38 results on '"Walter HS"'
Search Results
2. Secret shopper studies: an unorthodox design that measures inequities in healthcare access
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Kelsey A. Rankin, Alison Mosier-Mills, Walter Hsiang, and Daniel H. Wiznia
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Secret shopper ,Healthcare delivery ,Methodology ,Phone interviews ,Accessibility ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Secret shopper studies are particularly potent study designs that allow for the gathering of objective data for a variety of research hypotheses, including but not limited to, healthcare delivery, equity of healthcare, and potential barriers to care. Of particular interest during the COVID-19 pandemic, secret shopper study designs allow for the gathering of data over the phone. However, there is a dearth of literature available on appropriate methodological practices for these types of studies. To make these study designs more widely accessible, here we outline the case for using the secret shopper methodology and detail best practices for designing and implementing them.
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- 2022
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3. Urgent care center wait times increase for COVID-19 results in August 2020, with rapid testing availability limited
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Laurie C Yousman, Akshay Khunte, Walter Hsiang, Siddharth Jain, Howard Forman, and Daniel Wiznia
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COVID-19 ,COVID-19 testing ,Urgent care center ,Access to care ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background In a response to the pandemic, urgent care centers (UCCs) have gained a critical role as a common location for COVID-19 testing. We sought to characterize the changes in testing accessibility at UCCs between March and August 2020 on the basis of testing availability (including rapid antigen testing), wait time for test results, cost of visits, and cost of tests. Methods Data were collected using a secret shopper methodology. Researchers contacted 250 UCCs in 10 states. Investigators used a standardized script to survey centers on their COVID-19 testing availability and policies. UCCs were initially contacted in March and re-called in August. T-tests and chi-square tests were conducted to identify differences between March and August data and differences by center classification. Results Our results indicate that both polymerase chain reaction (PCR) tests to detect COVID-19 genetic material and rapid antigen COVID-19 tests have increased in availability. However, wait times for PCR test results have significantly increased to an average of 5.79 days. Additionally, a high proportion of UCCs continue to charge for tests and visits and no significant decrease was found in the proportion of UCCs that charge for COVID-19 testing from March to August. Further, no state reported a majority of UCCs with rapid testing available, indicating an overall lack of rapid testing. Conclusions From March to August, COVID-19 testing availability gradually improved. However, many barriers lie in access to COVID-19 testing, including testing costs, visit costs, and overall lack of availability of rapid testing in the majority of UCCs. Despite the passage of the CARES Act, these results suggest that there is room for additional policy to improve accessibility to testing, specifically rapid testing.
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- 2021
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4. Uveitis in cause of Morbus Adamantiades Behçet - an important differential diagnosis in childhood
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Link, K, Kojetinsky, C, Walter, HS, Garbe, AC, Elschner, F, Penzien, J, and Mueller, A
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ddc: 610 - Published
- 2006
5. Abstract P3-12-08: Venous thromboembolism in patients receiving chemotherapy for breast cancer
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Plant, RE, primary, Walter, HS, additional, and Ahmed, SI, additional
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- 2013
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6. Abstract P4-14-14: Phyllodes tumour of the breast: A retrospective analysis of 87 cases
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Walter, HS, primary, Esmail, F, additional, Krupa, J, additional, and Ahmed, SI, additional
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- 2012
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7. COVID-19 testing capabilities at urgent care centers in states with greatest disease burden [version 2; peer review: 2 approved]
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Walter Hsiang, Howard Forman, Siddharth Jain, Akshay Khunte, Grace Jin, Laurie Yousman, Michael Najem, Alison Mosier-Mills, and Daniel Wiznia
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Medicine ,Science - Abstract
While rapid and accessible diagnosis is paramount to monitoring and reducing the spread of disease, COVID-19 testing capabilities across the U.S. remain constrained. For many individuals, urgent care centers (UCCs) may offer the most accessible avenue to be tested. Through a phone survey, we describe the COVID-19 testing capabilities at UCCs and provide a snapshot highlighting the limited COVID-19 testing capabilities at UCCs in states with the greatest disease burden.
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- 2020
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8. Authors' Response to Correspondence Re Ethnic Differences in Radiotherapy Outcomes in a Majority South Asian Leicester Community.
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Patil N, Ma N, Mair M, Nazareth J, Sim A, Reynolds C, Freeman N, Chauhan M, Howells L, Peel D, Ahmad S, Sridhar T, and Walter HS
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- Humans, Neoplasms radiotherapy, Neoplasms ethnology, Radiotherapy, Treatment Outcome, Ethnicity, Asian People
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- 2024
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9. Monitoring of molecular responses to tirabrutinib in a cohort of exceptional responders with relapsed/refractory mantle cell lymphoma.
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Alqahtani ANM, Jayne S, Ahearne MJ, Trethewey CS, Duraisingham SS, Lehmann S, Cowley CM, Dyer MJS, and Walter HS
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Competing Interests: Martin J. S. Dyer has received research funding from Gilead Sciences. Harriet S. Walter has received research funding from Gilead Sciences. Sandrine Jayne has received research funding from Gilead Sciences. All the other authors declare no conflict of interest.
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- 2024
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10. BCL2 inhibition: back to the future!
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Dyer MJS and Walter HS
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- Humans, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Animals, Apoptosis drug effects, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism
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- 2024
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11. Oral Cavity Cancers: Ethnic Differences in Radiotherapy Outcomes in a Majority South Asian Leicester Community.
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Patil N, Ma N, Mair M, Nazareth J, Sim A, Reynolds C, Freeman N, Chauhan M, Howells L, Peel D, Ahmad S, Sridhar T, and Walter HS
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- Humans, Ethnicity, Treatment Outcome, United Kingdom, Asian People, Mouth Neoplasms ethnology
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Aims: Squamous cell carcinoma oral cavity cancers (SCCOCCs) have a higher reported incidence in South Asian countries. We sought to compare presenting stage and outcome by ethnicity in patients with SCCOCC treated with radical radiotherapy in a single centre in the UK., Materials and Methods: All patients with SCCOCC treated with radical radiotherapy at an oncology department in Leicester (UK) between 2011 and 2017 were identified. Baseline demographic, clinical data and 2-year treatment outcomes were reported., Results: Of the 109 patients included, 40 were South Asian and 59 were non-South Asian. South Asians had significantly poorer 2-year disease-free survival compared with non-South Asians (54.6% versus 73%, P = 0.01)., Conclusion: Our analysis suggests that South Asians with SCCOCC have poorer outcomes despite a younger age and similar disease characteristics. Environmental, social factors and differing biology of disease may be responsible and further research is required to inform targeted interventions., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)
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- 2024
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12. BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib.
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Jackson RA, Britton RG, Jayne S, Lehmann S, Cowley CM, Trethewey CS, Smith VM, Schmid R, Fegan C, Walter HS, and Dyer MJS
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- Humans, Mutation, Pyrimidines therapeutic use, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
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- 2023
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13. A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer.
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Jones R, Plummer R, Moreno V, Carter L, Roda D, Garralda E, Kristeleit R, Sarker D, Arkenau T, Roxburgh P, Walter HS, Blagden S, Anthoney A, Klencke BJ, Kowalski MM, and Banerji U
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- Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Gemcitabine, Lung Neoplasms drug therapy, Neoplasms etiology, Small Cell Lung Carcinoma drug therapy
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Purpose: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737., Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors., Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer., Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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14. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen.
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Thompson MC, Harrup RA, Coombs CC, Roeker LE, Pu JJ, Choi MY, Barr PM, Allan JN, Šimkovič M, Leslie L, Rhodes J, Chong EA, Kamdar M, Skarbnik A, Lansigan F, McCall B, Saja K, Dyer MJS, Walter HS, Lefebure M, Thadani-Mulero M, Boyer M, Biondo J, Sail K, Manzoor BS, Furman R, Bantilan KS, Goy A, Feldman T, Labella D, Schuster SJ, Park J, Palomba L, Zelenetz A, Eyre TA, Kater AP, Seymour JF, and Mato AR
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- Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Humans, Retreatment, Sulfonamides therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
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- 2022
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15. Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.
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Jackson RA, Smith VM, Jayne S, Drewes C, Bens S, Siebert R, Dyer MJS, and Walter HS
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- 2022
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16. Inequalities in cancer screening, prevention and service engagement between UK ethnic minority groups.
