Fixed Monthly versus Less Frequent Ranibizumab Dosing and Predictors of Visual Response in Exudative Age-Related Macular Degeneration

Purpose. To examine temporal patterns of visual acuity (VA) response to pooled 0.3 mg/0.5 mg ranibizumab treatment in patients with age-related macular degeneration and identify potential baseline predictors of response. Design. Retrospective analysis. Methods. Results from 1824 ranibizumab-treated patients receiving fixed monthly, quarterly, or as-needed dosing after three monthly loading doses in four phase III/IIIb trials (ANCHOR, MARINA, PIER, and SAILOR) were analyzed. Results. At month 3, 14.9% to 29.4% of patients had gained ≥15 letters. Not all patients achieved peak gains at month 3; many continued to have VA increases throughout treatment. After three monthly loading doses, continued monthly dosing resulted in further gains, as there were more delayed 15-letter responders at month 12 (14.7–16.1%) than with less frequent dosing (5.0–6.0%). Monthly dosing also resulted in more patients maintaining VA gains at later time points. Early 15-letter responders had lower baseline mean VA than delayed 15-letter responders in ANCHOR and MARINA; no other differences in baseline characteristics were noted. Conclusions. Although some patients have rapid improvements in VA, others do not experience peak VA until later during treatment. Continued monthly dosing resulted in a greater percentage of patients gaining ≥15 letters than with switching to less frequent dosing regimens

Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

Variations in concerns reported on the Patient Concerns Inventory (PCI) in head and neck cancer patients from different health settings across the world

Background: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). Methods: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. Results: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). “Fear of the cancer returning” (39%) and “dry mouth” (37%) were most common. Twenty-five percent (524) reported less than good QOL. Conclusion: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Voice Rehabilitation and Functional Outcomes Following Radiotherapy for Laryngeal Cancer

The overall aim of this thesis was to evaluate the effects of radiotherapy and voice rehabilitation on voice function and Health Related Quality of Life (HRQL) following treatment for laryngeal cancer. Patients treated for laryngeal cancer were prospectively studied pre-radiotherapy and 1, 6 and 12 months post-radiotherapy. Patients were randomized into a voice rehabilitation group, in which they received voice rehabilitation between 1 and 6 months post-radiotherapy, or a control group. Patient Reported Outcome (PRO) measures included the S-SECEL (Swedish Self-Evaluation of Communication Experiences after Laryngeal cancer), EORTC QLQ (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) and questions regarding hoarseness and vocal loudness. Acoustic, perceptual and temporal analyses were performed. The patients were also compared to a vocally healthy control group. After radiotherapy, a general deterioration of HRQL was observed in all patients treated for laryngeal cancer, the supraglottic cohort generally had inferior scores compared to the glottic cohort. Regarding voice quality, the glottic cohort appeared inferior to the vocally healthy control group both pre- and post-radiotherapy, while the supraglottic cohort was comparable to the vocally healthy control group. According to the S-SECEL results, improvement was seen in the voice rehabilitation group, results were maintained at the follow-up six months later. The control group had no statistically significant change in S-SECEL results. No statistically significant changes regarding acoustically measured voice quality were present in the short- or long-term follow-up. HRQL measures according to the EORTC improved after voice rehabilitation and remained at follow-up 6 months later. The control group showed no statistically significant change except for the Social function domain, which improved from baseline to 6 months post radiotherapy. Perceptually assessed roughness did not change during voice rehabilitation, however, a statistically significant deterioration was present for the control group between 6 and 12 months post-radiotherapy. Factors increasing the likelihood of communication improvement 12 months post radiotherapy were voice rehabilitation, poor speech scores and experiencing less voice use one month post-radiotherapy compared to pre-radiotherapy. Smoking affected communication negatively. In order to facilitate clinical interpretation of the S-SECEL, cut-off values as well as estimates of Minimum Clinically Important Differences (MCID) were identified for the instrument. Laryngeal cancer patients filled out the S-SECEL instrument and a question about acceptability of speech in a social context pre- and 12-months post oncologic treatment. Results at 12 months as well as the change between pre-treatment and 12-months follow-up were used for identification of cut-off values and estimates of MCID for each domain of the S-SECEL. When using the cut-off value, 36% of the participants scored above the value indicating the need for vocal rehabilitation at the 12-month follow-up. The results of this thesis demonstrated that voice function and HRQL is affected after radiotherapy. A large proportion had communication functioning indicating the need for vocal rehabilitation. Voice rehabilitation prevented voice deterioration and improved the self-perceived communication function and HRQL. The effects remained in the long-term. The findings suggest that voice rehabilitation could be beneficial to patients after radiotherapy for laryngeal cancer. Additionally it raises the importance of monitoring the communication and voice function through self-assessment and voice recordings

Living with dizziness impacts health‐related quality of life among older adults

Abstract Objective This study aimed to compare older adults reporting dizziness to those not reporting dizziness regarding health‐related quality of life (HRQL), distress due to dizziness, and balance confidence. A secondary aim was to investigate potential association between HRQL, number of falls, balance confidence, and distress due to dizziness. Methods Patients coming for bone density measurements answered questions regarding occurrence of dizziness. Patients reporting dizziness on a daily or weekly basis were considered eligible and invited for investigation at the Ear, Nose and Throat clinic at Södra Älvsborg Hospital, Sweden. Patients not reporting dizziness were considered eligible as controls. All patients answered the Dizziness Handicap Inventory (DHI), Activity Balance Confidence Scale (ABC‐scale), and Euro‐QoL‐5D‐3L questionnaires. Results A total of 55 dizzy patients came for physical investigation and answered the questionnaires and 47 non‐dizzy participants only answered the questionnaires. The dizzy participants reported lower levels of balance confidence, lower HRQL, more prior falls, and higher levels of distress due to dizziness than the non‐dizzy controls. Lower levels of balance confidence and higher level of distress due to dizziness were each associated with lower HRQL. Conclusion Dizziness, unsteadiness, and low balance confidence are associated with HRQL in a negative way. This is important to consider when measuring HRQL in a senior population, since a sensation of unsteadiness may indirectly contribute to low HRQL together with other symptoms. Level of evidence 2b

A longitudinal study of the Swedish MD Anderson Dysphagia Inventory in patients with oral cancer

Objective: The aim of this study was to investigate whether the Swedish MD. Anderson Dysphagia Inventory (MDADI) is able to detect changes in dysphagia symptoms over time for patients with head and neck cancer (HNC). Methods: One hundred and forty‐two patients with resectable tumors of the oral cavity were included prior to treatment. The patients filled out the MDADI, European Organization for Research and Treatment of Cancer Quality of Life questionnaire Core 30 (EORTC QLQ‐C30) and the HNC module (H&amp;N35) at baseline and at least one follow‐up at 6 and/or 12 months after oncologic treatment. A control group without dysphagia (n = 115) was included. Results: Self‐perceived swallowing function decreased in all domains at 6 months, and improved between 6 and 12 months. The changes were similar to the changes of the EORTC domains, indicating a sensitivity to change. However, even if improvements were seen at 12 months, the values were still inferior compared to baseline values, and the values of a control group without dysphagia. Convergent validity was found with values of the MDADI and EORTC domains producing similar results, and moderate correlations as hypothesized. Patients with moderate‐severe dysphagia according to the MDADI (&lt;60 points) demonstrated inferior values of the EORTC domains compared to patients with scores above 60 points. Conclusion: The Swedish MDADI was found to be sensitive to change, and showed convergent results when compared to other established instruments. The threshold value for the MDADI (&lt;60 points) indicating moderate‐severe dysphagia may be a valuable addition in the clinical use

Characterization of dysphagia and laryngeal findings in COVID-19 patients treated in the ICU-An observational clinical study.

BackgroundDysphagia appears to be common in patients with severe COVID-19. Information about the characteristics of dysphagia and laryngeal findings in COVID-19 patients treated in the intensive care unit (ICU) is still limited.ObjectivesThe aim of this study was to evaluate oropharyngeal swallowing function and laryngeal appearance and function in patients with severe COVID-19.MethodA series of 25 ICU patients with COVID-19 and signs of dysphagia were examined with fiberendoscopic evaluation of swallowing (FEES) during the latter stage of ICU care or after discharge from the ICU. Swallowing function and laryngeal findings were assessed with standard rating scales from video recordings.ResultsPooling of secretions was found in 92% of patients. Eleven patients (44%) showed signs of silent aspiration to the trachea on at least one occasion. All patients showed residue after swallowing to some degree both in the vallecula and hypopharynx. Seventy-six percent of patients had impaired vocal cord movement. Erythema of the vocal folds was found in 60% of patients and edema in the arytenoid region in 60%.ConclusionImpairment of oropharyngeal swallowing function and abnormal laryngeal findings were common in this series of patients with severe COVID-19 treated in the ICU. To avoid complications related to dysphagia in this patient group, it seems to be of great importance to evaluate the swallowing function as a standard procedure, preferably at an early stage, before initiation of oral intake. Fiberendoscopic evaluation of swallowing is preferred due to the high incidence of pooling of secretion in the hypopharynx, silent aspiration, and residuals. Further studies of the impact on swallowing function in short- and long-term in patients with COVID-19 are warranted

Characteristics of Patients Losing Vision after 2 Years of Monthly Dosing in the Phase III Ranibizumab Clinical Trials

To investigate the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in the pivotal ranibizumab phase III trials. Retrospective analysis. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trials. Demographics and lesion characteristics at baseline and month 24 were compared in patients with ≥15 letters VA loss and patients with ≥15 letters VA gain from baseline to month 24. Additional evaluations of fundus photographs from these patients were performed to assess features of non-exudative AMD, such as geographic atrophy (GA) and retinal pigment epithelium (RPE) abnormalities. Differences in lesion characteristics between patients who lost versus gained ≥15 letters of VA from baseline to month 24. At month 24, 9% of ranibizumab-treated patients from MARINA and 10% of ranibizumab-treated patients from ANCHOR had lost ≥15 letters VA; 30% of ranibizumab-treated patients from MARINA and 38% of ranibizumab-treated patients from ANCHOR had gained ≥15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions. At month 24, an increased area of RPE abnormality was associated with VA loss in both the MARINA ( P = 0.0008) and ANCHOR ( P = 0.0046) trials. Increased total lesion area at month 24 was associated with VA loss in both trials. In MARINA, the increase in total lesion area was attributable to an increase in the angiographic designation of atrophic scar among VA losers ( P = 0.0043), but in ANCHOR it was attributable to an increased area of choroidal neovascularization (CNV) ( P = 0.039) but not an increased area of leakage ( P = 0.17). Increased areas of GA, fibrosis, and hemorrhage were not associated with VA loss. Vision loss after 2 years of monthly ranibizumab therapy was associated with lesion characteristics commonly associated with suppressed CNV, such as pigmentary abnormalities, atrophic scar, and the absence of leakage. Future VA improvements in patients receiving ranibizumab therapy may require preservation of photoreceptor and RPE function rather than strategies that target CNV. Proprietary or commercial disclosure may be found after the references