A comprehensive review and characterization of nasopharyngeal carcinoma clinical trials

Abstract Objective Although standard of care for primary nasopharyngeal carcinoma (NPC) is chemoradiotherapy, there remains no consensus on management of recurrent or metastatic disease. We characterized recent clinical trials on NPC to assess trends in NPC treatment and establish promising areas for future research. Study Design Retrospective database study. Setting ClinicalTrials.gov database. Methods Retrospective review of all NPC trials from November 1999 to June 2021. For each study, the following variables were extracted: study characteristics, intervention, outcome measures, and inclusion criteria. Secondary searches via PubMed and Google scholar determined trial publication status. Results A total of 448 clinical trials were identified: 72 (16%) observational and 376 (84%) interventional, of which there were 30 (8%) Phase I, 183 (49%) Phase II, 86 Phase III (23%), and 5 (1%) Phase IV trials. Fifty‐four percent of trials included only primary NPC while 111 (25%) exclusively studied recurrent cancers. The most common interventions were cisplatin (n = 64) and intensity modulated radiation therapy (n = 54); there were 38 trials involving PD‐1 monoclonal antibodies. Thirty‐four studies examined quality of life measures, including xerostomia and mucositis. Of the completed studies, 53.2% have published manuscripts. Poor patient accrual was the most common reason for premature study termination. Conclusions Novel immunotherapies have been increasingly incorporated into NPC studies in recent years, however, chemotherapy and radiation, despite their numerous side effects, are still widely used due to their clinical effectiveness. Future trials are warranted to determine the optimal therapeutic regimens to decrease relapse rates and side effects

Psychological distress experienced by parents caring for an immunosuppressed child during the COVID-19 pandemic

The COVID-19 pandemic has proved unique in both its unpredictability and the extent to which it has continued to impact on daily life since March 2020. Among the immunosuppressed population the challenges of the COVID-19 pandemic are cumulative to the ever-present challenges of living with a long-term condition.This prospective longitudinal study explored patterns of concern experienced by 467 British parents caring for an immunosuppressed child during the first 2 years of the COVID-19 pandemic and related this to parental mental wellbeing.Most parents slowly adapted or were resilient to the ever-changing stressors of the COVID-19 pandemic. However, 12% experienced high levels of concern throughout the first 2 years of the pandemic. This group was also more likely to report emotional mental health problems towards the end of this period.The experience of emotional mental health problems among parents caring for an immunosuppressed child was related to low household income, single parenting, difficult access to greenspace, and higher level of exposure to COVID positive cases and COVID restrictions (North of England).Parents reported that optimism, reduction of isolation, and support promoted coping and management of the challenges of the COVID-19 pandemic. More reliable COVID information and periodic medical-condition-specific guidance would have been appreciated.These findings can increase clinical awareness of high-risk parental groups and make an important contribution to the planning of appropriate targeted psychological family interventions

Parental concern for clinically vulnerable child during first 18 months of the COVID pandemic

Background: The uncertainties surrounding the COVID-19 pandemic have been associated with increased parental concern. The aim of this study is to explore if this increased level of concern is associated with certain individual/household characteristics or if parents adapted to the ever-changing realities of the COVID-19 pandemic over time. Methods: This prospective study explored COVID-19 concern trajectories and associated family characteristics of 765 UK parents caring for an immunosuppressed child during the first 18 months of the pandemic using growth mixture modelling. Qualitative analysis was performed to examine in more detail the source of concern. Results: Four different trajectories of parental COVID-19 concern were identified. Ongoing very high concern was associated with caring for children with nephrotic or respiratory disease; having a child on an organ transplant waiting list; residency in the North of England; or parental vocational inactivity. Explicit concerns voiced by the parents generally followed national trends, but vulnerable status specific concerns were also reported. Conclusion: Diagnosis and prescribed medication of the immunosuppressed child, geographical location, household composition, and employment status of parent were associated with the different concern trajectories. This information can be helpful in targeting psychological family care where it is most needed. Impact: Many British parents caring for a clinically vulnerable child during the first 18 months of the COVID-19 pandemic showed high levels of concern with little sign of psychological adaptation.Consistent with findings from non-vulnerable populations, parents mentioned the impact of shielding and repeated isolation on their child’s education, social life, and mental health.Unique to the clinically vulnerable population, parents were worried about child’s health status, impact of delayed healthcare, and were confused by the contradictory information received from government, doctors, and media.Psychological family care can be targeted to those parents at greater risk for high levels of concern.</p

Changes in otolaryngology application requirements and match outcomes: Are we doing any better?

Abstract Objectives Otolaryngology‐specific requirements were piloted to minimize applicant and program burdens. We investigated the impact of introducing and then removing these requirements on Match outcomes. Methods 2014–2021 National Resident Matching Program® data were examined. The primary outcome was the impact of Otolaryngology Resident Talent Assessment (ORTA; prematch 2017, postmatch 2019) and Program‐Specific Paragraph (PSP; implemented 2016, optional 2018) on applicant numbers and match rates. Secondary survey analysis assessed candidate perceptions of PSP/ORTA. Results Applicant numbers declined significantly during PSP/ORTA (18.9%; p = 0.001). With the optional PSP and postmatch ORTA, applicant numbers increased significantly (39.0%; p = 0.002). Examined individually, mandatory PSP was associated with a significant decline in applicants (p = 0.007), whereas postmatch ORTA was associated with significant increases in applicants (p = 0.010). ORTA and PSP negatively impacted the decision to apply to otolaryngology in 59.8% and 51.3% of applicants, respectively. Conversely, match rate success improved significantly from 74.8% to 91.2% during PSP/ORTA (p = 0.014), followed by a significant decline to 73.1% after PSP was made optional and ORTA moved to postmatch (p = 0.002). Conclusions ORTA and PSP correlated with decreased applicant numbers and increased match rate success. As programs seek ways to remove barriers to applying to otolaryngology, the potential consequences of an increasing pool of unmatched candidates must also be considered

Telemedicine in the Era of Coronavirus Disease 2019 (COVID-19): A Neurosurgical Perspective

Despite the substantial growth of telemedicine and the evidence of its advantages, the use of telemedicine in neurosurgery has been limited. Barriers have included medicolegal issues surrounding provider reimbursement, interstate licensure, and malpractice liability as well as technological challenges. Recently, the coronavirus disease 2019 (COVID-19) pandemic has limited typical evaluation of patients with neurologic issues and resulted in a surge in demand for virtual medical visits. Meanwhile, federal and state governments took action to facilitate the rapid implementation of telehealth programs, placing a temporary lift on medicolegal barriers that had previously limited its expansion. This created a unique opportunity for widespread telehealth use to meet the surge in demand for remote medical care. After initial hurdles and challenges, our experience with telemedicine in neurosurgery at Penn Medicine has been overall positive from both the provider and the patients\u27 perspective. One of the unique challenges we face is guiding patients to appropriately set up devices in a way that enables an effective neuroexamination. However, we argue that an accurate and comprehensive neurologic examination can be conducted through a telemedicine platform, despite minor weaknesses inherent to absence of physical presence. In addition, certain neurosurgical visits such as postoperative checks, vascular pathology, and brain tumors inherently lend themselves to easier evaluation through telehealth visits. In the era of COVID-19 and beyond, telemedicine remains a promising and effective approach to continue neurologic patient care

Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas.

PURPOSE: Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA. PROCEDURES: Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and H&E images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence. RESULTS: In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence. CONCLUSION: Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections. CLINICAL TRIAL: NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1)

Lentiviral gene therapy for X-linked chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

BACKGROUND:Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE:Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS:In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS:Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS:Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology