Citations

PURPOSE At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS). METHODS CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression. RESULTS At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%). CONCLUSION D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

Abstract Objective To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). Methods Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March–December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. Results Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years; 94.5% females; 40.5% Asian; 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR; 95% CI: 1.2; 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6; 0.4, 0.8) and nrAIDs (0.5; 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6; 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2; 1.1, 4.2) and injection site pain (2.9; 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5; 0.3, 0.9). Conclusion While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy individuals, providing reassurance regarding COVID-19 vaccination safety in SLE.

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. GBM tumors proximal to the lateral ventricles have a worse prognosis with multifocality, recurrence, and lower overall survival. Studies suggest this increased aggressiveness is attributed to cerebrospinal fluid (CSF), as we have previously observed transcriptomic changes in GBM cells upon CSF exposure. GlioVis database reveals chitinase 3-like protein 1 (CHI3L1), a glycoprotein secreted by immune and cancer cells, is associated with poor prognosis and co-expressed with pro-inflammatory and tissue remodeling genes. We suggest exposure to CSF elevates CHI3L1 expression, consequently impacting malignancy-associated gene expression in patient-derived GBM lines. We first evaluated if patient CSF influences the expression of CHI3L1. GBM cells were treated with artificial CSF, non-cancer CSF, or cancer CSF for 72 hours. qPCR revealed significant increases in CHI3L1 (p< 0.0001), SPP1, and CD44 expression in cancer CSF groups compared to artificial CSF. CHI3L1 expression at the protein level is also increased by cancer CSF when profiled using Western Blot. Additionally, ELISA results indicated significantly higher levels of CHI3L1 in CSF samples obtained from patients with high-grade tumors compared to non-cancer samples. Next, we assessed if exogenous CHI3L1 stimulates GBM malignancy at the cellular level. An effective concentration of recombinant human CHI3L1 was determined through Alamar Blue assay, showing 500 ng/ml CHI3L1 increases viability in primary patient cell lines compared to non-treated media. Recombinant CHI3L1 also increases cell migration in Transwell assay. qPCR revealed Vimentin (p< 0.001) and Twist (p< 0.0001) expression significantly increases while E-cadherin (p< 0.001) significantly decreases in CHI3L1-treated groups, consistent with EMT and migratory activity. Ultimately, this study shows CHI3L1 is a CSF-induced factor in GBM and could be a therapeutic target as it enhances tumor malignancy by increasing proliferation, migration, and malignancy-promoting gene expression.

Abstract Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

Abstract Bridging the gap between education and medical practice, centralized hospital-based 3D printing, or what is termed point-of-care (POC) manufacturing, has been rapidly growing in the United States as well as internationally. This article provides insights into the considerations and the current workflow of creating 3D-printed anatomical models at the POC. Case studies are introduced to show the complex range of anatomical models that can be produced while also exploring how patient care benefits. It describes the advanced form of communication in medicine. The advantages as well as pitfalls of using the patient-specific 3D-printed models at the POC are addressed, demonstrating the fundamental knowledge needed to create 3D-printed anatomical models through POC manufacturing.

Abstract Purpose: To compare vascular parameters, assessed by endothelin-1 (ET-1) blood levels, Laser Doppler Imaging (LDI) of distal phalanx, and nailfold capillaroscopy (NC), between open-angle glaucoma (OAG) patients with low (LTDH) and high-tension optic disc hemorrhages (HTDH). Methods: In this prospective study, patients were classified as LTDH if presenting an IOP<16 mmHg and HTDH if an IOP³16 mmHg at the time of DH detection. Demographic and ophthalmological data, ET-1 concentration, LDI (before and after 1, 10 and 20 minutes after cold stimulation) and NC findings were evaluated. Results: Thirty-tree patients were included (mean age, 62.3±13 years). Regarding ET-1 blood level, it was 65% higher in the LTDH group (2.27±1.46 pg/ml) compared to the HTDH (1.37±0.57 pg/ml; p=0.03). In addition, there was a significant negative correlation between ET-1 blood concentration and IOP at the time of DH detection (r=-0.45; p=0.02). Blood flow measurement in LTDH patients were lower than those observed in patients with HTDH 10 and 20 minutes after cold stimulus (p<0.01). Conclusion: Patients developing DH with lower IOPs have higher ET-1 blood levels and more peripheral vascular dysfunction (than those with higher IOPs), as estimated by LDI. These findings suggest that distinct underling mechanisms maybe involved in patients developing DH with different IOP ranges.

Abstract Background Pancreatic cancer is one of the leading causes of cancer deaths worldwide. Current chemoradiation therapy suffers from normal tissue toxicity. To overcome this problem, we are proposing incorporating nanoparticles as radiosensitizers and as drug delivery vehicles into current chemoradiation regimes. Gold nanoparticles (GNPs) and Docetaxel (DTX) have shown very promising synergetic radiosensitization effects despite DTX toxicity to normal tissues. Here, we explored the effect of DTX prodrug encapsulated in lipid nanoparticles (LNPDTX−P) on GNP uptake in pancreatic cancer models in vitro and in vivo. Methods For the in vitro experiment, pancreatic cancer cell line, MIA PaCa-2, were cultured and dosed with 7.5 µg/mL of GNPs (of ~ 11 nm in diameter functionalized with PEG and RGD peptide) and with 45 nM of free DTX or equivalent dose of LNPDTX−P. For the in vivo experiment, MIA PaCa-2 were implanted subcutaneously in NRG mice and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or equivalent dose of LNPDTX−P. GNPs content in mice and in cells were measured using Inductively Coupled Plasma–Mass Spectrometry (ICP–MS). Results The results show that LNPDTX−P treated tumour samples have no less than 191% increase in GNPs uptake compared to control samples in both in vitro and in vivo. The results also show that LNPDTX−P treated tumour samples have retained over 160% of GNPs compared to control samples in both in vitro and in vivo. No significant difference was found in GNP uptake or retention between free DTX and LNPDTX−P in tumour treated samples in vivo. Conclusions The results are very promising as LNPDTX−P have superior targeting of tumour tissues compared to free DTX due to their nano size and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX−P can be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcome. Current radiotherapy treatments can hugely benefit from the effects of these two radiosensitizers boosting the radiation dose to the tumour while reducing the normal tissue dose. This in return will improve patient outcome and quality of life.

PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 −12 ), immunohistochemistry (86%, P = 4.6 × 10 −3 ), or tumor mutational burden (80%, P = 9.1 × 10 −4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 −5 ). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P &lt; .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P &lt; .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.