Publications by authors named "Ellen Solomon"

50 Publications

Patient-Focused Websites Related to Postpartum Pelvic Floor Health: A DISCERN Quality Analysis.

Female Pelvic Med Reconstr Surg 2021 Oct 7. Epub 2021 Oct 7.

From the Division of Urogynecology and Reconstructive Pelvic Surgery, University of Massachusetts Medical School, Worcester Division of Urogynecology, UMMS-Baystate Medical Center, Springfield, MA.

Objective: The aim of the study was to evaluate the quality of patient-focused websites addressing postpartum pelvic floor health.

Methods: The Google search engine was used to perform a search of the following 3 terms: (1) "postpartum pelvic floor (PPF)," (2) "postpartum leaking urine (PLU)," and (3) "postpartum leaking stool (PLS)." The top 20 results from each search term were evaluated using the DISCERN quality appraisal tool and Journal of the American Medical Association (JAMA) benchmark criteria by 2 independent researchers. Websites were also categorized by type. Cohen κ was performed to determine interrater reliability between reviewers. The Kruskal-Wallis test was used to evaluate the differences in DISCERN and JAMA criteria scores.

Results: The weighted mean κ between the investigators for each search term was κ = 0.47 (range = 0.163 [PPF] to 0.759 [PLU]), suggesting moderate agreement between reviewers. There was a significant difference in mean DISCERN scores between the terms, with "postpartum leaking urine" yielding the highest mean score. When comparing DISCERN scores by category, society- and government-sponsored websites (mean = 55 ± 13) scored significantly higher than other categories. Using JAMA criteria, mean scores ranged between 1.83 and 2.83/4, but there were no significant differences between websites.

Conclusions: The overall quality of health information available on the internet regarding postpartum pelvic health is low. Higher-quality search results are found within society- and government-sponsored websites as well as under the search term "postpartum leaking urine." It is important for health care providers to guide their patients to websites with reliable information about postpartum pelvic floor recovery.
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http://dx.doi.org/10.1097/SPV.0000000000001101DOI Listing
October 2021

Short-Term Outcomes of Vaginal Hysterectomy at the Time of Robotic Sacrocolpopexy.

Female Pelvic Med Reconstr Surg 2021 01;27(1):e223-e226

Department of Obstetrics and Gynecology, Yale University, New Haven, CT.

Objective: With the introduction of robotic sacrocolpopexy (RSC) at our institution in 2008, we noted a reduction in residents' vaginal hysterectomy (VH) experience. In 2012, we made a transition to perform VH on all robotic sacrocolpopexies. Our objective was to report our short-term outcomes and adverse events.

Methods: In this case series, we evaluated women who underwent VH with concomitant RSC for stages II to IV pelvic organ prolapse between 2012 and 2017. In these cases, the vesicovaginal and rectovaginal spaces were developed transvaginally. Descriptive analysis including demographics, short-term outcomes, and adverse events are reported.

Results: In this group of 209 women, median (interquartile interval) duration of follow-up was 49 (26-60) weeks. The majority of the women were white (84.7%) and postmenopausal (80.9%), with a mean (SD) age of 59 (9) years. At a median follow-up time of 49 weeks, pelvic organ prolapse quantification revealed 20 patients (12.4%) with Ba or Bp greater or equal to 0 and 1.4% of patients required repeat prolapse surgery. Among 9 women (4.3%) with postoperative fever, 4 (1.9%) were treated for pelvic collection/abscess. Of 5 women (2.4%) who had venous thromboembolism, 3 (1.4%) were diagnosed with pulmonary embolism. There were 18 patients (8.6%) treated for urinary tract infection within 6 postoperative weeks. Mesh exposure was noted in 16 (7.7%) of the patients, and 11 (6.2%) required reoperation.

Conclusions: Vaginal hysterectomy at the time of RSC may increase the risk of infection and mesh exposure compared with procedures without concomitant hysterectomy.
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http://dx.doi.org/10.1097/SPV.0000000000000898DOI Listing
January 2021

Anterior Bilateral Sacrospinous Ligament Fixation: A Safe Route for Apical Repair.

Female Pelvic Med Reconstr Surg 2020 08;26(8):e33-e36

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT.

