Promoting hearing and cognitive health in audiologic rehabilitation for the well-being of older adults.

OBJECTIVE: With our aging population, an increasing number of older adults with hearing loss have cognitive decline. Hearing care practitioners have an important role in supporting healthy aging and should be knowledgeable about cognitive decline and associated management strategies to maximize successful hearing intervention. METHODS: A review of current research and expert opinion. RESULTS: This article outlines the association between hearing loss and cognitive decline/dementia, hypothesized mechanisms underlying this, and considers current research into the effects of hearing intervention on cognitive decline. Cognition into old age, cognitive impairment, dementia, and how to recognize cognitive decline that is not part of normal aging are described. Screening of older asymptomatic adults for cognitive decline and practical suggestions for the delivery of person-centered hearing care are discussed. Holistic management goals, personhood, and person-centered care in hearing care management are considered for older adults with normal cognitive aging through to dementia. A case study illustrates important skills and potential management methods. Prevention strategies for managing hearing and cognitive health and function through to older age, and strategies to maximize successful hearing aid use are provided. CONCLUSION: This article provides evidence-based recommendations for hearing care professionals supporting older clients to maximize well-being through the cognitive trajectory.

Social-emotional well-being and adult hearing loss: clinical recommendations.

Aim: Best-practice in audiological rehabilitation takes a holistic client- and family-centred approach and considers hearing care in the context of personal well-being. Hearing loss not only impairs the ability to hear, but can also compromise the ability to communicate, thus negatively impacting both social and emotional well-being. Hearing care professionals play a key role in fostering their client's well-being. This paper aims to provide evidence-based recommendations to ensure inclusion of social-emotional well-being in audiologic rehabilitation clinical practice.Methods: A review of current research and expert opinion.Results: This guide proposes a 5-step plan which includes: identifying the client's social-emotional well-being; including family members in audiological rehabilitation; incorporating social-emotional needs and goals in an individualized management plan; relating identified hearing needs and goals to rehabilitation recommendations; and using counselling skills and techniques to explore and monitor social-emotional well-being. Each component of the 5-step plan is discussed and clinical considerations are presented.Conclusion: These comprehensive recommendations provide guidance to hearing care professionals looking to ensure clients' social-emotional well-being are considered throughout the rehabilitation journey.

International Practice Recommendations for the Recognition and Management of Hearing and Vision Impairment in People with Dementia.

INTRODUCTION: Hearing, vision, and cognitive impairment commonly co-occur in older people. However, the rate of recognition and appropriate management of combined hearing and vision impairment in people with dementia impairment is low. The aim of this work was to codevelop internationally relevant, multidisciplinary practice recommendations for professionals involved in the diagnosis, care, and management of older people with these concurrent conditions. METHODS: We applied consensus methods with professional and lay expert stakeholders, using an adapted version of the World Health Organization Handbook for Guideline Development. The development involved 4 phases and included: (1) collating existing evidence, (2) filling the gaps in evidence, (3) prioritising evidence, and (4) refining the final list of recommendations. Each phase encompassed various methodologies including a review of existing guidelines within the 3 clinical domains, systematic reviews, qualitative studies, a clinical professional consortium, surveys, and consensus meetings with interdisciplinary domain experts. RESULTS: The task force evaluated an initial list of 26 recommendations, ranking them in the order of priority. A consensus was reached on 15 recommendations, which are classified into 6 domains of "awareness and knowledge," "recognition and detection," "evaluation," "management," "support," and "services and policies." Pragmatic options for implementation for each domain were then developed. CONCLUSION: This is the first set of international, interdisciplinary practice recommendations that will guide the development of multidisciplinary services and policy to improve the lives of people with dementia and hearing and vision impairment.

Providing Hearing Assistance to Veterans in the Emergency Department: A Qualitative Study.

