a yeast-two-hybrid (Y2H) analysis to screen for ubiquitin variant (UbV) inhibitors of a human deubiquitinase (DUB), ubiquitin-specific protease 2 (USP2). The Y2H screen used USP2 as the bait and a prey library consisting of UbVs randomized at four specific positions, which were known to interact with USP2 from phage display analysis. The screen yielded numerous UbVs that bound to USP2 both as a Y2H interaction in vivo and as purified proteins in vitro. The Y2H-derived UbVs inhibited the catalytic activity of USP2 in vitro with nanomolar-range potencies, and they bound and inhibited USP2 in human cells. Mutational and structural analysis showed that potent and selective inhibition could be achieved by just two substitutions in a UbV, which exhibited improved hydrophobic and hydrophilic contacts compared to the wild-type ubiquitin interaction with USP2. Our results establish Y2H as an effective platform for the development of UbV inhibitors of DUBs in vivo, providing an alternative strategy for the analysis of DUBs that are recalcitrant to phage display and other in vitro methods., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Published
2019
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