Development and usability testing of an electronic patient-reported outcome (ePRO) solution for patients with inflammatory diseases in an Advanced Therapy Medicinal Product (ATMP) basket trial.

BACKGROUND: Electronic patient-reported outcome (ePRO) systems are increasingly used in clinical trials to provide evidence of efficacy and tolerability of treatment from the patient perspective. The aim of this study is twofold: (1) to describe how we developed an electronic platform for patients to report their symptoms, and (2) to develop and undertake usability testing of an ePRO solution for use in a study of cell therapy seeking to provide early evidence of efficacy and tolerability of treatment and test the feasibility of the system for use in later phase studies. METHODS: An ePRO system was designed to be used in a single arm, multi-centre, phase II basket trial investigating the safety and activity of the use of ORBCEL-C™ in the treatment of patients with inflammatory conditions. ORBCEL-C™ is an enriched Mesenchymal Stromal Cells product isolated from human umbilical cord tissue using CD362+ cell selection. Usability testing sessions were conducted using cognitive interviews and the 'Think Aloud' method with patient advisory group members and Research Nurses to assess the usability of the system. RESULTS: Nine patient partners and seven research nurses took part in one usability testing session. Measures of fatigue and health-related quality of life, the PRO-CTCAE™ and FACT-GP5 global tolerability question were included in the ePRO system. Alert notifications to the clinical team were triggered by PRO-CTCAE™ and FACT-GP5 scores. Patient participants liked the simplicity and responsiveness of the patient-facing app. Two patients were unable to complete the testing session, due to technical issues. Research Nurses suggested minor modifications to improve functionality and the layout of the clinician dashboard and the training materials. CONCLUSION: By testing the effectiveness, efficiency, and satisfaction of our novel ePRO system (PROmicsR), we learnt that most people with an inflammatory condition found it easy to report their symptoms using an app on their own device. Their experiences using the PROmicsR ePRO system within a trial environment will be further explored in our upcoming feasibility testing. Research nurses were also positive and found the clinical dashboard easy-to-use. Using ePROs in early phase trials is important in order to provide evidence of therapeutic responses and tolerability, increase the evidence based, and inform methodology development. TRIAL REGISTRATION: ISRCTN, ISRCTN80103507. Registered 01 April 2022, https://www.isrctn.com/ISRCTN80103507.

More and more patients tell clinicians how they feel by completing questionnaires electronically. Therefore, it is important to assess how easy it is for patients to do this. In this study, we describe how we developed an electronic platform for patients to report their symptoms and how we tested the usability of this platform with patient partners and research nurses. Once the electronic platform was developed, quality of life and symptoms questionnaires were programmed onto it. Alerts were sent to the clinical team if specific scores were obtained on the symptoms questionnaires. Although two patient partners were not able to finish the testing session because of technical issues, the ones who completed the session liked its simplicity and responsiveness. The research nurses also liked the system and only suggested minor modifications. Following this testing, we refined the electronic platform to test it further in a larger study which investigates the safety and use of a drug. We hope that thanks to this electronic platform, we will obtain useful information on the safety and efficacy of treatment.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3.

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1ß. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant's diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

Clinical and Histopathologic Characteristics of Metastatic and Locally Advanced Cutaneous Basal Cell Carcinomas.

ABSTRACT: Locally advanced or metastatic basal cell carcinomas (laBCCs or mBCCs) are rare, with few case series providing information on their epidemiology. We aimed to describe the clinical and histologic features of locally advanced and metastatic basal cell carcinomas. Forty cases of laBCC or mBCC were identified by searching Vanderbilt's database from 1984 to January 2019. A retrospective chart review was performed. Pathology slides were available for 23 cases (13 mBCCs and 10 laBCCs). Twenty-one of 23 cases were Clark level IV or V, with a mean depth of invasion of >7 mm for both types. The mean mitotic rate was 4.4 mitoses/mm2 for laBCCs and 3.3 mitoses/mm2 for mBCCs. Ulceration was identified in 7 laBCC and 8 mBCC cases. Perineural invasion was present in 2 laBCC and 6 mBCC cases, with 3 mBCCs invading nerves >0.1 mm. Of 13 mBCC cases, histologic subtypes included infiltrative (n = 9), nodular (n = 7), morpheaform (n = 4), and superficial (n = 2), with multiple patterns present in some specimens. 10 of 13 patients with mBCC had local recurrence before metastasis. In summary, we identified several potential markers of high-risk BCC, including perineural invasion, deep invasion, elevated mitotic rate, and local recurrence of the primary tumor.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

Cutaneous Metastases From a Cribriform Adenocarcinoma of the Minor Salivary Glands.

Cutaneous metastases from solid tumor malignancies often emanate from breast, gastrointestinal, and lung tumors. Adenocarcinomas from minor salivary gland cancers may involve the skin contiguously but rarely as metastatic deposits. Furthermore, these metastases are usually locoregional and not distal. Recently, an uncommon neoplasm termed cribriform adenocarcinoma of the minor salivary glands has been described, and although it often spreads to cervical lymph nodes, metastatic involvement of the skin has not been reported.