INTRODUCTION: Effective communication is essential to good health care, and hearing loss disrupts patient-provider communication. For the more than 2 million veterans with severe hearing loss, communication is particularly challenging in noisy health care environments such as emergency departments. The purpose of this qualitative study was to describe patient and provider perspectives of feasibility and potential benefit of providing a hearing assistance device, a personal amplifier, during visits to an emergency department in an urban setting affiliated with the Department of Veterans Affairs. METHODS: This qualitative descriptive study was conducted in parallel with a randomized controlled study. We completed a semistructured interview with 11 veterans and 10 health care providers to elicit their previous experiences with patient-provider communication in the ED setting and their perspectives on hearing screening and using the personal amplifier in the emergency department. Interview data were analyzed using content analysis and Atlas.ti V8.4 software (Scientific Software Development GmbH, Berlin, Germany). RESULTS: The veteran sample (n = 11) had a mean age of 80.3 years (SD = 10.2). The provider sample included 7 nurses and 3 physicians. In the ED setting, hearing loss disrupts patient-provider communication. Screening for hearing loss in the emergency department was feasible except in urgent/emergent cases. The use of the personal amplifier made communication more effective and less effortful for both veterans and providers. DISCUSSION: Providing the personal amplifier improved the ED experience for veterans and offers a promising intervention that could improve health care quality and safety for ED patient populations.

Identifying the approaches used by audiologists to address the psychosocial needs of their adult clients.

OBJECTIVE: To identify the approaches taken by audiologists to address their adult clients' psychosocial needs related to hearing loss. DESIGN: A participatory mixed methods design. Participants generated statements describing the ways in which the psychosocial needs of their adult clients with hearing loss are addressed, and then grouped the statements into themes. Data were obtained using face-to-face and online structured questions. Concept mapping techniques were used to identify key concepts and to map each of the concepts relative to each other. STUDY SAMPLE: An international sample of 65 audiologists. RESULTS: Ninety-three statements were generated and grouped into seven conceptual clusters: Client Empowerment; Use of Strategies and Training to Personalise the Rehabilitation Program; Facilitating Peer and Other Professional Support; Providing Emotional Support; Improving Social Engagement with Technology; Including Communication Partners; and Promoting Client Responsibility. CONCLUSIONS: Audiologists employ a wide range of approaches in their attempt to address the psychosocial needs associated with hearing loss experienced by their adult clients. The approaches described were mostly informal and provided in a non-standardised way. The majority of approaches described were not evidence-based, despite the availability of several options that are evidence-based, thus highlighting the implementation gap between research and clinical practice.

Audiological approaches to address the psychosocial needs of adults with hearing loss: perceived benefit and likelihood of use.

OBJECTIVE: To explore the perceived benefit and likely implementation of approaches used by audiologists to address their adult clients' psychosocial needs related to hearing loss. DESIGN: Adults with hearing loss and audiologists completed separate, but related, surveys to rate their perceived benefit and also their likely use of 66 clinical approaches (divided over seven themes) that aim to address psychosocial needs related to hearing loss. STUDY SAMPLE: A sample of 52 Australian adults with hearing loss, and an international sample of 19 audiologists. RESULTS: Overall, participants rated all of the approaches highly on both benefit and likelihood of use; the highest ranked theme was Providing Emotional Support. Cohort comparisons showed that audiologists ranked the approaches significantly higher than did adults with hearing loss. Overall, participants ranked the themes higher on benefit than on the likelihood to use scales. CONCLUSIONS: Adults with hearing loss and audiologists recognise the importance of approaches that address the psychosocial impacts of hearing loss in audiological rehabilitation. However, both groups placed slightly greater value on the internal-based approaches (the clients own emotional response, empowerment, and responsibility), and slightly less emphasis on the external-based approaches (being supported by communication partners, support groups or other health professionals).

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia.

BACKGROUND: Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia. METHODS: We enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer. RESULTS: The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag. CONCLUSIONS: The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by cytopenia and a propensity to develop acute myeloid leukemia (AML). The management of lower-risk (LR) MDS with persistent cytopenias remains suboptimal. Eltrombopag (EPAG), a thrombopoietin receptor agonist, can improve platelet counts in LR-MDS and tri-lineage hematopoiesis in aplastic anemia (AA). We conducted a phase 2 dose modification study to investigate the safety and efficacy of EPAG in LR-MDS. EPAG dose was escalated from 50 mg/day, to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a PNH clone, marrow hypocellularity, thrombocytopenia with or without other cytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with previous EPAG studies in AA; no patients discontinued drug due to adverse events. Three patients developed reversible grade-3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued EPAG after achieving a robust response (median time 16 months); four of them reinitiated EPAG due to declining counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to AML on study. In conclusion, EPAG was well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.

Application of Rasch Analysis to the Evaluation of the Measurement Properties of the Hearing Handicap Inventory for the Elderly.

