Saturation mutagenesis-reinforced functional assays for disease-related genes.

Interpretation of disease-causing genetic variants remains a challenge in human genetics. Current costs and complexity of deep mutational scanning methods are obstacles for achieving genome-wide resolution of variants in disease-related genes. Our framework, saturation mutagenesis-reinforced functional assays (SMuRF), offers simple and cost-effective saturation mutagenesis paired with streamlined functional assays to enhance the interpretation of unresolved variants. Applying SMuRF to neuromuscular disease genes FKRP and LARGE1, we generated functional scores for all possible coding single-nucleotide variants, which aid in resolving clinically reported variants of uncertain significance. SMuRF also demonstrates utility in predicting disease severity, resolving critical structural regions, and providing training datasets for the development of computational predictors. Overall, our approach enables variant-to-function insights for disease genes in a cost-effective manner that can be broadly implemented by standard research laboratories.

Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a significant cause of morbidity and mortality. Abatacept is a selective costimulation modulator, used for the treatment of rheumatologic diseases, and was recently the first drug to be approved by the US Food and Drug Administration for the prophylaxis of acute graft-versus-host disease. We conducted a phase 2 study to evaluate the efficacy of abatacept in steroid-refractory cGVHD. The overall response rate was 58%, seen in 21 out of 36 patients, with all responders achieving a partial response. Abatacept was well tolerated with few serious infectious complications. Immune correlative studies showed a decrease in interleukin -1α (IL-1α), IL-21, and tumor necrosis factor α as well as decreased programmed cell death protein 1 expression by CD4+ T cells in all patients after treatment with abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that abatacept is a promising therapeutic strategy for the treatment of cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01954979.

Trends in epidemiology and primary treatment of anal squamous cell carcinoma in the Netherlands (1990-2021).

A rapid increase in the incidence of anal squamous cell carcinoma (SCC) was reported in several countries over the past decades. This study assessed trends in epidemiology and primary treatment over a 32-year period (1990-2021) using the Netherlands Cancer Registry. The study population included 4273 patients, 44.2% male and 55.8% female (median age 63 years). The age-standardised incidence rate (European Standardised Rate, ESR) increased from 0.5 to 1.6 per 100,000, which entailed an average annual percentage change (AAPC) of 5.0% (95% confidence interval [CI]: 4.5%-5.8%). While incidence among females increased continuously over the total period (AAPC 4.9%; 95%CI: 4.4%-5.6%), to 1.8 per 100,000 ESR in 2021, incidence among males increased until 2016 (annual percentage change [APC] of 6.3%; 95%CI: 5.6%-10.7%), after which it seemed to stabilise (APC -2.1%; 95%CI: -16.8%-4.5%). Significant trends were also observed in distribution of age, tumour stage and primary treatment modalities. Five-year relative survival (RS) was estimated using the Pohar-Perme estimator, and this improved from 56.1% in 1990-1997 (95%CI: 49.3%-62.4%) to 67.9% in 2014-2021 (95%CI: 64.7%-70.9%), but remained poor for stage IV disease. Evaluation through a multivariable Poisson regression model demonstrated diagnosis in the most recent period to be independently associated with better RS, in addition to female sex, younger age, early disease stage and any treatment. In conclusion, the rising incidence of anal SCC seems to decline in males, but not in females, and advances in diagnostics and therapeutic management have likely contributed to improved prognosis.

Effect of menstrual cycle and menopause on human gastric electrophysiology.

Chronic gastroduodenal symptoms disproportionately affect females of childbearing age; however, the effect of menstrual cycling on gastric electrophysiology is poorly defined. To establish the effect of the menstrual cycle on gastric electrophysiology, healthy subjects underwent noninvasive Body Surface Gastric Mapping (BSGM; 8x8 array) with the validated symptom logging App (Gastric Alimetry, New Zealand). Participants included were premenopausal females in follicular (n = 26) and luteal phases (n = 18) and postmenopausal females (n = 30) and males (n = 51) were controls. Principal gastric frequency (PGF), body mass index (BMI) adjusted amplitude, Gastric Alimetry Rhythm Index (GA-RI), Fed:Fasted Amplitude Ratio (ff-AR), meal response curves, and symptom burden were analyzed. Menstrual cycle-related electrophysiological changes were then transferred to an established anatomically accurate computational gastric fluid dynamics model (meal viscosity 0.1 Pas) to predict the impact on gastric mixing and emptying. PGF was significantly higher in the luteal versus follicular phase [mean 3.21 cpm, SD (0.17) vs. 2.94 cpm, SD (0.17), P < 0.001] and versus males [3.01 cpm, SD (0.2), P < 0.001]. In the computational model, this translated to 8.1% higher gastric mixing strength and 5.3% faster gastric emptying for luteal versus follicular phases. Postmenopausal females also exhibited higher PGF than females in the follicular phase [3.10 cpm, SD (0.24) vs. 2.94 cpm, SD (0.17), P = 0.01], and higher BMI-adjusted amplitude [40.7 µV (33.02-52.58) vs. 29.6 µV (26.15-39.65), P < 0.001], GA-RI [0.60 (0.48-0.73) vs. 0.43 (0.30-0.60), P = 0.005], and ff-AR [2.51 (1.79-3.47) vs. 1.48 (1.21-2.17), P = 0.001] than males. There were no differences in symptoms. These results define variations in gastric electrophysiology with regard to human menstrual cycling and menopause.NEW & NOTEWORTHY This study evaluates gastric electrophysiology in relation to the menstrual cycle using a novel noninvasive high-resolution methodology, revealing substantial variations in gastric activity with menstrual cycling and menopause. Gastric slow-wave frequency is significantly higher in the luteal versus follicular menstrual phase. Computational modeling predicts that this difference translates to higher rates of gastric mixing and liquid emptying in the luteal phase, which is consistent with previous experimental data evaluating menstrual cycling effects on gastric emptying.

Gastric Alimetry Expands Patient Phenotyping in Gastroduodenal Disorders Compared with Gastric Emptying Scintigraphy.

INTRODUCTION: Gastric emptying testing (GET) assesses gastric motility, however, is nonspecific and insensitive for neuromuscular disorders. Gastric Alimetry (GA) is a new medical device combining noninvasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared with GET. METHODS: Patients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline, 99m TC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: (i) sensorimotor, (ii) continuous, and (iii) other. RESULTS: Seventy-five patients were assessed, 77% female. Motility abnormality detection rates were as follows: GET 22.7% (14 delayed, 3 rapid), GA spectral analysis 33.3% (14 low rhythm stability/low amplitude, 5 high amplitude, and 6 abnormal frequency), and combined yield 42.7%. In patients with normal spectral analysis, GA symptom phenotypes included sensorimotor 17% (where symptoms strongly paired with gastric amplitude, median r = 0.61), continuous 30%, and other 53%. GA phenotypes showed superior correlations with Gastroparesis Cardinal Symptom Index, Patient Assessment of Upper Gastrointestinal Symptom Severity Index, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores ( P > 0.05). Delayed emptying was not predictive of specific GA phenotypes. DISCUSSION: GA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with increased correlation with symptoms and psychometrics compared with gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders.

Impact of diagnostic genetics on remission MRD and transplantation outcomes in older patients with AML.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Initial management of newly diagnosed WHO grade 2-3 adult meningioma following surgery: results from the Dutch Brain Tumour Registry (2016-2021).

PURPOSE: Meningiomas classified as grade 2-3 according to the World Health Organisation (WHO) require combined surgery and in most cases radiotherapy (RT). Their initial management was evaluated using the Dutch Brain Tumour Registry. METHODS: The study included 393 patients aged ≥ 18 years with newly diagnosed meningioma WHO grade 2-3 between 2016 and 2021. Factors associated with adjuvant RT < 6 months following surgery were identified using logistic regression analyses, thereby accounting for variation between CNS regional tumour boards through mixed-effect modelling. This variation was further assessed by funnel plots for case-mix adjusted ratios of RT across tumour boards. The association with patients' survival at 5 years was evaluated with inverse probability-weighted accelerated failure (Weibull) models. Analyses were performed on multiple imputed datasets (m = 10) to account for missing data. RESULTS: Adjuvant RT was administered to 22.2% (59/266) of patients with WHO grade 2 meningioma following a total resection, to 61.1% (58/95) following a partial resection, and to 68.8% (22/32) of patients with WHO grade 3 meningioma (61.5% after partial and 73.7% after total resection). RT was associated with grade 3, partial resection, bone invasion, and absence of multiple lesions. Management varied across tumour boards for grade 2 meningioma following total resection. Adjuvant RT was associated with survival benefit in case of grade 3 disease (hazard ratio: 0.40, 95%-confidence interval: 0.16-0.95, p = 0.04). CONCLUSION: This national review revealed variation across CNS regional tumour boards in the management of grade 2 meningioma following total resection, and demonstrated survival benefit of adjuvant RT in grade 3 meningioma.

Referral patterns of GIST patients: data from a nationwide study.

BACKGROUND: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells' behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

Idiopathic Slow Transit Constipation: Pathophysiology, Diagnosis, and Management.

Slow transit constipation (STC) has an estimated prevalence of 2-4% of the general population, and although it is the least prevalent of the chronic constipation phenotypes, it more commonly causes refractory symptoms and is associated with significant psychosocial stress, poor quality of life, and high healthcare costs. This review provides an overview of the pathophysiology, diagnosis, and management options in STC. STC occurs due to colonic dysmotility and is thought to be a neuromuscular disorder of the colon. Several pathophysiologic features have been observed in STC, including reduced contractions on manometry, delayed emptying on transit studies, reduced numbers of interstitial cells of Cajal on histology, and reduced amounts of excitatory neurotransmitters within myenteric plexuses. The underlying aetiology is uncertain, but autoimmune and hormonal mechanisms have been hypothesised. Diagnosing STC may be challenging, and there is substantial overlap with the other clinical constipation phenotypes. Prior to making a diagnosis of STC, other primary constipation phenotypes and secondary causes of constipation need to be ruled out. An assessment of colonic transit time is required for the diagnosis and can be performed by a number of different methods. There are several different management options for constipation, including lifestyle, dietary, pharmacologic, interventional, and surgical. The effectiveness of the available therapies in STC differs from that of the other constipation phenotypes, and prokinetics often make up the mainstay for those who fail standard laxatives. There are few available management options for patients with medically refractory STC, but patients may respond well to surgical intervention. STC is a common condition associated with a significant burden of disease. It can present a clinical challenge, but a structured approach to the diagnosis and management can be of great value to the clinician. There are many therapeutic options available, with some having more benefits than others.

Normative Values for Body Surface Gastric Mapping Evaluations of Gastric Motility Using Gastric Alimetry: Spectral Analysis.

INTRODUCTION: Body surface gastric mapping (BSGM) is a new noninvasive test of gastric function. BSGM offers several novel and improved biomarkers of gastric function capable of differentiating patients with overlapping symptom profiles. The aim of this study was to define normative reference intervals for BSGM spectral metrics in a population of healthy controls. METHODS: BSGM was performed in healthy controls using Gastric Alimetry (Alimetry, New Zealand) comprising a stretchable high-resolution array (8 × 8 electrodes; 196 cm 2 ), wearable Reader, and validated symptom-logging App. The evaluation encompassed a fasting baseline (30 minutes), 482 kCal meal, and 4-hour postprandial recording. Normative reference intervals were calculated for BSGM metrics including the Principal Gastric Frequency, Gastric Alimetry Rhythm Index (a measure of the concentration of power in the gastric frequency band over time), body mass index (BMI)-adjusted amplitude (µV), and fed:fasted amplitude ratio. Data were reported as median and reference interval (5th and/or 95th percentiles). RESULTS: A total of 110 subjects (55% female, median age 32 years [interquartile range 24-50], median BMI 23.8 kg/m 2 [interquartile range 21.4-26.9]) were included. The median Principal Gastric Frequency was 3.04 cycles per minute; reference interval: 2.65-3.35 cycles per minute. The median Gastric Alimetry Rhythm Index was 0.50; reference interval: ≥0.25. The median BMI-adjusted amplitude was 37.6 µV; reference interval: 20-70 µV. The median fed:fasted amplitude ratio was 1.85; reference interval ≥1.08. A higher BMI was associated with a shorter meal-response duration ( P = 0.014). DISCUSSION: This study provides normative reference intervals for BSGM spectral data to inform diagnostic interpretations of abnormal gastric function.

Revealing tumor microstructure with oscillating diffusion encoding MRI in pre-surgical and post-treatment glioma patients.

PURPOSE: We hypothesized that the time-dependent diffusivity at short diffusion times, as measured by oscillating gradient spin echo (OGSE) diffusion MRI, can characterize tissue microstructures in glioma patients. THEORY AND METHODS: Five adult patients with known diffuse glioma, including two pre-surgical and three with new enhancing lesions after treatment for high-grade glioma, were scanned in an ultra-high-performance gradient 3.0T MRI system. OGSE diffusion MRI at 30-100 Hz and pulsed gradient spin echo diffusion imaging (approximated as 0 Hz) were obtained. The ADC and trace-diffusion-weighted image at each acquired frequency were calculated, that is, ADC (f) and TraceDWI (f). RESULTS: In pre-surgical patients, biopsy-confirmed solid enhancing tumor in a high-grade glioblastoma showed higher ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and lower TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\ (f)}{\mathrm{TraceDWI}\ \left(0\ \mathrm{Hz}\right)} $$ , compared to that at same OGSE frequency in a low-grade astrocytoma. In post-treatment patients, the enhancing lesions of two patients who were diagnosed with tumor progression contained more voxels with high ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and low TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\left(\mathrm{f}\right)}{\mathrm{TraceDWI}\left(0\ \mathrm{Hz}\right)} $$ , compared to the enhancing lesions of a patient who was diagnosed with treatment effect. Non-enhancing T2 signal abnormality lesions in both the pre-surgical high-grade glioblastoma and post-treatment tumor progressions showed regions with high ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and low TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\ \left(\mathrm{f}\right)}{\mathrm{TraceDWI}\ \left(0\ \mathrm{Hz}\right)} $$ , consistent with infiltrative tumor. The solid tumor of the glioblastoma, the enhancing lesions of post-treatment tumor progressions, and the suspected infiltrative tumors showed high diffusion time-dependency from 30 to 100 Hz, consistent with high intra-tumoral volume fraction (cellular density). CONCLUSION: Different characteristics of OGSE-based time-dependent diffusivity can reveal heterogenous tissue microstructures that indicate cellular density in glioma patients.

Calibration of concomitant field offsets using phase contrast MRI for asymmetric gradient coils.

PURPOSE: Asymmetric gradient coils introduce zeroth- and first-order concomitant field terms, in addition to higher-order terms common to both asymmetric and symmetric gradients. Salient to compensation strategies is the accurate calibration of the concomitant field spatial offset parameters for asymmetric coils. A method that allows for one-time calibration of the offset parameters is described. THEORY AND METHODS: A modified phase contrast pulse sequence with single-sided bipolar flow encoding is proposed to calibrate the offsets for asymmetric, transverse gradient coils. By fitting the measured phase offsets to different gradient amplitudes, the spatial offsets were calculated by fitting the phase variation. This was used for calibrating real-time pre-emphasis compensation of the zeroth- and first-order concomitant fields. RESULTS: Image quality improvement with the proposed corrections was demonstrated in phantom and healthy volunteers with non-Cartesian and Cartesian trajectory acquisitions. Concomitant field compensation using the calibrated offsets resulted in a residual phase error <3% at the highest gradient amplitude and demonstrated substantial reduction of image blur and slice position/selection artifacts. CONCLUSIONS: The proposed implementation provides an accurate method for calibrating spatial offsets that can be used for real-time concomitant field compensation of zeroth and first-order terms, substantially reducing artifacts without retrospective correction or sequence specific waveform modifications.

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

Epidemiology of adult meningioma: Report from the Dutch Brain Tumour Registry (2000-2019).

BACKGROUND AND PURPOSE: Meningiomas are the most common primary tumours of the central nervous system. This study aimed to provide comprehensive nationwide estimates on the incidence, prevalence and prognostic impact of meningioma diagnosis in the Netherlands. METHODS: Adult patients diagnosed with meningioma in 2000-2019 were selected from the Dutch Brain Tumour Registry (DBTR), part of the Netherlands Cancer Registry (NCR). Time trends in age-adjusted incidence and prevalence rates were evaluated using the estimated annual percentage change (EAPC). Relative survival rates were calculated using the Pohar Perme estimator. Case completeness of the DBTR/NCR was estimated through record linkage with one of the Dutch neuro-oncology centres. RESULTS: From a total of 23,454 cases of meningioma, 11,306 (48.2%) were histologically confirmed and 12,148 (51.8%) were radiological diagnoses. Over time, the incidence of diagnosis increased from 46.9 per 1,000,000 inhabitants (European Standardized Rate [ESR]) to 107.3 (EAPC 4.7%, p < 0.01), with an increase in the incidence of radiological diagnoses from 14.0 to 70.2 per 1,000,000 ESR (EAPC 9.1%, p < 0.01). The prevalence of meningioma was estimated at 1012/1,000,000 on 1 January 2020, with almost 17,800 individuals having had a diagnosis of meningioma. Relative survival rate at 10 years for grade 1 meningiomas was 91.0% (95% confidence interval [CI] 89.4%-92.3%), 71.3% (95% CI 66.8%-75.2%) for grade 2 meningiomas and 36.4% (95% CI 27.3%-45.6%) for grade 3 meningiomas. Local case completeness was estimated at 97.6% for histologically confirmed meningiomas and 84.5% for radiological diagnoses. CONCLUSION: With a near-complete registry, meningioma prevalence was estimated at over 1000 per 1,000,000 inhabitants.

Baseline Characteristics of Canadian Patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: The Psoriasis Longitudinal Assessment and Registry (PSOLAR) is a global, prospective, longitudinal, disease-based registry. It serves as a post-marketing safety commitment with a focus on patients with moderate to severe plaque psoriasis who are candidates for systemic therapy. OBJECTIVES: To describe the baseline disease demographics and clinical characteristics of a Canadian subgroup of participants enrolled in PSOLAR. METHODS: Baseline demographic/disease characteristics, medical histories, and previous psoriasis treatments for Canadian patients in PSOLAR were summarized using descriptive statistics. RESULTS: There were 1896 patients analyzed in the Canadian subgroup at 37 clinical sites, accounting for 15.7% of the global PSOLAR population. Baseline disease and clinical characteristics were as expected for a moderate to severe psoriasis population and were generally similar to the global PSOLAR population. Two distinctions were noted in the Canadian subgroup versus those enrolled globally: a higher proportion of patients were overweight/obese (84.7% vs. 80.4%) and male (61.4% vs. 54.7%). In addition, the Canadian subgroup had numerically higher historical peak disease activity (PGA score 3.35 vs. 3.1) and longer disease duration (22.3 years vs. 17.5 years). Canadian PSOLAR patients reported a variety of comorbidities, including psoriatic arthritis (31.5%), hypertension (34.6%), hyperlipidemia (24.3%), mental illness (24.1%), and inflammatory bowel disease (1.6%). CONCLUSION: The Canadian subgroup of PSOLAR patients was generally similar to those enrolled globally with respect to baseline disease demographics and clinical characteristics. Multiple comorbidities are noted in the Canadian subgroup, underscoring the need for a holistic approach to the treatment of psoriatic patients.

Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Immunogenicity and Reactogenicity.

The severe acute respiratory syndrome coronavirus 2 messenger RNA vaccine-induced humoral response and reactogenicity profile are described in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Findings showed that 75.0% (by Simoa assay) or 80.0% (by Roche assay) of the HSCT cohort had a positive antibody response on series completion, compared with 100% in the healthy cohort.

A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation.

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti-PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti-PD-1 antibody for post-alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti-PD-1 therapy post-alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

Phenotypic and functional characterization of the CD6-ALCAM T-cell co-stimulatory pathway after allogeneic cell transplantation.

CD6 is a co-stimulatory receptor expressed on T cells that binds activated leukocyte cell adhesion molecule (ALCAM), expressed on antigen presenting cells, epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T-cell activation, proliferation, and trafficking. In this study we examined expression of CD6 by reconstituting T cells in 95 patients after allogeneic cell transplantation and evaluated the effects of itolizumab, an anti- CD6 monoclonal antibody, on T-cell activation. CD6 T cells reconstituted early after transplant with CD4 regulatory T cells (Treg)-expressing lower levels of CD6 compared to conventional CD4 T cells (Tcon) and CD8 T cells. After onset of acute graft-versus-host disease (aGvHD), CD6 expression was further reduced in Treg and CD8 T cells compared to healthy donors, while no difference was observed for Tcon. ALCAM expression was highest in plasmacytoid dendritic cells (pDC), lowest in myeloid dendritic cells (mDC) and intermediate in monocytes and was generally increased after aGvHD onset. Itolizumab inhibited CD4 and CD8 T-cell activation and proliferation in preGvHD samples, but inhibition was less prominent in samples collected after aGvHD onset, especially for CD8 T cells. Functional studies showed that itolizumab did not mediate direct cytolytic activity or antibody-dependent cytotoxicity in vitro. However, itolizumab efficiently abrogated the costimulatory activity of ALCAM on T-cell proliferation, activation and maturation. Our results identify the CD6-ALCAM pathway as a potential target for aGvHD control and a phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGvHD is currently ongoing (clinicaltrials gov. Identifier: NCT03763318).