Objectives: Traditionally, sacrospinous ligament fixation is performed unilaterally with a posterior dissection for correction of apical vaginal prolapse. There is limited information on alternative techniques including bilateral application and use of anterior vaginal dissection for this procedure. The objective of this study is to evaluate the anatomic and perioperative outcomes in women who have undergone bilateral sacrospinous ligament fixation through an anterior approach.

Methods: This cohort represents women in our prospective repository who underwent anterior approach bilateral sacrospinous ligament fixation between September 2011 and June 2014. Concomitant procedures were performed as indicated. Pelvic organ prolapse quantification points were measured preoperatively and at 6 weeks and 6 months postoperatively and were compared. Perioperative outcome measures and adverse events were also analyzed.

Results: In this cohort, 144 women underwent anterior approach to bilateral sacrospinous ligament fixation. The patients' mean age was 57.8 ± 10.9 years, and the average body mass index was 29.6 ± 5.8 kg/m. In patients who underwent anterior approach bilateral sacrospinous ligament fixation, points Aa, Ba, C, Gh, Ap, and Bp remained at stage I or less when compared with pelvic organ prolapse quantification measurements at the baseline. Perioperative and postoperative complications were minimal, with 1 (0.7%) patient requiring a blood transfusion and 3 (2%) patients suffered from intraoperative lower urinary tract injuries, none of which were attributable to the sacrospinous fixation part of the procedure.

Conclusions: Anterior approach bilateral sacrospinous ligament fixation is a safe and effective procedure for reestablishing apical support in a patient with apical vaginal prolapse.
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http://dx.doi.org/10.1097/SPV.0000000000000857DOI Listing
August 2020

Pelvic Floor Disorders.

Obstet Gynecol Clin North Am 2019 Sep;46(3):527-540

Obstetrics and Gynecology, Division of Female Pelvic Surgery, University of Massachusetts-Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199, USA.

Pelvic floor disorders commonly affect women and may cause distress and difficulty with daily functions and self-image. Urinary incontinence may present as stress incontinence, urgency incontinence, or in some combination (mixed incontinence). Symptomatic pelvic organ prolapse (POP) occurs when the patient is bothered by the sensation of a herniation of the pelvic organs through the vagina. Although POP is often distressing and embarrassing, it is not considered life-threatening unless the patient cannot urinate or defecate. There are numerous ways to treat these conditions, including conservative (including observation), medical, and surgical management.
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http://dx.doi.org/10.1016/j.ogc.2019.04.010DOI Listing
September 2019

Sling Plication for Failed Midurethral Sling Procedures: A Case Series.

Female Pelvic Med Reconstr Surg 2019 Jan/Feb;25(1):e4-e6

Yale Urogynecology and Pelvic Reconstructive Surgery, Yale School of Medicine, New Haven, CT.

Objectives: The aim of this article is to report the outcomes of sling plications performed on women who presented with persistent stress urinary incontinence after midurethral sling.

Methods: All women who underwent sling plication for persistent stress urinary incontinence after placement of either retropubic or transobturator midurethral sling were included in this case series. For plication, first, the suburethral incision was opened. After mobilization of the mesh in the midline, the sling was plicated with absorbable sutures. Descriptive data were extracted from the electronic medical record. Postoperative stress urinary incontinence was diagnosed based on patients' response to the relevant question on the urinary distress inventory and compared this outcome with respect to the original sling placement approach.

Results: We identified 36 women who underwent sling plication between March 2013 and November 2016: 26 (72.2%) following a retropubic and 10 (27.7%) following a transobturator sling. Median time between midurethral sling and plication procedure was 6.8 weeks (range, 2-148 weeks). Median follow-up after sling plication was 17 weeks (range, 2-104 weeks). Overall, 24 women (66.6%) reported subjective resolution of stress incontinence. Success rate for plication of retropubic slings was 20 (76.9%) of 26 and significantly higher compared with 4 (40%) of 10 for transobturator slings (P = 0.034). There were no mesh erosions or persistent urinary retention after sling plication.

Conclusions: Sling shortening by plication is an effective low-risk option for the management of persistent stress urinary incontinence following a midurethral sling. This approach was found to be more successful after retropubic slings.
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http://dx.doi.org/10.1097/SPV.0000000000000630DOI Listing
April 2019

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Am J Transplant 2018 06 1;18(6):1370-1379. Epub 2018 Feb 1.

NHS Lothian, Edinburgh, UK.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
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http://dx.doi.org/10.1111/ajt.14594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001640PMC
June 2018

Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice.

Blood 2018 02 30;131(6):636-648. Epub 2017 Nov 30.

Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in Pml mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all- retinoic acid in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared with wild-type cells, primary Pml cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.
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http://dx.doi.org/10.1182/blood-2017-07-794784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805489PMC
February 2018

The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A.

Endocr Pathol 2017 Mar;28(1):41-48

Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.

The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RET reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.
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http://dx.doi.org/10.1007/s12022-016-9451-6DOI Listing
March 2017

Assessment of Minimal Residual Disease in Standard-Risk AML.

N Engl J Med 2016 Feb 20;374(5):422-33. Epub 2016 Jan 20.

From the Molecular Oncology Unit and Cancer Genetics Laboratory, Department of Medical and Molecular Genetics, Guy's Hospital (A.I.), the Department of Medical and Molecular Genetics (M.A.S., J.V.J., E.S., D.G.) and Department of Asthma, Allergy and Respiratory Science (H.F., F.M.), Faculty of Life Sciences and Medicine, King's College London, the Department of Haematology, University College London (Y.P., D.C.L., R.E.G.), and the Innovation Department, Cancer Research UK (N.B.), London, the Experimental Cancer Medicine Centre (A. Gilkes) and Department of Haematology (R.K.H., A.K.B.), Cardiff University School of Medicine, and the Haematology Clinical Trials Unit, Cardiff University (A. Grech), Cardiff, West Midlands Regional Genetics Laboratory, Birmingham (J.M., K.W., S.A., M.G.), MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine and Department of Haematology, University of Oxford and Oxford University Hospitals NHS Trust, and the National Institute for Health Research Oxford Biomedical Research Centre (P.V.), Oxford, the Department of Clinical Immunology, University of Birmingham, Birmingham (S.D.F.), and the Centre for Clinical Haematology, Nottingham University Hospital, Nottingham (N.R.) - all in the United Kingdom.

Background: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission.

Methods: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction.

Results: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status.

Conclusions: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).
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http://dx.doi.org/10.1056/NEJMoa1507471DOI Listing
February 2016

Interventions to decrease pain and anxiety in patients undergoing urodynamic testing: A randomized controlled trial.

Neurourol Urodyn 2016 11 30;35(8):975-979. Epub 2015 Jul 30.

Department of Urogynecology and Reconstructive Pelvic Surgery, Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio.

Aims: To determine if music (at 60 beats/min) or watching a pre-procedure educational video decreases pain and anxiety in women undergoing multichannel urodynamic testing compared to usual care.

Methods: Women undergoing multichannel urodynamic testing at a tertiary care center were randomized to one of three groups: usual care (UC), music (M), in which music was played throughout the urodynamic test, or video (V), in which subjects watched an informational video on the procedure prior to undergoing the test. Visual analog scales (VAS) were used to measure patient's pain and anxiety before and after the test. Demographic information was obtained and five-item Likert questionnaires were given to assess information seeking behavior, preparedness, embarrassment, and privacy.

Results: 98 subjects were included in this analysis. In the overall group, mean perceived pain on the pre-test VAS was significantly higher than the post-test VAS with pre-test mean (SD) 47(±30) and post-test mean (SD) 26(±23), P = 0.0001. Overall the anxiety pre-test VAS was significantly greater than post-test VAS with pre-test mean (SD) 46.9(±29) and post-test mean 17.9(±18), P = 0.0001. There were no differences in pain and anxiety scores between the two intervention groups and usual care. Patients who were randomized to usual care or the video arm felt more prepared for the test compared to patients who were randomized to the music arm, with (mean ± SD): usual care (42 ± 8), video (43 ± 9), music (37 ± 11), P = 0.002.

Conclusions: Music and an educational video do not decrease pain or anxiety in subjects undergoing multichannel urodynamics compared to usual care. Neurourol. Urodynam. 35:975-979, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/nau.22840DOI Listing
November 2016

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.

Blood 2015 May 24;125(19):2985-94. Epub 2015 Mar 24.

Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.
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http://dx.doi.org/10.1182/blood-2014-12-613703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463809PMC
May 2015

Removing a misplaced retropubic midurethral sling from the urethra and bladder neck using ear, nose, and throat instruments.

Obstet Gynecol 2015 Jan;125(1):58-61

Center for Urogynecology and Pelvic Reconstructive Surgery, Obstetrics, Gynecology & Women's Health Institute, Cleveland Clinic, Cleveland, Ohio.

Background: The retropubic tension-free vaginal tape (TVT) procedure is a common procedure with complications attributed to voiding dysfunction, bladder perforation, and bleeding. We present a case of successful removal of a retropubic midurethral sling from the urethra using a head lamp and a combination of ear, nose, and throat instruments.

Case: A 63-year-old woman presented to our clinic with the symptom of gross hematuria after having undergone a TVT procedure. On office cystoscopy, the sling was noted to be placed within the urethral mucosa. Removal of the mesh was performed using a nasal speculum, left and right ethmoid scissors, left and right Blakesley graspers, and a head lamp to dissect the mesh directly out of the urethra.

Conclusion: The utilization of ear, nose, and throat tools allowed us to resect the intraurethral mesh without necessitating incision of the urethral sphincter.
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http://dx.doi.org/10.1097/AOG.0000000000000568DOI Listing
January 2015

The Quality of Health Information Available on the Internet for Patients With Pelvic Organ Prolapse.

Female Pelvic Med Reconstr Surg 2015 Jul-Aug;21(4):225-30

From the *Department of Obstetrics and Gynecology, Division of Urogynecology and Pelvic Surgery, Baystate Medical Center, Springfield, MA; and †Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH; ‡Division of Woman and Baby, University Medical Center Utrecht, Utrecht, the Netherlands; and §Department of Obstetrics and Gynecology, Magee Womens Hospital, Pittsburgh, PA; ∥Center for Female Pelvic Medicine and Reconstructive Surgery, Obstetrics, Gynecology and Women's Health Institute, Cleveland, OH.

Objective: This study aimed to assess the quality of Web sites that provide information on pelvic organ prolapse using validated quality measurement tools.

Methods: The Google search engine was used to perform a search of the following 4 terms: "pelvic organ prolapse," "dropped bladder," "cystocele," and "vaginal mesh." The DISCERN appraisal tool and JAMA benchmark criteria were used to determine the quality of health information of each Web site. Cohen κ was performed to determine interrater reliability between reviewers. Kruskal-Wallis and Wilcoxon rank sum tests were used to compare DISCERN scores and JAMA criteria among search terms.

Results: Interrater reliability between the two reviewers using DISCERN was κ = 0.71 [95% confidence interval (CI), 0.68-0.74] and using JAMA criteria was κ = 0.98 (95% CI, 0.74-1.0). On the basis of the DISCERN appraisal tool, the search term "vaginal mesh" had significantly lower Web site quality than "pelvic organ prolapse" and "cystocele," respectively [mean difference of DISCERN score, -14.65 (95% CI, -25.50 to 8.50, P < 0.0001) and -12.55 (95% CI, -24.00 to 7.00, P = 0.0007)]. "Dropped bladder" had significantly lower Web site quality compared to "pelvic organ prolapse" and "cystocele," respectively (mean difference of DISCERN score, -9.55 (95% CI, -20.00 to 3.00, P = 0.0098) and -7.80 (95% CI, -18.00 to 1.00, P = 0.0348). Using JAMA criteria, there were no statistically significant differences between Web sites.

Conclusions: Web sites queried under search terms "vaginal mesh" and "dropped bladder" are lower in quality compared with the Web sites found using the search terms "pelvic organ prolapse" and "cystocele."
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http://dx.doi.org/10.1097/SPV.0000000000000156DOI Listing
April 2016

Histopathology of excised midurethral sling mesh.

Int Urogynecol J 2015 Apr 7;26(4):591-5. Epub 2014 Nov 7.

Obstetrics/Gynecology and Women's Health Institute, Center for Urogynecology and Pelvic Reconstructive Surgery, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk A81, Cleveland, OH, USA,

Introduction And Hypothesis: The objective of this study was to compare the histological characteristics of pathological specimens of excised midurethral sling mesh and surrounding vaginal tissue in patients who presented preoperatively with pain and/or exposure of mesh to patients who underwent mesh excision for voiding dysfunction without pain and/or erosion.

Methods: This is a retrospective case-control study of women who underwent excision of midurethral sling mesh between 2008 and 2013. Three groups were identified: (1) voiding dysfunction without pain or exposure (control group), (2) pain and/or mesh exposure, and (3) voiding dysfunction with pain and/or mesh exposure. All original pathological specimens were rereviewed by one pathologist blinded to indication for excision and the previous pathology report. Degree of inflammation and fibrosis were recorded based on a 4-point scale along with the presence of giant cell reaction.

Results: A total of 130 subjects met inclusion criteria: 60 (46.2 %) with voiding dysfunction only, 21 (16.2 %) with pain/erosion, and 49 (37.7 %) with both pain/exposure and voiding dysfunction. The voiding dysfunction only group was found to have significantly higher levels of inflammation, median grade 2 (1-3), compared to the other two groups with a p value of 0.007. There were no statistical differences in fibrosis and giant cell reaction between the three groups.

Conclusions: Midurethral sling mesh excised for voiding dysfunction demonstrates elevated levels of inflammation compared to mesh that is excised for pain and/or exposure. The vaginal tissue fibrosis and giant cell reaction are similar in patients who undergo mesh excision for voiding dysfunction and pain, and/or mesh exposure.
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http://dx.doi.org/10.1007/s00192-014-2553-0DOI Listing
April 2015

Laparoscopic repair of recurrent lateral enterocele and rectocele.

Int Urogynecol J 2015 Jan 16;26(1):145-6. Epub 2014 Sep 16.

Department of Obstetrics and Gynecology, Division of Urogynecology and Pelvic Surgery, Baystate Medical Center, 759 Chestnut Street, Springfield, MA, 01199, USA,

It is difficult to determine what types of procedures should be attempted in patients who have recurrent prolapse. We present a case of recurrent lateral enterocele and rectocele after the patient had undergone multiple surgeries for pelvic organ prolapse (POP), including a vaginal hysterectomy, bladder-neck suspension, anterior colporrhaphy, site-specific rectocele repair, apical mesh implant, iliococcygeus vault suspension, and transobturator suburethral sling procedure. With recurrence, the patient underwent robot-assisted laparoscopic sacral colpopexy, tension-free vaginal tape transobturator sling insertion, rectocele repair, and perineorrhaphy with cystoscopy. She then presented with defecatory outlet obstruction and constipation and subsequently was treated with a stapled transanal rectal resection. The patient returned with continued defecatory dysfunction and a recurrent lateral enterocele and rectocele. The recurrence was treated laparoscopically using a lightweight polypropylene mesh. The postoperative period was uneventful. Two years later, the patient reported decreased defecatory symptoms and no further symptomatic prolapse.
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http://dx.doi.org/10.1007/s00192-014-2465-zDOI Listing
January 2015

The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells.

EMBO J 2013 Jul 31;32(13):1941-52. Epub 2013 May 31.

Department of Medical and Molecular Genetics, King's College London, London, UK.

Germ cells and adult stem cells maintain tissue homeostasis through a finely tuned program of responses to both physiological and stress-related signals. PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the POK family of transcription factors, acts as an epigenetic regulator of stem cell maintenance in germ cells and haematopoietic stem cells. We identified L1 retrotransposons as the primary targets of PLZF. PLZF-mediated DNA methylation induces silencing of the full-length L1 gene and inhibits L1 retrotransposition. Furthermore, PLZF causes the formation of barrier-type boundaries by acting on inserted truncated L1 sequences in protein coding genes. Cell stress releases PLZF-mediated repression, resulting in L1 activation/retrotransposition and impaired spermatogenesis and myelopoiesis. These results reveal a novel mechanism of action by which, PLZF represses retrotransposons, safeguarding normal progenitor homeostasis.
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http://dx.doi.org/10.1038/emboj.2013.118DOI Listing
July 2013

Residency training in pediatric and adolescent gynecology across obstetrics and gynecology residency programs: a cross-sectional study.

J Pediatr Adolesc Gynecol 2013 Jun 6;26(3):180-5. Epub 2013 Apr 6.

Department of Obstetrics and Gynecology, Obstetrics, Gynecology, and Women's Health Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Study Objective: To estimate the prevalence of Pediatric and Adolescent Gynecology formal training in the United States Obstetric and Gynecology residency programs.

Design: Prospective, anonymous, cross-sectional study.

Participants: United States program directors of Obstetrics and Gynecology residency programs, N = 242; respondents 104 (43%).

Results: 104 residency programs responded to our survey. Among the 104 residency programs, 63% (n = 65) have no formal, dedicated Pediatric and Adolescent Gynecology clinic, while 83% (n = 87) have no outpatient Pediatric and Adolescent Gynecology rotation. There is no significant difference in the amount of time spent on a Pediatric and Adolescent Gynecology rotation among residents from institutions with a Pediatric and Adolescent Gynecology fellowship (P = .359), however, the number of surgeries performed is significantly higher than those without a Pediatric and Adolescent Gynecology fellowship (P = .0020). When investigating resident competency in Pediatric and Adolescent Gynecology, program directors reported that residents who were taught in a program with a fellowship-trained Pediatric and Adolescent Gynecology faculty were significantly more likely to be able to interpret results of selected tests used to evaluate precocious puberty than those without (P = .03).

Conclusions: Residency programs without fellowship trained Pediatric and Adolescent Gynecology faculty or an established Pediatric and Adolescent Gynecology fellowship program may lack formal training and clinical exposure to Pediatric and Adolescent Gynecology. This information enables residency directors to identify deficiencies in their own residency programs and to seek improvement in resident clinical experience in Pediatric and Adolescent training.
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http://dx.doi.org/10.1016/j.jpag.2013.02.003DOI Listing
June 2013

Common postoperative pulmonary complications after hysterectomy for benign indications.

Am J Obstet Gynecol 2013 Jan 15;208(1):54.e1-5. Epub 2012 Nov 15.

Center for Urogynecology and Pelvic Reconstructive Surgery, Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, OH, USA.

Objective: The purpose of this study was to estimate the incidence of postoperative pulmonary complications after hysterectomy for benign indications.

Study Design: This was a retrospective cohort study of all women who underwent hysterectomy for benign indications at the Cleveland Clinic from Jan. 1, 2001, to Dec. 31, 2009. Exclusion criteria incorporated patients who underwent hysterectomy for premalignant or malignant conditions. Pulmonary complications were defined as postoperative pneumonia, respiratory failure, atelectasis, and pneumothorax based on International classification of diseases, ninth revision, codes.

Results: In the 9-year study period, 3226 women underwent hysterectomy for benign indications (abdominal, 38.4%; vaginal, 39.3%; laparoscopic, 22.3%). Ten of the 3226 women (0.3%; 95% confidence interval, 0.17-0.57%) who underwent hysterectomy were identified with postoperative pulmonary complications. Among the different types of hysterectomy, the incidence of pulmonary complications was not different (total abdominal hysterectomy, 0.9%; vaginal hysterectomy, 0.12%; laparoscopic hysterectomy, 0.9%; P = .8).

Conclusion: The incidence of postoperative pulmonary complications after hysterectomy for benign indications is low.
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http://dx.doi.org/10.1016/j.ajog.2012.11.006DOI Listing
January 2013

MAP1B Interaction with the FW Domain of the Autophagic Receptor Nbr1 Facilitates Its Association to the Microtubule Network.

Int J Cell Biol 2012 10;2012:208014. Epub 2012 May 10.

Department of Medical and Molecular Genetics, Kings College London, London SE1 9RT, UK.

Selective autophagy is a process whereby specific targeted cargo proteins, aggregates, or organelles are sequestered into double-membrane-bound phagophores before fusion with the lysosome for protein degradation. It has been demonstrated that the microtubule network is important for the formation and movement of autophagosomes. Nbr1 is a selective cargo receptor that through its interaction with LC3 recruits ubiquitinated proteins for autophagic degradation. This study demonstrates an interaction between the evolutionarily conserved FW domain of Nbr1 with the microtubule-associated protein MAP1B. Upon autophagy induction, MAP1B localisation is focused into discrete vesicles with Nbr1. This colocalisation is dependent upon an intact microtubule network as depolymerisation by nocodazole treatment abolishes starvation-induced MAP1B recruitment to these vesicles. MAP1B is not recruited to autophagosomes for protein degradation as blockage of lysosomal acidification does not result in significant increased MAP1B protein levels. However, the protein levels of phosphorylated MAP1B are significantly increased upon blockage of autophagic degradation. This is the first evidence that links the ubiquitin receptor Nbr1, which shuttles ubiquitinated proteins to be degraded by autophagy, to the microtubule network.
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http://dx.doi.org/10.1155/2012/208014DOI Listing
August 2012

BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.

Cancer Cell 2011 Dec;20(6):797-809

Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.
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http://dx.doi.org/10.1016/j.ccr.2011.11.014DOI Listing
December 2011

Autophagic receptors Nbr1 and p62 coregulate skeletal remodeling.

Autophagy 2010 Oct 27;6(7):981-3. Epub 2010 Oct 27.

King's College London, Department of Medical and Molecular Genetics, London, England, UK.

Skeletal remodeling is an ongoing process requiring the coordinated action of different cell types to maintain homeostatic control of bone synthesis and degradation. Mutations in p62/SQSTM1 are associated with sporadic and 5q35-linked Paget Disease of Bone (PDB), characterized by focal increased bone turnover. These mutations cluster in the ubiquitin associated (UBA) domain and are thought to lead to enhancement of NFκB pathway activation involved in osteoclastogenesis and hyper-responsiveness to receptor activator of nuclear factorκB ligand (RANKL). The structurally similar selective autophagic receptor, Nbr1, binds to LC3 and p62 and is sequestered into autophagosomes, whereas it accumulates in autophagic-deficient tissues. We have shown that truncation of Nbr1 in a murine model, where it can still interact with p62 but not LC3, leads to increased osteoblast differentiation and activity in vivo. This results in an age-dependent increase in bone mass and bone mineral density. This is a molecular consequence of loss of autophagy receptor function via deletion of its C-terminal UBA domain, and/or modulation of the p38 MAPK cellular signaling pathway.
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http://dx.doi.org/10.4161/auto.6.7.13155DOI Listing
October 2010

Risk of deep venous thrombosis and pulmonary embolism in urogynecologic surgical patients.

Am J Obstet Gynecol 2010 Nov 30;203(5):510.e1-4. Epub 2010 Aug 30.

Center for Urogynecology and Reconstructive Pelvic Surgery, Obstetrics, Gynecology, and Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA.

Objective: We sought to determine the incidence of symptomatic deep venous thrombosis and pulmonary embolism, collectively referred to as venous thromboembolic events (VTE), in patients undergoing urogynecologic surgery to guide development of a VTE prophylaxis policy for this patient population.

Study Design: We conducted a retrospective analysis of VTE incidence among women undergoing urogynecologic surgery over a 3-year period. All patients wore sequential compression devices intraoperatively through hospital discharge.

Results: Forty of 1104 patients (3.6%) undergoing urogynecologic surgery were evaluated with chest computed tomography, lower extremity ultrasound, or both for suspicion of VTE postoperatively. The overall rate of venous thromboembolism in this population was 0.3% (95% confidence interval, 0.1-0.8).

Conclusion: Most women undergoing incontinence and reconstructive pelvic surgery are at a low risk for VTE. Sequential compression devices appear to provide adequate VTE prophylaxis in this patient population.
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http://dx.doi.org/10.1016/j.ajog.2010.07.021DOI Listing
November 2010

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.

Proc Natl Acad Sci U S A 2010 Jul 29;107(29):12913-8. Epub 2010 Jun 29.

King's College London, Department of Medical and Molecular Genetics, London SE1 9RT, United Kindom.

The neighbor of Brca1 gene (Nbr1) functions as an autophagy receptor involved in targeting ubiquitinated proteins for degradation. It also has a dual role as a scaffold protein to regulate growth-factor receptor and downstream signaling pathways. We show that genetic truncation of murine Nbr1 leads to an age-dependent increase in bone mass and bone mineral density through increased osteoblast differentiation and activity. At 6 mo of age, despite normal body size, homozygous mutant animals (Nbr1(tr/tr)) have approximately 50% more bone than littermate controls. Truncated Nbr1 (trNbr1) co-localizes with p62, a structurally similar interacting scaffold protein, and the autophagosome marker LC3 in osteoblasts, but unlike the full-length protein, trNbr1 fails to complex with activated p38 MAPK. Nbr1(tr/tr) osteoblasts and osteoclasts show increased activation of p38 MAPK, and significantly, pharmacological inhibition of the p38 MAPK pathway in vitro abrogates the increased osteoblast differentiation of Nbr1(tr/tr) cells. Nbr1 truncation also leads to increased p62 protein expression. We show a role for Nbr1 in bone remodeling, where loss of function leads to perturbation of p62 levels and hyperactivation of p38 MAPK that favors osteoblastogenesis.
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http://dx.doi.org/10.1073/pnas.0913058107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919976PMC
July 2010

The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.

