IMPORTANCE: A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis. ...OBJECTIVE: To characterize the exposure characteristics and clinical manifestations of PPS–associated maculopathy. DESIGN, SETTING, AND PARTICIPANTS: In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019. MAIN OUTCOMES AND MEASURES: Drug exposure, visual acuity, and retinal imaging characteristics. RESULTS: Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (−0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes 53%) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes 23%; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities. CONCLUSIONS AND RELEVANCE: These findings suggest that PPS–associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium–photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.
Gene transfer using adeno-associated virus (AAV) vectors has great potential for treating human disease. Recently, questions have arisen about the safety of AAV vectors, specifically, whether ...integration of vector DNA in transduced cell genomes promotes tumor formation. This study addresses these questions with high-dose liver-directed AAV-mediated gene transfer in the adult mouse as a model (80 AAV-injected mice and 52 controls). After 18 months of follow-up, AAV-injected mice did not show a significantly higher rate of hepatocellular carcinoma compared with controls. Tumors in mice treated with AAV vectors did not have significantly different amounts of vector DNA compared with adjacent normal tissue. A novel high-throughput method for identifying AAV vector integration sites was developed and used to clone 1029 integrants. Integration patterns in tumor tissue and adjacent normal tissue were similar to each other, showing preferences for active genes, cytosine-phosphate-guanosine islands, and guanosine/cysteine-rich regions. Gene expression data showed that genes near integration sites did not show significant changes in expression patterns compared with genes more distal to integration sites. No integration events were identified as causing increased oncogene expression. Thus, we did not find evidence that AAV vectors cause insertional activation of oncogenes and subsequent tumor formation.
Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to ...describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States.
This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO
)/fraction of inspired oxygen (FiO
) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression-Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio.
Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (
=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (
=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (
=20) of patients improved or remained stable according to the CGI-I.
In patients hospitalized with COVID-19 and mild-to-moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit-risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.
Purpose
This study aimed to better understand the patient perspective and treatment experience of relapsed and/or refractory multiple myeloma (RRMM).
Methods
This qualitative study enrolled adult ...RRMM patients from 6 US clinics who had ≥ 3 months of life expectancy, ≤ 6 prior lines of therapy, and ≥ 1 treatment regimen with a proteasome inhibitor and immunomodulator, or a CD38 monoclonal antibody or an alkylating agent, and a steroid. In-person semi-structured qualitative interviews were conducted to capture concepts that were relevant and important to patients. Topics included RRMM symptoms and impacts and the mode of administration, frequency, duration, convenience, side effects, and overall experience with RRMM treatment.
Results
A total of 22 patients completed interviews. At enrollment, 59.1% of participants were using regimens containing dexamethasone, 36.4% daratumumab, 27.3% carfilzomib, and 18.2% lenalidomide. More participants had experience using intravenous or injectable therapy alone (40.9%) than oral therapy alone (18.2%). Back pain and fatigue were the most frequently reported symptoms (40.9% each); 27.3% reported no symptoms. Most participants reported physical function limitations (86.4%), emotional impacts (77.3%), MM-related activity limitations (72.7%), and sleep disturbances (63.6%). Most participants perceived treatment effectiveness based on physician-explained clinical signs (68.2%) and symptom relief (40.9%). Participants experienced gastrointestinal adverse events (59.1%), fatigue (59.1%), sleep disturbances (31.8%), and allergic reactions (31.8%) with treatment. Key elements of treatment burden included the duration of a typical treatment day (68.2%), treatment interfering with daily activities (54.5%), and infusion duration (50.0%).
Conclusions
These results provide treatment experience–related data to further understand RRMM treatment burden and better inform treatment decision-making.
IMPORTANCE: Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS). OBJECTIVE: To evaluate the disease course in PPS-associated ...maculopathy after drug cessation. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019. MAIN OUTCOMES AND MEASURES: Change in visual acuity and retinal imaging characteristics over time. RESULTS: Of the 11 included patients, all were female, and the median (interquartile range IQR) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year. CONCLUSIONS AND RELEVANCE: These retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.
Purpose
Neuroendocrine tumors (NETs) negatively impact patients’ quality of life. Octreotide long-acting release (LAR) and lanreotide depot are somatostatin analogs (SSAs) approved to treat NETs. The ...study objective was to explore SSA treatment experiences and preferences of patients with NETs.