Pancreatic fat necrosis in a 10-year-old girl: A case report and review of the literature.

We report here a case of a young girl with pancreatitis and pancreatic fat necrosis (PFN). This condition is rare in the pediatric age group, and its etiopathogenesis is different from disease in adults. Whereas PFN in adults typically results from pancreatitis secondary to pancreatic duct obstruction, alcohol abuse, and pancreatic adenocarcinoma, in children it appears to arise in a setting of systemic disease, often involving a genetic disorder.

An atypical pleomorphic lipomatous tumor arising on the cheek.

Pathologists and dermatopathologists commonly encounter tumors with adipocyte differentiation. Most are of minimal clinical significance. Those exhibiting atypical spindle cell morphology have been reported but the terminology for such neoplasms is unsettled. Tumors with both spindle cell and pleomorphic morphology are rare, with equally unsettled descriptive nomenclature. Recently, a series of such tumors, termed atypical pleomorphic lipomatous tumor, has been published. They resided in the deep soft tissue or subcutis. To date, such a tumor has not been reported with dermal involvement.

Identifying and managing concerns about GPs in England: an interview study and case-series analysis.

BACKGROUND: Underperforming doctors have been the focus of sustained interest from the media, policymakers, and researchers. GPs are more likely to be the subject of a complaint than any other type of doctor in the UK, and the management of concerns in primary care needs improvement, yet more is known about how concerns are managed in secondary care. AIM: Although formal policies for NHS England's management of concerns are clear, little is known about how these are put into practice. This study explores how concerns are identified, investigated, and managed at a regional level. DESIGN AND SETTING: A qualitative study of the management of concerns in primary care across eight area teams. METHOD: The study comprised two main strands: in-depth interviews with NHS England staff; and the analysis of case file data. RESULTS: The process for raising concerns was identified as inconsistent and disparate, with potential weaknesses to address. The concerns process was flexible. A trade-off between adaptability and consistency was evident, but the correct balance of the two is difficult to establish. Performance concerns were most common, followed by behaviour. Conduct was the next most frequently raised concern, and a small number of health cases were identified. Outcomes of cases appeared to be dependent on the doctor's engagement and response rather than necessarily the nature of a concern or the consequences of a doctor's actions. CONCLUSION: The way practices handle complaints and concerns remains unexamined, even though they are a key route for patient complaints.

Levamisole-induced vasculopathy with gastric involvement in a cocaine user.

Reports of levamisole-induced vasculopathy (LIV) secondary to use of levamisole-contaminated cocaine largely have been limited to the skin. We report the case of a 35-year-old woman with painful purpuric lesions affecting the cheeks, nose, ears, arms, and legs of several days' duration. She recently had used crack cocaine. A biopsy of a lesion on the right arm demonstrated leukocytoclastic vasculitis. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. An upper gastrointestinal endoscopy was performed and demonstrated hemorrhagic erosions of the esophagus and stomach similar in appearance to the cutaneous lesions. Because dermatologists often are the specialists making the diagnosis of LIV, it is important they inform other involved clinicians that the skin may not be the sole repository of vascular insult.

Risk Factors for Basal Cell Carcinoma in Men Younger Than 40 Years: A Case-Control Study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in the United States and is more prevalent in older populations. OBJECTIVE: The aim of this study was to investigate BCC risk factors in male patients younger than 40 years. MATERIALS AND METHODS: A consecutive series of male patients with pathology-proven BCC and younger than 40 years at time of diagnosis were retrospectively identified along with matched controls. Phone interviews were conducted using a structured questionnaire, and differences between patients with and without BCC were investigated. RESULTS: A total of 50 patients with BCC and 27 controls were included in this study. Compared with controls, patients with BCC worked outdoor jobs for longer lengths of time (43.2 vs 15.6 months; p = .04), were more likely to have a family history of skin cancer (66% vs 44%; p = .02), and were more likely to use sunscreen heavily after biopsy (p = .02). Patients with multiple BCCs (n = 20) were more likely to have a history of substantial recreational sun exposure (p = .01) than patients with solitary lesions (n = 30). CONCLUSION: The authors conclude that outdoor sun exposure in patients with underlying genetic susceptibility is the most likely mechanism of BCC formation in young male patients.

Cutaneous infection with Mycobacterium obuense.

This report describes the presence of cutaneous nodules and ulceration of the right leg of 1-year duration in an elderly woman. Prior biopsies had demonstrated dermal and subcutaneous granulomatous inflammation. Special stains for microorganisms and cultures were repeatedly negative. Polymerase chain reaction evaluation of the tissue block demonstrated the presence of Mycobacterium obuense.

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 1011 viral particles (vp)/mL or 3 × 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 1011 vp/mL, n = 21; 3 × 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.