OBJECTIVES: The aim of this research was to evaluate the measurement properties of the Hearing Handicap Inventory for the Elderly (HHIE). The HHIE is one of the most widely used patient-reported outcome measures in audiology. It was originally developed in the United States in the 1980s as a measure of the social and emotional impact of hearing loss in older adults. It contains 25 items that are accompanied by a 3-point response scale. To date, the measurement properties of the HHIE have primarily been assessed via traditional psychometric analysis techniques (e.g., Cronbach's alpha and Principal Components Analysis). However, traditional techniques are now known to have several limitations in comparison to more modern approaches. Therefore, this research used a modern psychometric analysis technique, namely Rasch analysis, to evaluate the HHIE. DESIGN: Rasch analysis was performed on HHIE data collected from 380 adults with hearing loss. The participants were principally recruited from the participant database of the National Institute for Health Research Nottingham Biomedical Research Centre in the United Kingdom. Additional participants were recruited from two UK audiology clinics and the online forum of a UK hearing loss charity. Rasch analysis was used to assess the measurement properties of the HHIE (i.e., fit to the Rasch model, unidimensionality, targeting, and person separation reliability) and its individual items (i.e., response dependency, fit, Differential Item Functioning, and threshold ordering). RESULTS: The HHIE was found to have several strong measurement properties. Specifically, it was well-targeted and had high person separation reliability. However, it displayed poor fit to the Rasch model and was not unidimensional. The majority of the items were free of response dependency (i.e., redundancy) and were suited to the 3-point response scale. However, two items were found to be better suited to a dichotomous response scale. Furthermore, nine items were identified as being candidates for removal from the questionnaire, as they exhibited poor fit and/or Differential Item Functioning (i.e., item bias) associated with gender. The measurement properties of the HHIE could be improved by removing these items and adjusting the scores of the two items that require a dichotomous response scale. These amendments resulted in a 16-item version of the HHIE that had good fit to the Rasch model and that was unidimensional. CONCLUSIONS: It is vital to ensure that high-quality outcome measures are used in audiology research and practice. This study evaluated one of the foremost outcome measures in this field: the HHIE. The results demonstrated that the HHIE had several strong measurement properties. Amending the HHIE, such as by removing items exhibiting poor fit, could further enhance its quality. A unique aspect of this study was the application of Rasch analysis to the evaluation of the HHIE. It is recommended that future studies use modern techniques to develop and identify high-quality, hearing-specific outcome measures.

Danazol Treatment for Telomere Diseases.

BACKGROUND: Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS: In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS: After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS: In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).

Simplified/Same Day(s)-GOLF as First-line Treatment of Metastatic Carcinoma of Unknown Primary (CUP), Suggestive of Pancreatobiliary Tumors.

BACKGROUND: Carcinoma of unknown primary represents a therapeutic challenge in oncological practice. Evidence lacks to support particular chemotherapy selection and empirical therapies are commonly extrapolated from data on patients where primary tumor site is known. Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil was previously developed to treat pancreatic cancer. These agents have also demonstrated activities in other gastrointestinal malignancies. Considering promising anti-tumor effects of GOLF, we performed a retrospective study to investigate anti-tumor activity and safety of a simplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil in patients with Carcinoma of unknown primary in whom immunohistostaining was suggestive of either upper gastrointestinal cancers or pancreatobiliary cancers. METHODS: This retrospective study included 18 patients recorded to have a diagnosis of Carcinoma of unknown primary between Aug 2010-Dec 2015, who received biweekly G 1000 mg/m2, O 85 mg/m2, L 200 mg/m2 and F 2400 mg/m2 over 46-h on day 1 with pegfilgrastim on day 3 every 14 days. IHC staining pattern favored upper GI origin, including stomach, bile duct or pancreas. Tumor assessments were repeated every 8 weeks. RESULTS: Median age was 67 years (range: 46-76), with ECOG PS<2, and 50% were women. Median number of cycles was 4 (range: 3-14). 7 partial responses were obtained (RR: 39%) and 7 achieved stable disease with overall disease control of 78%. Median time to tumor progression was 4 months (range: 2-9). 8 (44%) patients received liver-directed therapy and 1 underwent HIPEC (5%). Median survival time was 10.5 months (range: 6.7-14.5) and 1-year overall survival rate was 35%. Grade 3-4 toxicities included neutropenia, febrile neutropenia, thrombocytopenia, nausea, diarrhea, mucositis and oxaliplatin-induced neuropathy. CONCLUSION: Simplified Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil regimen appears to be feasible with promising activity for Carcinoma of unknown primary and deserves to be evaluated in future trials.

A plasma microRNA signature as a biomarker for acquired aplastic anemia.

Aplastic anemia is an acquired bone marrow failure characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the bone marrow. In aplastic anemia, a major challenge is to develop immune biomarkers to monitor the disease. We measured circulating microRNAs in plasma samples of aplastic anemia patients in order to identify disease-specific microRNAs. A total of 179 microRNAs were analyzed in 35 plasma samples from 13 aplastic anemia patients, 11 myelodysplastic syndrome patients, and 11 healthy controls using the Serum/Plasma Focus microRNA Polymerase Chain Reaction Panel. Subsequently, 19 microRNAs from the discovery set were investigated in the 108 plasma samples from 41 aplastic anemia patients, 24 myelodysplastic syndrome patients, and 43 healthy controls for validation, confirming that 3 microRNAs could be validated as dysregulated (>1.5-fold change) in aplastic anemia, compared to healthy controls. MiR-150-5p (induction of T-cell differentiation) and miR-146b-5p (involvement in the feedback regulation of innate immune response) were elevated in aplastic anemia plasma, whereas miR-1 was decreased in aplastic anemia. By receiver operating characteristic curve analysis, we developed a logistic model with these 3 microRNAs that enabled us to predict the probability of a diagnosis of aplastic anemia with an area under the curve of 0.86. Dysregulated expression levels of the microRNAs became normal after immunosuppressive therapy at 6 months. Specifically, miR-150-5p expression was significantly reduced after successful immunosuppressive therapy, but did not change in non-responders. We propose 3 novel plasma biomarkers in aplastic anemia, in which miR-150-5p, miR-146b-5p, and miR-1 can serve for diagnosis and miR-150-5p for disease monitoring. Clinicaltrials.gov identifiers:00260689, 00217594, 00961064.

Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution.

First-line therapy of severe aplastic anemia (SAA) with high-dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower, more moderate dose in combination with aggressive supportive care to determine whether severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine and antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pretherapy blood counts, and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5 patients, confirmed fungal infections were documented in 6, and 9 patients died. Nine patients (41%) responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 patients, and cytogenetic abnormalities (including monosomy 7) were observed in 4 patients. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283.

Opening the Market for Lower Cost Hearing Aids: Regulatory Change Can Improve the Health of Older Americans.

Hearing loss is a leading cause of disability among older people. Yet only one in seven US adults who could benefit from a hearing aid uses one. This fraction has not increased over the past 30 years, nor have hearing aid prices dropped, despite trends of steady improvements and price reductions in the consumer electronics industry. The President's Council on Science and Technology has proposed changes in the regulation of hearing aids, including the creation of a "basic" low-cost over-the-counter category of devices. We discuss the potential to reduce disability as well as to improve public health, stakeholder responses to the president's council's proposal, and public health efforts to further mitigate the burden of disability stemming from age-related hearing loss.

Cross-cultural adaptation of an Arabic version of the 10-item hearing handicap inventory.

OBJECTIVE: The purpose of this study was to translate and culturally adapt an Arabic version of the hearing handicap inventory for the elderly - screening (HHIE-S). DESIGN: The HHIE-S was translated following cross-cultural adaptation guidelines, and pretested in 20 elderly patients with hearing impairment. Next, the adapted Arabic HHIE-S underwent psychometric evaluation. The results were confirmed by pure-tone audiometer (PTA) examination. The patients completed the HHIE-S again after one hour. The validation of the questionnaire using Cronbach's alpha (internal consistency), (construct validity), and intraclass correlation coefficients (repeatability) was performed. STUDY SAMPLE: Twenty elderly subjects with hearing impairment were recruited for the pretesting stage, and 100 elderly subjects were recruited for the psychometric evaluation stage. Patients with acute illness, functional dependency, cognitive impairment, and previous users of hearing aids were excluded. RESULTS: The adapted Arabic HHIE-S showed good internal consistency (α = 0.902). Construct validity was good, as high correlations were found between the scale and the PTA outcome (r = 0.688, p = 0.000). Repeatability was high (ICC = 0.986). CONCLUSIONS: This study showed that the adapted Arabic HHIE-S is a valid and reliable questionnaire for the assessment of handicapping hearing impairment in Egyptian elderly patients.

Horse versus rabbit antithymocyte globulin in acquired aplastic anemia.

BACKGROUND: In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem-cell transplantation and improves blood counts and survival. Although horse ATG is the standard therapy, rabbit ATG is more potent in depleting peripheral-blood lymphocytes and is preferred in other clinical circumstances. METHODS: From December 2005 through July 2010, we performed a randomized trial comparing these two ATG formulations in conventional regimens. Patients were treated at a single facility. The primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to enroll 60 patients each for the rabbit-ATG and horse-ATG groups and was powered to detect a difference of 25 percentage points in the response rate. RESULTS: A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse-ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit-ATG group (P=0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P=0.008) in the respective groups when stem-cell-transplantation events were not censored. CONCLUSIONS: In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.).

Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia.

Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P = .16). For relapsed disease (n = 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n = 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260.

Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia.

In severe aplastic anemia, approximately one-third of responders to standard horse antithymocyte globulin (h-ATG) plus cyclosporine (CsA) will relapse. Anecdotal experience has suggested that a gradual CsA taper might avoid relapse, but this practice has not been rigorously assessed prospectively. In 2003, we adopted a strategy to taper CsA beyond 6 months, with the intention to reduce hematologic relapse compared with our extensive historical experience. In total, 102 patients received h-ATG/CsA for 6 months in two sequential clinical protocols: 67 patients (66%) responded and all had the CsA dose tapered per protocol over the subsequent 18 months (total of 2 years). The rate of relapse at 5 years was 33% (95% CI 27-44%), which did not differ from our large historical relapse experience (patients treated before 2003) of 30-40%, in protocols in which CsA was simply discontinued at 6 months. However, time to relapse was prolonged by about 1 year with the longer CsA course. The rates of clonal evolution and overall survival did not differ between the two cohorts. We infer from this large prospective study that CsA taper as implemented delayed but did not prevent relapse. The kinetics of relapse with long course CsA does suggest that a lower long-term dose might be adequate to maintain patients in remission.

Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia.

The effectiveness of salvage therapy for aplastic anemia patients unresponsive to initial rabbit antithymocyte globulin (r-ATG) or cyclophosphamide is not known. We investigated the administration of standard horse ATG (h-ATG) plus cyclosporine (CsA) in patients who were refractory to initial r-ATG/CsA (n = 19) or cyclophosphamide/CsA (n = 6) (registered at clinicaltrials.gov as NCT00944749). The primary endpoint was hematologic response at 3 months and was defined as no longer meeting the criteria for severe aplastic anemia. Of the 19 patients who received r-ATG as initial therapy, 4 (21%) achieved a hematologic response by 3 months, and of the 6 patients who received cyclophosphamide, only 1 (17%) responded by 6 months. Among the responders there were no cases of relapse, and in nonresponders 2 patients evolved to monosomy 7. The overall survival for the cohort at 3 years was 68% (95% CI, 50-91%). These results suggest that only a minority can be successfully salvaged after receiving as first therapy either r-ATG or cyclophosphamide. Although h-ATG may be utilized in the salvage setting, the overall response rate probably will be lower than when h-ATG is used as initial treatment.

Co-occurrence of idiopathic granulomatous hepatitis and primary biliary cirrhosis.

BACKGROUND: PBC is an autoimmune disease affecting the bile ducts. Granulomas can be found in portal triads in 45 % of patients with PBC. Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, elevated levels of liver enzyme tests, particularly the serum alkaline phosphatase, and granulomas in the portal and lobular regions of the liver. Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can be made only if PBC has been excluded. STUDY: We reviewed instances in which PBC and idiopathic granulomatous hepatitis occurred in the same patient. RESULTS: We report three patients in whom both diseases occurred: 1) A patient with PBC who was diagnosed 15 years later with idiopathic granulomatous hepatitis; 2) A patient with idiopathic granulomatous hepatitis who developed PBC 12 years later; and 3) A patient who had features of both idiopathic granulomatous hepatitis and PBC at the time of initial diagnosis. CONCLUSIONS: Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. Knowing this association is important, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly.