Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions.

Allergist-immunologists face significant challenges as experts in an ever-evolving field of neuroimmunology. Among these challenges is the increasingly frequent need to counsel patients with suspected mast cell activation disorders about perceived comorbidities, which may include hypermobile Ehlers-Danlos syndrome, amplified pain syndrome, fibromyalgia, burning sensation syndromes, migraines, irritable bowel syndrome, and postural orthostatic tachycardia syndrome. Patients may experience comorbid anxiety, panic disorder, and depression associated with disturbed sleep, fatigue, and cognitive impairment that often worsen when their physical symptoms increase in severity. These conditions may mimic mast cell activation disorders and are emotionally taxing for patients and clinicians because they are often accompanied by vague diagnostic courses, perceived unmanageability, social stigma, and significant impairment in quality of life. Combined with relatively poorly researched therapies, it is no surprise that clinicians may feel overwhelmed or find it difficult to provide consistently compassionate care for this population. In this article, we review available therapies for these conditions, which run the gamut from physical therapy to antidepressants to multimodal pain control. We highlight the benefit of multidisciplinary care within the primary care home, which includes an important role by the allergist-immunologist. By outlining simple approaches to initial treatment, we hope to empower clinicians with the tools needed to curb emotional burnout and embrace this patient population with compassion.

Repeat resection for recurrent glioblastoma in the temozolomide era: a real-world multi-centre study.

INTRODUCTION: In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model. METHODS: This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death. RESULTS: 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1-0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1-2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1-0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3-1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0-17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4-0.9), local recurrence (aOR: 1.7; 95% CI: 1.1-3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1-2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1-2, 9.0 months and a score of 3, 4.0 months (log-rank test, p-value < 0.05). CONCLUSION: Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Voluntary participation in flipped classroom application sessions has a negligible effect on assessment outcomes in an accelerated pass-fail course.

Increasingly, basic science educators at medical and health science programs are faced with the challenge of delivering fundamental science content using evidence-based pedagogical approaches that build students' fund of knowledge while also supporting their development as self-regulated learners. This has led to an increased use of active learning-based pedagogies such as flipped classroom teaching. However, there are many open questions about the conditions necessary for successful flipped classroom sessions. In particular, the role of student compliance (i.e., participation, engagement, attendance) in mediating performance needs to be evaluated. This is especially important in accelerated curricula where multiple basic science disciplines are integrated together in pass-fail courses, presenting challenges to both students' time and cognitive load. Data on prematriculation performance, in-class participation, weekly quiz performance, and summative assessment performance from three cohorts of medical students (n = 146) at a new medical school were collected and analyzed. We found that historically high-performing students more readily participated in flipped classroom application sessions compared with historically lower-performing students. Correlational analysis of performance on weekly formative quizzes and the summative course exam was not related to in-class participation. However, performance on weekly formative quizzes played the most significant role in students' performance on summative exams. Efforts to understand the benefits of in-class participation beyond short-term assessment performance, such as long-term knowledge retention or development of noncognitive skills, should be undertaken to justify using such time- and human resource-intensive pedagogies.NEW & NOTEWORTHY This study explores the use of flipped classroom teaching in a voluntary and accelerated medical school course. We found that historically high-performing students attend class, whereas historically low-performing students do not attend class as readily. Formative assessment performance appears to be more important than participation in determining the final grade. Correlation of high performance (>90%) with participation may differentiate students who excel in our curriculum from those who simply pass with superficial knowledge.

MicroRNA Signatures in the Upper Urinary Tract Urothelial Carcinoma Scenario: Ready for the Game Changer?

Upper urinary tract urothelial carcinoma (UTUC) represents a minor subgroup of malignancies arising in the urothelium of the renal pelvis or ureter. The estimated annual incidence is around 2 cases per 100,000 people, with a mean age at diagnosis of 73 years. UTUC is more frequently diagnosed in an invasive or metastatic stage. However, even though the incidence of UTUC is not high, UTUC tends to be aggressive and rapidly progressing with a poor prognosis in some patients. A significant challenge in UTUC is ensuring accurate and timely diagnosis, which is complicated by the non-specific nature of symptoms seen at the onset of disease. Moreover, there is a lack of biomarkers capable of identifying the early presence of the malignancy and guide-tailored medical treatment. However, the growing understanding of the molecular biology underlying UTUC has led to the discovery of promising new biomarkers. Among these biomarkers, there is a class of small non-coding RNA biomarkers known as microRNAs (miRNAs) that are particularly promising. In this review, we will analyze the main characteristics of UTUC and focus on microRNAs as possible novel tools that could enter clinical practice in order to optimize the current diagnostic and prognostic algorithm.

Technology-supported Acceptance and Commitment Therapy for chronic health conditions: A systematic review and meta-analysis.

Chronic health conditions (CHCs) are common and associated with functional limitations. Acceptance and commitment therapy (ACT) shows promise in improving functioning, quality of life, and distress across several CHCs. The purpose of this study was to conduct a systematic review of technology-supported ACT for CHCs and perform a meta-analysis on functioning and ACT process outcomes. Multiple databases were systematically searched for randomized controlled trials. A total of 20 unique studies with 2,430 randomized participants were included. CHCs addressed in these studies were chronic pain (k = 9), obesity/overweight (k = 4), cancer (k = 3), hearing loss (k = 1), HIV (k = 1), multiple sclerosis (k = 1), and tinnitus (k = 1). Internet and telephone were the most used technology platforms. All studies included therapist contact with considerable heterogeneity between studies. Random effects meta-analyses found medium effect sizes showing technology-supported ACT outperformed comparator groups on measures of function at post-treatment (Hedges' g = -0.49; p = 0.002) and follow-up (Hedges' g = -0.52; p = 0.02), as well as ACT process outcomes at post-treatment (Hedges' g = 0.48; p < 0.001) and follow-up (Hedges' g = 0.44; p < 0.001). Technology-supported ACT shows promise for improving function and ACT process outcomes across a range of CHCs. Recommendations are provided to optimize technology-supported ACT for CHCs. PROSPERO registration number: CRD42020200230.

Design of a foundational sciences curriculum: Applying the ICAP framework to pharmacology education in integrated medical curricula.

Expectations for physicians are rapidly changing, as is the environment in which they will practice. In response, preclerkship medical education curricula are adapting to meet these demands, often by reducing the time for foundational sciences. This descriptive study compares preclerkship pharmacology education curricular practices from seven allopathic medical schools across the United States. We compare factors and practices that affect how pharmacology is integrated into the undergraduate medical education curriculum, including teaching techniques, resources, time allocated to pharmacology teaching, and assessment strategies. We use data from seven medical schools in the United States, along with results from a literature survey, to inform the strengths and weaknesses of various approaches and to raise important questions that can guide future research regarding integration of foundational sciences in medical school and health professions' curricula. In this comparative study, we found that there is significant heterogeneity in the number of hours dedicated to pharmacology in the preclerkship curriculum, whereas there was concordance in the use of active learning pedagogies for content delivery. Applying the ICAP (Interactive, Constructive, Active, Passive) Framework for cognitive engagement, our data showed that pharmacology was presented using more highly engaging pedagogies during sessions that are integrated with other foundational sciences. These findings can serve as a model that can be applied beyond pharmacology to other foundational sciences such as genetics, pathology, microbiology, biochemistry, etc.

The importance of collaboratively designing pharmacology education programs.

A grounded knowledge of pharmacology is essential for healthcare providers to improve the quality of patients' lives, avoid medical errors, and circumvent potentially dangerous drug-drug interactions. One of the greatest tools to achieve this foundational knowledge of pharmacology is the dedicated pharmacology educators who teach in health sciences programs. Too often, the pharmacology educators responsible for teaching this material are left siloed at their own institutions with little room for dialog and collaboration. As scientists, we know that it is through dialog and collaboration that ideas grow, are refined, and improve. More collaborative work is needed to identify and describe best practices for pharmacology education in health sciences programs. While evidence-based, outcomes-focused studies are the optimum standard for this work, there is also a place for descriptive studies and innovative reports.

Single-Session Acceptance and Commitment Therapy (ACT) Interventions for Patients with Chronic Health Conditions: A Systematic Review and Meta-Analysis.

RATIONALE: Chronic health conditions (CHCs) are costly and difficult to manage. Patients often struggle with behavioral adherence to complex treatment regimens and experience psychiatric distress. Acceptance and Commitment Therapy (ACT) is a transdiagnostic behavioral approach that aims to improve functioning and quality of life (QoL), which are important treatment outcomes for this population. Preliminary efficacy of multi-session ACT in patients with CHCs has been demonstrated, and single-session ACT interventions have since been developed to increase feasibility, acceptability, and accessibility. The purpose of this systematic review and meta-analysis was to describe the literature on single-session ACT intervention studies in CHC populations with regards to (1) study design and methodology, (2) patient characteristics and conditions targeted, and (3) efficacy for outcomes across various domains, using narrative and quantitative methods. METHODS: PsycINFO, PubMed, and Web of Science were systematically searched in August 2020. Studies of single-session ACT interventions in adult patients with CHCs that reported quantitative outcomes in any of the following domains were included: (a) functioning and related domains (e.g., disability, QoL, well-being); (b) mental health; (c) physical health; (d) ACT processes. Both controlled and uncontrolled studies were included. Study quality was assessed using the Psychotherapy Outcome Study Methodology Rating Scale (POMRF). Between-group random effects meta-analysis was conducted on general functioning outcomes. RESULTS: Fourteen manuscripts reporting outcomes from 13 studies (N = 793) met inclusion criteria. Ten studies were identified by their authors as pilot or feasibility trials. Eight studies used comparison or control groups. Twelve studies delivered the ACT content in workshop format. Studies recruited for a variety of conditions. Narrative review found that between- and within-group effect sizes showed generally positive results favoring single-session ACT overall (69%), especially for measures of functioning and related domains (88%), mental health (67%), and ACT processes (73%). Meta-analysis found that ACT did not significantly outperform comparison groups on measures of general functioning (Hedges' g: -0.51, 95% confidence interval: [-1.19, 0.16]; I 2 = 86%; K = 5) despite a medium-sized pooled effect. DISCUSSION: Use of single-session ACT interventions in CHC populations is an emergent field. There is preliminary evidence for the acceptability, feasibility, and efficacy of these interventions, which provides support for further testing in fully-powered RCTs. Additional RCTs will enable larger meta-analyses and stronger conclusions about efficacy. Recommendations for future trials are provided.

Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong chinese patients.

INTRODUCTION: Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well characterized. METHODS: This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan's criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression. RESULTS: A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value: .01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value: .007). CONCLUSION: The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese.

The Role of Circulating Biomarkers in the Oncological Management of Metastatic Renal Cell Carcinoma: Where Do We Stand Now?

Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches.

Current methods in translational cancer research.

Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.

Skin Architecture, Kidney Transplantation, and Their Relationship to Basal and Squamous Cell Carcinomas.

BACKGROUND/AIM: Squamous cell carcinoma (SCC) is highly prevalent in kidney transplant patients (KT). It is characterized by the presence of an inflammatory infiltrate. In this study, we examined the presence of similar infiltrates in intact skin, which could be regarded as a precancerous step. PATIENTS AND METHODS: We retrospectively analyzed skin biopsies of 19 non-transplanted patients with a diagnosis of SCC or basal cell carcinoma (BCC) and 17 KT with either SCC or BCC. RESULTS: KT showed increased inflammatory infiltrate in the subepithelial region, compared to non-transplanted patients. The density of basal cell nuclei was also different among the four groups with an interaction effect between tumor type and transplantation. The extent of inflammatory infiltrates did not correlate with the eGFR and proteinuria. CONCLUSION: KT with a non-melanoma skin cancer show increased intact skin inflammatory infiltrate and alterations in the density of the basal cell layer compared to non-transplanted patients.

Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas.

BACKGROUND/AIMS: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. METHODS: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. RESULTS: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased -density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. CONCLUSION: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.

How to assess kidney function in oncology patients.

Assessment of kidney function in oncology patients is a fundamental factor in profiling the survival risk, determining the appropriate dose of chemotherapeutic drugs, and defining a patient eligibility for clinical trials with novel agents. Both overestimation and underestimation of kidney function may affect the treatment efficacy and outcomes. Overestimation may lead to overdosing or inappropriate agent selection and the corresponding toxicity, whereas underestimation may be responsible for underdosing or inappropriate agent exclusion and subsequent treatment failure. This is of utmost importance in patients with cancer. Evaluation of kidney function is not only limited to the estimation of glomerular filtration rate or creatinine clearance. An accurate assessment of kidney function is advisable to reduce variability in decision making and ultimately the therapeutic outcomes of toxicity and clinical benefit. Therefore, additional studies are needed to investigate the validity of currently used formulas estimating kidney function in this population as well as their applicability to traditional chemotherapy, novel targeted therapies, and immunotherapies. Because of rapid discovery and development of new cancer agents, a reliable and comprehensive manner to screen for potential nephrotoxicity is critically important. As kidney function not only is limited to glomerular filtration rate changes but also involves tubular and even vascular dysfunction, urinalysis and kidney imaging studies should also be considered before therapeutic decisions are taken. However, several questions remain regarding these new technologies such as kidney-on-a-chip systems for the assessment of kidney function and injury, particularly in oncology, and it has yet to be implemented in clinical practice.

Words of advice: preparing to teach.

You have spent most of your training learning how to be successful in a research laboratory. But are you ready to step in front of a class and teach? This Words of Advice article provides guidance and resources for designing a course using backward design and for becoming an effective teacher, especially in today's new format of large, interactive classes.

The renal adverse effects of cancer immunotherapy.

Over the past decade, the development and clinical use of immunotherapy agents has increased exponentially. As clinical experience builds with these agents so too does our understanding of the associated adverse effects. In particular, the effects of immunotherapy on the kidneys, individual nephrons, and kidney function remain less well described than the adverse effects on barrier organ systems such as the gastrointestinal tract and skin. However, phase IV post-marketing surveillance and clinical case studies together with basic research has begun to reveal mechanisms by which immunotherapy mediates renal adverse effects. This work may lead to improvements in treatment guidelines and therapy. These advances are particularly important as post-cancer survival increases leaving patients to cope with the consequences of not only the cancer, but the short- and long-term adverse effects of treatment. Here we discuss the major renal adverse effects encountered with individual immunotherapeutic agents, putative mechanisms, their current management, and how cancer survivorship programs can help patients who have been treated with immunotherapy.