Induction of Endoscopic Response, Remission, and Ulcer-Free Endoscopy With Upadacitinib Is Associated With Improved Clinical Outcomes and Quality of Life in Patients With Crohn's Disease.

BACKGROUND: We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn's disease (CD) treated with upadacitinib (UPA). METHODS: This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52. RESULTS: A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn's Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not. CONCLUSIONS: Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD. CLINICAL REGISTRATION NUMBER: U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823).

In patients with Crohn's disease treated with 12 weeks of upadacitinib, a greater proportion with early improvements in endoscopic response, remission, healing, and ulcer-free endoscopy, vs those without improvements, attained long-term meaningful improvements in clinical outcomes and quality of life.

Content Validity and Psychometric Evaluation of the Crohn's Symptom Severity (CSS) Questionnaire in Patients with Moderately to Severely Active Crohn's Disease.

INTRODUCTION: Individuals living with Crohn's disease (CD) experience burdensome symptoms. As such, it is important to measure CD symptom severity in clinical research. The goal of this study was to evaluate the content validity, psychometric performance, and score interpretability of a new patient-reported instrument, the Crohn's Symptom Severity (CSS) questionnaire, among adolescents and adults with moderately to severely active CD. METHODS: Cognitive debriefing interviews (N = 30; n = 20 adults, n = 10 adolescents) were conducted to evaluate the content validity of the CSS. Additionally, the CSS scores were evaluated for reliability and validity using data from a phase 3 randomized clinical trial of risankizumab (NCT03105128; N = 850). Meaningful within-patient change (MWPC) thresholds were estimated using anchor-based methods. RESULTS: All interview participants (n = 30/30, 100.00%) reported the CSS was easy to complete and most participants (n = 28/29, 96.55%) reported that the CSS was relevant to their experience of CD. Among the clinical trial subjects (N = 850) the following was found for the CSS: mostly acceptable item-total correlations (0.26-0.79); weak to moderate inter-item correlations (r = 0.07-0.57), good internal consistency (Cronbach's α = 0.76-0.87); intraclass correlation coefficients ranged from 0.48 to 0.70, not consistently exceeding the acceptable range for test-retest reliability (0.70); acceptable convergent validity and known-groups results; and demonstrated sensitivity to change. Analyses supported an MWPC estimate of 6-11 points. CONCLUSIONS: This study supports use of the CSS for measuring CD symptoms and sleep impact among adolescents and adults aged 16 and older with moderately to severely active CD in clinical research. TRIAL REGISTRATION: NCT03105128 (registration date 4 April 2017).

More Time Spent with Clear Skin and No Itch with Upadacitinib versus Dupilumab for Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients' quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. METHODS: This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. RESULTS: This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8-13.4 times as many days with an EASI 90 response and 7.0-10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. CONCLUSIONS: Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

BACKGROUND AND AIMS: Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. METHODS: Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. RESULTS: Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. CONCLUSIONS: In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.

Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2).

BACKGROUND: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. OBJECTIVE: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis. METHODS: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16. RESULTS: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. CONCLUSIONS: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).

Atopic dermatitis, or eczema, is a condition that causes painful itchy dry skin, which is burdensome for patients and has a negative impact on quality of life. These symptoms frequently lead to disruption of daily activities such as school and work, decreased self-confidence, social isolation, anxiety, depression, and sleep disturbance. Symptoms of atopic dermatitis, such as itch and sleep disturbance, can only be assessed by patients. Therefore, it is important to consider patients' perceptions of their symptoms and the related impact on their quality of life, especially when evaluating treatment benefits. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. In two clinical trials (Measure Up 1 and Measure Up 2), we investigated how treatment with upadacitinib (15-mg or 30-mg dose) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis would impact their symptoms and quality of life over a 1-year period. We measured changes over time in patients' assessments of itch, pain, other skin-related symptoms, sleep, daily activities, emotional state, mental health, and overall quality of life. Patients treated with upadacitinib experienced improvements in symptoms of atopic dermatitis and quality of life within the first 1­2 weeks of treatment. These improvements continued to steadily increase in the following weeks and lasted through 1 year of treatment. In conclusion, once-daily treatment with upadacitinib 15 or 30 mg led to early and lasting improvements in the well-being of patients with atopic dermatitis.

Economic Burden of Fatigue in Inflammatory Bowel Disease.

Background: This retrospective study gathered medical/pharmacy claims data on patients with inflammatory bowel disease (IBD) between January 01, 2000 and March 31, 2019 from the IBM MarketScan commercial claims database to assess the real-world impact of fatigue on healthcare costs in patients newly diagnosed with IBD. Methods: Eligible participants were ≥18 years, newly diagnosed with IBD (≥2 separate claims), and had ≥12 months of continuous database enrollment before and after fatigue diagnosis. The date of fatigue diagnosis was the index date; participants were followed for 12 months post-index. Patients with (cases) or without (controls) fatigue were matched 1:1 by propensity score matching. Patients with evidence of prior IBD diagnosis/treatment, or those with a chronic disease other than IBD wherein fatigue is the primary symptom, were excluded. Healthcare resource utilization (HCRU), including hospitalizations, inpatient and outpatient visits, and associated costs were compared between cases and controls. Results: Matched IBD cohorts (21 321 cases/21 321 controls) were identified (42% Crohn's disease [CD] and 58% ulcerative colitis [UC]) with similar baseline characteristics (average age: 46 years; 60% female). Cases versus controls had significantly more all-cause outpatient visits (incidence rate ratio [IRR], 95% confidence intervals [95% CI]: 1.64 [1.61, 1.67], P < .001) and all-cause hospitalizations (IRR [95% CI]: 1.92 [1.81, 2.04], P < .001); as well as significantly higher all-cause total direct healthcare costs (mean: $24 620 vs. $15 324; P < .001). Similar findings were observed for IBD-related outcomes, as well as in CD- and UC-specific subgroups. Conclusions: Presence of fatigue is associated with an increase in HCRU and total medical costs among patients newly diagnosed with IBD.

Acute Kidney Injury from Intravitreal Anti-vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several observational studies have reported acute kidney injury from intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for retinal diseases. However, systematic reviews and meta-analyses of randomized controlled trials on this critical topic are scant. OBJECTIVE: To evaluate acute kidney injury risk associated with intravitreal anti-VEGF drugs in patients with retinal diseases. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials on 12 July, 2023, and included randomized controlled trials reporting acute kidney injury between anti-VEGF drugs (e.g., aflibercept, bevacizumab, brolucizumab, and ranibizumab) and controls for retinal diseases (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic retinopathy/diabetic macular edema, retinal vein occlusion, and myopic choroidal neovascularization). Data were synthesized by a fixed-effects model for pooling odds ratios (ORs) using the Peto method. RESULTS: We included 13 randomized controlled trials (four and nine trials for aflibercept and ranibizumab, respectively) with a total of 4282 participants. The meta-analysis indicated intravitreal anti-VEGF drugs did not increase the acute kidney injury risk, compared with controls (odds ratio [OR]: 1.00, 95% confidence interval [CI] 0.49-2.04, I2: 0%), and no differences in the acute kidney injury risk were observed between different anti-VEGF drugs (OR: 1.10, 95% CI 0.27-4.43, I2: 0% for aflibercept; OR: 0.97, 95% CI 0.42-2.22, I2: 0% for ranibizumab) and between different retinal diseases (OR: 4.61, 95% CI 0.07-284.13, I2: not applicable for age-related macular degeneration; OR: 0.90, 95% CI 0.42-1.93, I2: 0% for diabetic retinopathy/diabetic macular edema; OR: 1.57, 95% CI 0.16-15.88, I2: 0% for retinal vein occlusion). CONCLUSIONS: Intravitreal anti-VEGF drugs were not associated with an acute kidney injury risk, regardless of which anti-VEGF drugs (aflibercept or ranibizumab) or retinal diseases (age-related macular degeneration, diabetic retinopathy/diabetic macular edema, or retinal vein occlusion) were involved. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO CRD42021267854.

Comparative Efficacy of Targeted Systemic Therapies for Moderate-to-Severe Atopic Dermatitis without Topical Corticosteroids: An Updated Network Meta-analysis.

INTRODUCTION: The treatment landscape for moderate-to-severe atopic dermatitis (AD) continues to expand. This network meta-analysis (NMA) updates a previously conducted NMA to include data from the most recent phase 3 trials to assess the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate-to-severe AD. METHODS: Data from recent phase 3 monotherapy trials of lebrikizumab, ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), were included in the analyses, along with other eligible phase 3/4 randomized placebo-controlled trials for abrocitinib, baricitinib, dupilumab, tralokinumab, and upadacitinib identified through a systemic literature review in Silverberg et al. (Dermatol Ther (Heidelb) 12(5):1181-1196, 2022). The proportion of patients achieving Eczema Area and Severity Index (EASI) improvement ≥ 90% from baseline (EASI-90), EASI improvement ≥ 75% from baseline (EASI-75), ≥ 4-point improvement on Pruritus Numerical Rating Scale from baseline (ΔNRS ≥ 4), and Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and reduction of ≥ 2 points from baseline (IGA 0/1) were evaluated using a Bayesian network meta-analysis. RESULTS: The updated NMA analyzed 13 unique placebo-controlled trials involving 7105 patients in 32 arms across 6 targeted therapies. Upadacitinib 30 mg was the most efficacious therapy across all endpoints at the primary timepoint (week 12 or 16) and at earlier timepoints, generally followed by abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg, and lebrikizumab 250 mg or abrocitinib 100 mg. Baricitinib 2 mg and tralokinumab were generally ranked lower across outcomes. CONCLUSIONS: Many factors need to be considered for treatment selection for AD, especially as new treatments continue to emerge. After incorporating recent placebo-controlled phase 3 data of lebrikizumab, upadacitinib 30 mg, upadacitinib 15 mg, and abrocitinib 200 mg remain the most efficacious targeted systemic therapies over 12-16 weeks of therapy in AD. These updated findings can help healthcare providers when creating a patient's personalized treatment plan.

Real-Time Tracking of Laryngeal Motion via the Surface Depth-Sensing Technique for Radiotherapy in Laryngeal Cancer Patients.

Radiotherapy (RT) is an important modality for laryngeal cancer treatment to preserve laryngeal function. During beam delivery, laryngeal motion remains uncontrollable and may compromise tumor-targeting efficacy. We aimed to examine real-time laryngeal motion by developing a surface depth-sensing technique with preliminary testing during RT-based treatment of patients with laryngeal cancer. A surface depth-sensing (SDS) camera was set up and integrated into RT simulation procedures. By recording the natural swallowing of patients, SDS calculation was performed using the Pose Estimation Model and deep neural network technique. Seven male patients with laryngeal cancer were enrolled in this prospective study. The calculated motion distances of the laryngeal prominence (mean ± standard deviation) were 1.6 ± 0.8 mm, 21.4 ± 5.1 mm, 6.4 ± 3.3 mm, and 22.7 ± 4.9 mm in the left-right, cranio-caudal, and anterior-posterior directions and for the spatial displacement, respectively. The calculated differences in the 3D margins for generating the planning tumor volume by senior physicians with and without SDS data were -0.7 ± 1.0 mm (-18%), 11.3 ± 6.8 mm (235%), and 1.8 ± 2.6 mm (45%) in the left-right, cranio-caudal, and anterior-posterior directions, respectively. The SDS technique developed for detecting laryngeal motion during swallowing may be a practical guide for individualized RT design in the treatment of laryngeal cancer.

Increased absolute lymphocyte count, increased absolute neutrophil count and low platelet to lymphocyte ratio as predicting factors in the superior disease control of refractory/relapsing gynecologic malignancies with anti PD-1 therapy: 10 years of experience in a single institution.

OBJECTIVE: Immune checkpoint inhibitors are rapidly being used in solid and hematologic malignancies, including gynecologic cancers. The high mortality and relapsing rates of advanced gynecologic malignancies remain a challenging issue. This study aimed to identify the predicting factors associated with survival prognosis and disease control in patients with refractory/relapsing (R/R) gynecologic malignancies receiving anti PD-1 therapy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 49 patients diagnosed with R/R gynecologic malignancies between July 2012 and June 2019 in Chang Gung Memorial Hospital, Taiwan. Among the 49 patients, 6 were excluded due to incomplete medical records or not receiving anti PD-1 therapy. The remaining 43 patients were further divided into responsive and non-responsive groups according to disease control for predicting prognostic factor analysis. RESULTS: For the 43 cases, the median age at diagnosis and disease follow-up length were 54 years and 29 months, respectively. Among them, 23 (53%) were categorized into the responsive group, and the remaining 20 (47%) were categorized into the non-responsive group. The mortality rates were 17% and 25% in the responsive and non-responsive groups, respectively. The responsive group had significantly higher absolute lymphocyte count (ALC), higher absolute neutrophil count (ANC) and low platelet to lymphocyte ratio (PLR) than the non-responsive group. A superior long-term survival trend was also observed in the responsive group, but the difference was not statistically significant. CONCLUSIONS: This study reinforced the hypothesis that high ALC, high ANC and low PLR are associated with superior disease control in patients with R/R gynecologic malignancies receiving anti PD-1 therapy.

Content Validity and Psychometric Evaluation of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Patients with Crohn's disease (CD) or ulcerative colitis (UC) frequently experience fatigue, although it is often overlooked in medical research and practice. AIMS: To explore patients' experience of fatigue and evaluate content validity, psychometric properties, and score interpretability of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in patients with CD or UC. METHODS: Concept elicitation and cognitive interviews were conducted with participants aged ≥ 15 years with moderately-to-severely active CD (N = 30) or UC (N = 33). To evaluate psychometric properties (reliability and construct validity) and interpretation of FACIT-Fatigue scores, data from two clinical trials were analyzed [ADVANCE (CD): N = 850; U-ACHIEVE (UC): 248]. Meaningful within-person change was estimated using anchor-based methods. RESULTS: Almost all interview participants reported experiencing fatigue. Over 30 unique fatigue-related impacts were reported per condition. The FACIT-Fatigue was interpretable for most patients. FACIT-Fatigue items had good internal consistency (Cronbach's α 0.86-0.88 for CD and 0.94-0.96 for UC); the total score displayed acceptable test-retest reliability (intraclass correlation coefficients > 0.60 for CD and > 0.90 for UC). FACIT-Fatigue scores had acceptable convergent validity with similar measures. A 7-10 point improvement for CD and 4-9 point improvement for UC on the FACIT-Fatigue total score may represent meaningful improvements. CONCLUSIONS: These results highlight the importance of fatigue among adolescents and adults with CD or UC and provide evidence that the FACIT-Fatigue is content valid and produces reliable, valid, and interpretable scores in these populations. Care should be taken if using the questionnaire with adolescents who may be less familiar with the word "fatigue." Clinical trial registration numbers NCT03105128 (date of registration: 4 April 2017) and NCT02819635 (date of registration: 28 June 2016).

Risk of retinal vein occlusion in colorectal cancer patients receiving anti-vascular endothelial growth factors - a population-based cohort study.

BACKGROUND: Anti-vascular endothelial growth factors (VEGFs) treatment has been associated with an increased risk of thromboembolic events. Therefore, the use of anti-VEGFs for patients with colorectal cancers (CRC) has raised concerns about the potential risk of retinal vein occlusion (RVO), an ocular disease caused by embolism or venous stasis. This study aims to evaluate the risk of RVO in patients with CRC treated with anti-VEGFs. METHOD: We conducted a retrospective cohort study using the Taiwan Cancer Registry and National Health Insurance Database. The study cohort comprised patients newly diagnosed with CRC between 2011 and 2017, who received anti-VEGF treatment. For each patient in the study cohort, a control group comprising four patients newly diagnosed with CRC, but not receiving anti-VEGF treatment, was randomly selected. A washout period of 12 months was implemented to identify new cases. The index date was defined as the date of the first prescription of anti-VEGF drugs. The study outcome was the incidence of RVO, as identified by ICD-9-CM (362.35 and 362.36) or ICD-10-CM codes (H3481 and H3483). Patients were followed from their index date until the occurrence of RVO, death or the end of the study period. Covariates, including patients' age at index date, sex, calendar year of CRC diagnosis, stage of CRC and comorbidities related to RVO, were included. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with adjustments for all covariates to compare the risk of RVO between the anti-VEGF and control groups. RESULTS: We recruited 6285 patients in the anti-VEGF group and 37,250 patients in the control group, with mean ages of 59.49 ± 12.11 and 63.88 ± 13.17 years, respectively. The incidence rates were 1.06 per 1000 person-years for the anti-VEGF group, and 0.63 per 1000 person-years for the controls. There was no statistically significant difference in RVO risk between the anti-VEGF and control groups (HR: 2.21, 95% CI: 0.87-5.61). CONCLUSION: Our results indicated no association between use of anti-VEGF and occurrence of RVO among CRC patients, although the crude incidence rate of RVO was higher in patients receiving anti-VEGF, compared to control patients. Future study with larger sample size is required to confirm our findings.

Dose Escalation Patterns of Advanced Therapies in Crohn's Disease and Ulcerative Colitis: A Systematic Literature Review.

INTRODUCTION: Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC. METHODS: Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]). RESULTS: Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks. CONCLUSION: Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation. PROSPERO REGISTRATION: CRD42021289251.

Effect of risankizumab on health-related quality of life in patients with Crohn's disease: results from phase 3 MOTIVATE, ADVANCE and FORTIFY clinical trials.

BACKGROUND: Crohn's disease has a substantial negative impact on health-related quality of life (HRQoL). AIM: To examine the effects of risankizumab on HRQoL in Crohn's disease METHODS: We analysed data from patients with Crohn's disease from 12-week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52-week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-item Short Form Health Survey (SF-36), EuroQol 5-Dimension-5-Level (EQ-5D-5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52. RESULTS: At week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT-F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p < 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF-36 physical and mental component summary scores, EQ-5D-5L and activity impairment within work productivity measures. CONCLUSIONS: Risankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease-specific and general patient-reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

Bilateral Optic Neuritis after COVID-19 Vaccination: A Case Report.

BACKGROUND: Neuro-ophthalmic manifestations after vaccines are rare, with optic neuritis (ON) being the most common presentation. Patients with vaccine-related ON are similar to those with idiopathic ON. The temporal relationship between vaccination against and the occurrence of ON is vital. Here, we report a case of bilateral ON after the administration of the ChAdOx1-S nCoV-19 SARS-CoV-2 vaccine. CASE: A 49-year-old healthy Asian female presented with sudden onset of bilateral blurred vision within 2 days. She complained of photophobia and extraocular pain upon movement over 3 days. Upon examination, her best corrected visual acuity (BCVA) was 20/30 in the right eye and 20/200 in the left eye. Anterior segment findings were unremarkable, with normal intraocular pressure. Fundoscopic examination revealed bilateral disc edema with vessel engorgement. Visual field examination revealed profound visual field defect in both eyes. She denied any trauma, use of new medication or medical history. She had received the ChAdOx1 nCoV-19 SARS-CoV-2 vaccine 14 days prior. Under suspicion of vaccine-related optic neuritis, she was given intravenous methylprednisolone 1 gm/day for 3 days, shifting to oral prednisolone under gradual tapering for 2 weeks. CONCLUSIONS: Typically presenting with sudden-onset visual decline and extraocular pain during movement, acute ON is generally idiopathic. Bilateral ON is rare, but quick identification is important because it can potentially lead to permanent loss of vision if left untreated. Vaccination-induced ON is even rarer but not difficult to treat. However, such patients require further evaluation and long-term follow-up because they may be prone to other neurological disorders in the future.

Serous retinal detachment secondary to an unsuccessful transarterial embolization in a post-traumatic carotid-cavernous sinus fistula patient: A case report.

A carotid-cavernous sinus fistula (CCF) is an abnormal communication between the cavernous sinus and the carotid arterial system. Direct CCFs arise from a direct connection between the cavernous sinus and the cavernous portion of the internal carotid artery. Nowadays, endovascular neurosurgery has become the first-line treatment modality for direct CCFs owing to the high complete obliteration rate. However, reversal of the clinical symptoms may not always be congruous after the endovascular intervention. Herein, we present a 50-year-old patient who manifested diplopia, ophthalmoplegia, and orbital congestion after a traffic accident. He had suffered head injury with right side frontal intracranial hemorrhage 1 month before the ophthalmic presentation. He came to our department primarily because of declining vision and for the above symptoms, and was diagnosed with direct type CCF, for which he received transarterial coil embolization. Unexpectedly, he later presented with serous retinal detachment accompanied by ocular ischemic syndrome secondary to recurrent CCF 1 month after the intervention, so repeat coil embolization was performed.

The Role of Corticosteroids in Treating Acute Ocular Toxoplasmosis in an Immunocompetent Patient: A Case Report.

Background: This study aimed to report a case who was treated with corticosteroids and anti- parasitic agents for ocular toxoplasmosis, but who progressed to acute retinal necrosis, and finally retinal detachment. Case Presentation: A 42-year-old man presented to the ophthalmology clinic with a 1-month history of progressive blurred vision and floaters in his right eye. His best visual acuity (VA) was 20/20 in both eyes. The anterior segment was unremarkable. Funduscopic examination of the right eye revealed active lesions of whitish foci of chorioretinitis with surrounding edema along the superonasal vessels, and retinal vasculitis with perivascular sheathing. Serologic testing was positive for Toxoplasma gondii IgM and IgG, but negative for other virus- and syphilis infections. Ocular toxoplasmosis was diagnosed. Corticosteroids and anti-parasitic agents were given simultaneously, but his right eye VA became 20/100. Funduscopic examination revealed retinal necrosis with localized retinal breaks. We immediately performed focal photocoagulation, however, his right eye progressed to retinal detachment and required vitrectomy. Conclusion: Early administration of systemic corticosteroids in patients with acquired acute ocular toxoplasmosis may lead to complications that impair vision. Intensive observation should be arranged after corticosteroid use.