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Abraham S, Foreman N, Sidat Z, Sandhu P, Marrone D, Headley C, Akroyd C, Nicholson S, Brown K, Thomas A, Howells LM, and Walter HS
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- Early Detection of Cancer, Ethnic and Racial Minorities, Ethnicity, Humans, United Kingdom, Minority Groups, Neoplasms diagnosis
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More people in the UK are living with cancer than ever before. With an increasingly ethnically diverse population, greater emphasis must be placed on understanding factors influencing cancer outcomes. This review seeks to explore UK-specific variations in engagement with cancer services in minority ethnic groups and describe successful interventions. The authors wish to highlight that, despite improvement to engagement and education strategies, inequalities still persist and work to improve cancer outcomes across our communities still needs to be prioritised. There are many reasons why cancer healthcare inequities exist for minority communities, reported on a spectrum ranging from cultural beliefs and awareness, through to racism. Strategies that successfully enhanced engagement included language support; culturally-sensitive reminders; community-based health workers and targeted outreach. Focusing on the diverse city of Leicester the authors describe how healthcare providers, researchers and community champions have worked collectively, delivering targeted community-based strategies to improve awareness and access to cancer services.
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- 2022
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17. Limitations of Monitoring Disease Progression Using Circulating Tumor DNA in Lymphoma: An Example From Primary Cutaneous DLBCL Leg-type.
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Trethewey CS, Walter HS, Alqahtani ANM, Schmid R, Guttery DS, Griffin Y, Ahearne MJ, Saldanha GS, Jayne SPN, and Dyer MJS
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- 2022
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18. Chronic lymphocytic leukaemia therapy: is less more?
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Walter HS and Dyer MJS
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- Humans, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
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Competing Interests: We declare no competing interests.
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- 2022
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19. Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.
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Jafri M, Kristeleit H, Misra V, Baxter M, Ahmed S, Jegannathen A, Jain A, Maskell D, Barthakur U, Edwards G, Walter HS, Walshaw R, Khan M, Borley A, and Rea D
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- Humans, Aged, Middle Aged, Female, Retrospective Studies, Furans therapeutic use, Ketones therapeutic use, United Kingdom, Treatment Outcome, Breast Neoplasms pathology
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Introduction: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK., Methods: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS)., Results: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042)., Discussion/conclusion: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
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- 2022
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20. Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma.
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Feeney L, Jain Y, Beasley M, Donnelly O, Kong A, Moleron R, Nallathambi C, Rolles M, Sanghera P, Tin A, Ulahannan D, Walter HS, Webster R, and Metcalf R
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Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12-15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.
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- 2021
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21. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma.
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Morschhauser F, Dyer MJS, Walter HS, Danilov AV, Ysebaert L, Hodson DJ, Fegan C, Rule SA, Radford J, Cartron G, Bouabdallah K, Davies AJ, Spurgeon S, Rajakumaraswamy N, Li B, Humeniuk R, Huang X, Bhargava P, Jürgensmeier JM, and Salles G
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- Adult, Aged, Female, Humans, Male, Middle Aged, Antineoplastic Agents therapeutic use, Imidazoles therapeutic use, Indazoles therapeutic use, Lymphoma, B-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Purines therapeutic use, Pyrazines therapeutic use, Pyrimidines therapeutic use, Quinazolinones therapeutic use
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- 2021
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22. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents.
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Roeker LE, Dreger P, Brown JR, Lahoud OB, Eyre TA, Brander DM, Skarbnik A, Coombs CC, Kim HT, Davids M, Manchini ST, George G, Shah N, Voorhees TJ, Orchard KH, Walter HS, Arumainathan AK, Sitlinger A, Park JH, Geyer MB, Zelenetz AD, Sauter CS, Giralt SA, Perales MA, and Mato AR
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- Humans, Retrospective Studies, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Lymphoma, Follicular
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Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options., (© 2020 by The American Society of Hematology.)
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- 2020
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23. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.
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Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, Karlin L, Dyer MJS, Mitra SS, Yi PC, Humeniuk R, Huang X, Zhou Z, Bhargava P, Jürgensmeier JM, and Fegan CD
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- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Female, Follow-Up Studies, Humans, Imidazoles administration & dosage, Indazoles administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Purines administration & dosage, Pyrazines administration & dosage, Pyrimidines administration & dosage, Quinazolinones administration & dosage, Tissue Distribution, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm drug effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Neoplasm Recurrence, Local drug therapy, Salvage Therapy
- Abstract
Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL., Patients and Methods: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day)., Results: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study., Conclusions: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598)., (©2020 American Association for Cancer Research.)
- Published
- 2020
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24. The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.
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Eyre TA, Roeker LE, Fox CP, Gohill SH, Walewska R, Walter HS, Forconi F, Broom A, Arumainathan A, Brander DM, Allan JN, Schuster SJ, Hill BT, Lansigan F, Cheson BD, Lamanna N, Coombs CC, Barr PM, Skarbnik AP, Shadman M, Ujjani CS, Pearson L, Pagel JM, Jacobs R, and Mato AR
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- Aged, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Humans, Recurrence, Sulfonamides pharmacology, Antineoplastic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Sulfonamides therapeutic use
- Abstract
Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2020
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25. Successful Treatment of Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type With Single-Agent Venetoclax.
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Walter HS, Trethewey CS, Ahearne MJ, Jackson R, Jayne S, Wagner SD, Saldanha G, and Dyer MJS
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- 2019
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26. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia.
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Flinn IW, Gribben JG, Dyer MJS, Wierda W, Maris MB, Furman RR, Hillmen P, Rogers KA, Iyer SP, Quillet-Mary A, Ysebaert L, Walter HS, Verdugo M, Klein C, Huang H, Jiang Y, Lozanski G, Pignataro DS, Humphrey K, Mobasher M, and Kipps TJ
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local drug therapy, Sulfonamides administration & dosage, Sulfonamides adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10
-4 ) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892., (© 2019 by The American Society of Hematology.)- Published
- 2019
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27. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy.
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Eyre TA, Walter HS, Iyengar S, Follows G, Cross M, Fox CP, Hodson A, Coats J, Narat S, Morley N, Dyer MJS, and Collins GP
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- Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Drug Resistance, Neoplasm, Humans, Lymphoma, Mantle-Cell diagnosis, Lymphoma, Mantle-Cell mortality, Protein Kinase Inhibitors therapeutic use, Recurrence, Retreatment, Sulfonamides administration & dosage, Sulfonamides adverse effects, Treatment Outcome, Antineoplastic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Lymphoma, Mantle-Cell drug therapy, Sulfonamides therapeutic use
- Published
- 2019
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28. Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines.
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Kozaki R, Vogler M, Walter HS, Jayne S, Dinsdale D, Siebert R, Dyer MJS, and Yoshizawa T
- Abstract
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL., Competing Interests: R.K. and T.Y. are employees of ONO Pharmaceuticals. M.J.S.D. receives research funding from ONO Pharmaceuticals.
- Published
- 2018
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29. Targeting anti-apoptotic BCL2 family proteins in haematological malignancies - from pathogenesis to treatment.
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Vogler M, Walter HS, and Dyer MJS
- Subjects
- Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Hematologic Neoplasms genetics, Hematologic Neoplasms pathology, Humans, Proto-Oncogene Proteins c-bcl-2 genetics, Sulfonamides pharmacology, Sulfonamides therapeutic use, Hematologic Neoplasms drug therapy, Molecular Targeted Therapy methods, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
- Abstract
The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-X
L (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics. The first BCL2-specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL), with surprisingly little toxicity given the expression of BCL2 in normal tissues. Despite success in CLL, where sensitivity to BCL2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B-cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL2 inhibition. In this review, we summarise the biology of BCL2 proteins, the mechanism of action of BH3-mimetics and the status of their clinical development in haematological malignancies., (© 2017 John Wiley & Sons Ltd.)- Published
- 2017
- Full Text
- View/download PDF
30. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059.
- Author
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Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, and Dyer MJS
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Disease-Free Survival, Female, Follow-Up Studies, Humans, Imidazoles adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Male, Pyrimidines adverse effects, Survival Rate, Imidazoles administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines administration & dosage
- Published
- 2017
- Full Text
- View/download PDF
31. Obinutuzumab-induced coagulopathy in chronic lymphocytic leukaemia with trisomy 12.
- Author
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Walter HS, Jayne S, Mensah P, Miall FM, Lyttelton M, and Dyer MJ
- Subjects
- Aged, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation, Receptor, Notch1 genetics, Antibodies, Monoclonal, Humanized adverse effects, Chromosomes, Human, Pair 12, Disseminated Intravascular Coagulation chemically induced, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Trisomy genetics, Trisomy pathology
- Abstract
Competing Interests: MJSD has acted as a consultant for and received honoraria from Roche Pharmaceuticals. The remaining authors declare no conflict of interest.
- Published
- 2016
- Full Text
- View/download PDF
32. New Agents to Treat Chronic Lymphocytic Leukemia.
- Author
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Walter HS, Salles GA, and Dyer MJ
- Subjects
- Female, Humans, Male, Antineoplastic Agents administration & dosage, Benzamides administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazines administration & dosage
- Published
- 2016
- Full Text
- View/download PDF
33. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.
- Author
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Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, Shah N, Hutchinson CV, Honda H, Duffy K, Birkett J, Jamieson V, Courtenay-Luck N, Yoshizawa T, Sharpe J, Ohno T, Abe S, Nishimura A, Cartron G, Morschhauser F, Fegan C, and Salles G
- Subjects
- Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, B-Lymphocytes pathology, Cohort Studies, Female, Humans, Imidazoles adverse effects, Imidazoles blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Pyrimidines adverse effects, Pyrimidines blood, B-Lymphocytes drug effects, Imidazoles therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Mantle-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines therapeutic use
- Abstract
We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
- View/download PDF
34. Does intravitreal injection of ranibizumab increase the risk for macular hole formation?
- Author
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Walter HS, Gatzioufas Z, El-Husseiny M, Stavridis E, and Seitz B
- Subjects
- Female, Humans, Antibodies, Monoclonal adverse effects, Retinal Detachment drug therapy, Retinal Perforations chemically induced, Retinal Perforations drug therapy, Retinal Pigment Epithelium pathology
- Published
- 2011
- Full Text
- View/download PDF
35. [Visual diagnosis: Waardenburg syndrome].
- Author
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Hager T, Walter HS, Seitz B, and Käsmann-Kellner B
- Subjects
- Child, Preschool, Humans, Male, Vision Disorders diagnosis, Retinal Diseases diagnosis, Waardenburg Syndrome diagnosis
- Abstract
Background: Waardenburg syndrome (WS) is a rare disease characterized by a sensorineural hearing loss and pigment anomalies of the iris, skin and hair due to mutations in PAX3. WS can be subdivided into four groups according to major and minor clinical signs., Case Report: We report the case of a 2 1/2-year-old coloured patient who presented in our department of paediatric ophthalmology for a syndrome search. The patient presented with hearing loss, brilliant blue iris colour and dystopia canthorum. The patient was slightly hypermetropic. Visual acuity was within normal limits according to the Cardiff acuity test. The ocular fundus examination revealed no abnormalities., Conclusion: According to the major and minor criteria defined by the Waardenburg consortium our patient showed the major criteria of WS1, i.e. hearing loss, hypopigmentation of the pigment epithelium of the iris and dystopic canthi. Diagnosis of WS is usually based on the clinical presentation. An additional molecular genetic analysis is possible.
- Published
- 2010
- Full Text
- View/download PDF
36. [Unclear deterioration of vision after renal transplant].
- Author
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Hild M, Walter HS, Milioti G, and Seitz B
- Subjects
- Adult, Diagnosis, Differential, Female, Humans, Kidney Transplantation adverse effects, Lens Diseases diagnosis, Lens Diseases etiology, Nephritis, Hereditary complications, Nephritis, Hereditary surgery, Vision Disorders diagnosis, Vision Disorders etiology
- Abstract
A 27-year-old female patient reported a variable but unsatisfactory visual acuity which had persisted for several years. The patient had been dependent on dialysis from the age of 14 years old and from then on also needed a hearing aid. A kidney had been transplanted 5 years ago. The diagnosis was anterior lenticonus due to Alport syndrome.
- Published
- 2009
- Full Text
- View/download PDF
37. Pattern ERG as an early glaucoma indicator in ocular hypertension: a long-term, prospective study.
- Author
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Bach M, Unsoeld AS, Philippin H, Staubach F, Maier P, Walter HS, Bomer TG, and Funk J
- Subjects
- Adult, Aged, Disease Progression, Humans, Intraocular Pressure, Longitudinal Studies, Middle Aged, Ocular Hypertension diagnosis, Pattern Recognition, Visual, Prospective Studies, ROC Curve, Retinal Ganglion Cells pathology, Visual Fields, Electroretinography methods, Glaucoma diagnosis, Retinal Diseases diagnosis, Vision Disorders diagnosis
- Abstract
Purpose: The conversion rate from untreated ocular hypertension (OHT) to glaucoma is only approximately 1% per year. Discrimination of nonconverters and potential converters would help reserve preventative treatment for those who need it and thus avoid unnecessary side effects and expenditure for those who do not. This prospective study was designed to assess the pattern electroretinogram (PERG) as an early indicator of dysfunction preceding glaucoma., Methods: Ninety-five eyes of 54 patients with intraocular pressure > or =25 mm Hg (or > or =23 mm Hg with additional risk factors), normal visual fields, normal optic disc cupping, and visual acuity > or =0.8 were evaluated. Every 6 months during a median follow-up of 8.2 years, the PERG and visual fields were obtained besides other standard diagnostics. PERGs were recorded in steady state mode in response to checkerboard stimuli at 15 reversals/s, and the amplitudes in response to check sizes of 0.8 degrees and 16 degrees as well as the ratio of the amplitude of responses to 0.8 degrees over that to 16 degrees checks were determined., Results: Glaucomatous visual field defects developed in eight eyes. For the PERG to 0.8 degrees checks and for the PERG ratio, analysis of the receiver-operating characteristic (ROC) yielded steadily increasing ROC areas before conversion (i.e., an increasing ability of the PERG to predict nonconversion or conversion). One year before conversion, the ROC area of the PERG ratio was 0.78; at a threshold of 1.06 this corresponded to a sensitivity of 80% and a specificity of 71%., Conclusions: The PERG can help to predict stability or progression to glaucoma in OHT at least 1 year ahead of conversion.
- Published
- 2006
- Full Text
- View/download PDF
38. [Resource utilisation and cost of amblyopia treatment].
- Author
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König HH, Walter HS, and Barry JC
- Subjects
- Amblyopia therapy, Costs and Cost Analysis statistics & numerical data, Fee Schedules statistics & numerical data, Germany, Humans, Patient Care Team economics, Patient Care Team statistics & numerical data, Utilization Review statistics & numerical data, Amblyopia economics, Amblyopia epidemiology, Health Care Costs statistics & numerical data, Health Resources economics, Health Resources statistics & numerical data, National Health Programs economics, National Health Programs statistics & numerical data
- Abstract
Background: The cost-effectiveness of screening for amblyopia is a controversial issue of international debate. The purpose of this study was to estimate the cost of amblyopia treatment to be used as a component for modelling the cost-effectiveness of prevention programmes. Cost was calculated from the perspective of the German social health insurance in the year 2002., Materials and Methods: A standardised detailed survey was conducted in writing among 13 experienced experts in amblyopia treatment from various offices and strabismological units in Germany. Average volumes of treatment items were estimated for a maximum treatment period of nine years. Cost was calculated using administrative prices (based on the social health insurance's uniform fee schedule for physician services and reference prices for therapeutic aids) and market prices., Results: The questionnaires were fully completed by 12 of the 13 experts. The mean total cost of treatment was estimated at 2.472 Euro (95 %-CI: 1.171 - 3.774) for strabismic amblyopia and 2.051 Euro (95 %-CI: 426 - 3.675) for amblyopia of refractive origin. About 70 % of the total cost was caused by the therapeutic aids (e. g. glasses, patches). The price of the patches had a marked impact on the total treatment cost., Conclusions: The results may be used for modelling the cost-effectiveness of screening programmes for the prevention of amblyopia.
- Published
- 2003
- Full Text
- View/download PDF
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