Nature 2009 Dec;462(7275):886-90

Department of Medical and Molecular Genetics, King's College London, Guy's Medical School Campus, London SE1 9RT, UK.

Mutations in BRCA1 are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase. However, its regulation remains poorly understood. Here we report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9. PIAS SUMO E3 ligases co-localize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro SUMO modification of the BRCA1/BARD1 heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase (SRUbL). Further, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.
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http://dx.doi.org/10.1038/nature08593DOI Listing
December 2009

Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia.

Blood 2010 Jan 2;115(2):326-30. Epub 2009 Nov 2.

Department of Medical & Molecular Genetics, King's College London School of Medicine, London, United Kingdom.

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.
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http://dx.doi.org/10.1182/blood-2009-07-235051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808156PMC
January 2010

Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy.

J Clin Oncol 2009 Aug 8;27(22):3650-8. Epub 2009 Jun 8.

Dept of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, United Kingdom.

Purpose: Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.

Methods: Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.

Results: MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial.

Conclusion: Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia.
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http://dx.doi.org/10.1200/JCO.2008.20.1533DOI Listing
August 2009

Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover.

FEBS Lett 2009 Jun 8;583(12):1846-52. Epub 2009 May 8.

King's College London, Department of Medical and Molecular Genetics, London, UK.

Nbr1, a ubiquitous kinase scaffold protein, contains a PB1, and a ubiquitin-associated (UBA) domain. We show here that the nbr1 UBA domain binds to lysine-48 and -63 linked polyubiquitin-B chains. Nbr1 also binds to the autophagic effector protein LC3-A via a novel binding site. Ubiquitin-binding, but not PB1-mediated p62/SQSTM1 interaction, is required to target nbr1 to LC3 and polyubiquitin-positive bodies. Nbr1 binds additionally to proteins implicated in ubiquitin-mediated protein turnover and vesicle trafficking: ubiquitin-specific peptidases USP8, and the endosomal transport regulator p14/Robld3. Nbr1 thus contributes to specific steps in protein turnover regulation disrupted in several hereditary human diseases.
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http://dx.doi.org/10.1016/j.febslet.2009.04.049DOI Listing
June 2009

PML nuclear bodies in the pathogenesis of acute promyelocytic leukemia: active players or innocent bystanders?

Front Biosci (Landmark Ed) 2009 Jan 1;14:1684-707. Epub 2009 Jan 1.

Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.

The promyelocytic leukemia gene (PML) encodes a protein which localizes to PML-nuclear bodies (NBs), sub-nuclear multi-protein structures, which have been implicated in diverse biological functions such as apoptosis, cell proliferation and senescence. However, the exact biochemical and molecular basis of PML function up until now has not been defined. Strikingly, over a decade ago, PML-NBs were found to be disrupted in acute promyelocytic leukemia (APL) in which PML is fused to the gene encoding retinoic acid receptor alpha (RARA) due to the t(15;17) chromosomal translocation, generating the PML-RARA chimeric protein. The treatment of APL patients with all-transretinoic acid (ATRA) and arsenic trioxide which target the PML-RARA oncoprotein results in clinical remission, associated with blast cell differentiation and reformation of the PML NBs, thus linking NB integrity with disease status. This review focuses on the current theories for molecular and biochemical functions of the PML-NBs, which would imply a role in the pathogenesis of APL, whilst also discussing the intriguing possibility that their disruption may not be in itself a significant oncogenic event.
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http://dx.doi.org/10.2741/3333DOI Listing
January 2009

Acute promyelocytic leukemia: a paradigm for differentiation therapy.

Cancer Treat Res 2010 ;145:219-35

Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.

Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARalpha oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.
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http://dx.doi.org/10.1007/978-0-387-69259-3_13DOI Listing
October 2010
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