Methods
Qualitative interviews were conducted in US adults (≥ 21 years) with NETs who had ≥ 6 months’ treatment with each SSA and transitioned from octreotide LAR to lanreotide depot within the previous year. Participants were asked open-ended questions about their experiences with octreotide LAR and lanreotide depot, treatment preferences, and SSA treatment attributes.
Results
Twenty participants (mean age: 58 years; 90% female; 85% white) completed interviews. The most common reasons for treatment transition were doctor recommendation (70%), treatment not working as expected (55%), and injection type preference (45%). Participants reported 34 unique favorable attributes of SSA treatment and 82 unique unfavorable attributes. Symptom control was the most frequently reported favorable attribute (associated with octreotide LAR by 60% of participants and lanreotide depot by 65%). Painful injection (65%) was most frequently cited unfavorable attribute for octreotide LAR and injection experience dependent on administrator (35%) for lanreotide depot. The three SSA treatment attributes rated as most important were side effects, symptom control, and ability to stabilize tumor
.
Conclusion
Our qualitative data provide valuable insight into the treatment attributes that patients with NETs consider important when making SSA treatment decisions. Factors related to injection administration, side effects, and symptom control are important to patients and should be included in patient-provider communications in clinical contexts.
Background
Multiple myeloma (MM) is a plasma cell malignancy characterized by the production of monoclonal light chains and immunoglobulin (M-protein), leading to impaired immune function, bone ...destruction, renal failure, and death. Existing and emerging MM therapies, including proteasome inhibitors (PI), immunomodulators (IMiDs), and monoclonal antibodies (mAB), delay progression and extend the lifespan but MM is incurable. However, more knowledge about patient experiences with treatments and their impact on everyday activities, including health-related quality of life (HRQOL) is needed for physicians and patients to make informed treatment decisions. This study aimed to gain a better understanding of the patient perspectives on treatment for relapsed and/or refractory multiple myeloma (RRMM).
Methods
This non-interventional, cross-sectional study involved semi-structured qualitative interviews with RRMM patients recruited from 6 U.S. clinics. Eligible RRMM patients (≥18 years) had at least 3 months of life expectancy, up to 6 prior lines of therapy, and at least one treatment regimen with a PI, IMiD, daratumumab, or an alkylating agent. Prior to conducting the patient interviews, a semi-structured qualitative interview guide was developed based on a literature review and formative/pilot discussions with MM expert clinicians (n=5) and patients (n=3). Within the interview guide, open-ended questions and targeted probes were used to facilitate discussions on topics including symptoms and impact of MM, mode of administration of treatment, tolerability, patients’ perception of indicators of effectiveness and overall experience. Qualitative coding and content analysis were conducted using Atlas.ti v8.0.
Results
Demographic characteristics, symptoms, and HRQOL impacts reported by interview participants (N=22) are presented in Table. At enrollment, 59% of patients were using regimens containing dexamethasone, 36% daratumumab, 27% carfilzomib, 18% lenalidomide. Most common co-morbidities included hypertension (41%), respiratory illnesses (32%), and GERD (27%). More patients had experience using IV/injectable (41%) alone compared with oral therapy (18%) alone; 41% of patients reported having experience with both modes. Back pain (41%) and fatigue (41%) were the symptoms reported most frequently by patients; 27% of patients reported no symptoms (See Table). Among impact concept categories most commonly reported by patients, 86% experienced physical function limitations (e.g. difficulty walking or standing), 77% reported emotional impacts (e.g. worry/fear or sadness/depression), 73% reported activity limitations related to MM, and 64% reported sleep disturbances (see Table). Regarding treatment experiences, most patients (68%) perceived effectiveness of their treatment based on laboratory test results explained by their physician, while 41% based treatment effectiveness on symptom relief. When asked about treatment tolerability, most patients described experiencing gastrointestinal side effects (59%), fatigue (59%), sleep disturbances (32%) and allergic reactions (32%). Regarding mode of treatment administration and regimens, participants most commonly reported the overall length of each treatment day (68%), treatment interfering with daily activities (55%), and length of infusion (50%) as key elements of treatment burden.
Conclusions
This study provides key insights into the impact on HRQOL from symptoms and treatment burden as well as patient perspectives on treatment effectiveness, tolerability, and modes of administration. Considering the evolution and complexity of MM management, and increasing regulatory emphasis on patient-centeredness, patient-relevant factors should be incorporated into future evaluation of MM treatments and patient outcomes.
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Bell:Millennium Pharmaceuticals, Inc.: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Ginchereau Sowell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Shah:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. McCarrier:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy.
Introduction: The treatment landscape for hemophilia A has evolved since the introduction of extended half-life (EHL) factor/non-factor VIII products, which allows for treatment personalization as ...per individual need, such as a less frequent infusion schedule and increased protection. Many different treatment attributes (e.g. safety, efficacy, and treatment burden) can influence patients' and caregivers' decisions in their choice of treatment. We used a discrete choice experiment (DCE) to elicit preferences from hemophilia A patients and caregivers for the treatment attributes of new EHL/non-factor products.
Methods: Adult patients and caregivers providing care for a young patient (<18 years) were recruited via a hemophilia A patient panel to complete an online survey with 2 components: (1) sociodemographic and treatment experience; (2) DCE with 12 treatment choice questions. Each question required respondents to choose between 2 hypothetical treatment profiles varying in terms of 6 attributes (Figure): safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type, and joint health studies. These attributes were selected based on a targeted literature review, 10 in-depth interviews with patients and caregivers, and clinical expert input. The results from the qualitative work have been previously published. The DCE survey was pilot tested with patients (N=3) and caregivers (N=3) for comprehensibility and revised prior to data collection. We used random parameters logit models to estimate preference weights and relative attribute importance scores.
Results: 113 patients (mean age: 35.5 years) and 96 caregivers (mean age of the child they cared for: 10.3 years) were included in the analysis. Among them, 88 patients (77.9%) self-reported having severe hemophilia while 81 (84.4%) caregivers reported that the child (<18 years) they cared for had severe hemophilia. Of these, 43 patients (38.1%) and 37 caregivers (38.5%) reported that their child with hemophilia used EHL/non-factor products. Among both patients and caregivers, the attributes from most to least important were as follows: (1) no safety concerns with too much clotting; (2) reducing annual bleeds from 5 to 0; (3) reducing weekly dosing from 4 to 1; (4) longer length of time the product has been approved for use (>6 years vs. <1 year); (5) factor product (vs. non-factor product), and (6) having studies demonstrating joint health improvement (vs. no studies) (Figure). The importance assigned to dosing frequency and bleed protection depended on the extent of improvement. For example, patients and caregivers valued having studies demonstrating joint health improvement more than they valued (a) a small improvement in bleed protection (i.e., 1/year to 0/year), or (b) a small improvement in dosing frequency (i.e., 2/week to 1/week). Lastly, further stratified analysis by patient and caregiver subgroups showed that patients viewed dosing frequency as the most important attribute influencing their treatment choices while caregivers valued safety the most. Among those who were not currently using EHL/non-factor products, the majority were willing to switch to EHL/non-factor products (81.4% of both cohorts). Bleed protection and dosing frequency were the most common reasons cited by respondents willing to switch treatments.
Conclusions: Besides safety, other attributes of products such as bleed protection and reducing dosing frequency had an important influence on hemophilia A patients' and caregivers' treatment choices in the DCE survey. The importance that patients and caregivers placed on these attributes also depended on the extent of bleed protection improvement or dosing reduction. Adult patients and caregivers making treatment decisions for their young patients may value dosing and safety of treatments differently. With more treatment options becoming available for people with hemophilia, it is important that patients and caregivers are well-informed about the comprehensive benefit-risk profile of different products to make the most optimal decisions to improve their current treatment and outcomes.
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Joshi:Pharmerit International: Employment. Ng:Pharmerit International: Employment. Botteman:Alnylam Pharmaceuticals: Consultancy; Pharmerit International: Employment, Equity Ownership; Daiichi Sankyo: Consultancy, Research Funding. Li:Bioverativ, a Sanofi Company: Employment. Shah:Pharmerit International: Employment. Jain:Sanofi Genzyme: Employment, Equity Ownership. Lyn:Sanofi Genzyme: Employment. Su:Sanofi Genzyme: Employment, Equity Ownership.
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