Two-sided Wilcoxon Rank Sum Test Research Articles

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. At OLE Week 96, participants who switched to B/F/TAF ( N = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).

662 Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p &lt; 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.

Abstract 15826: Single-Cell Analysis of Right Ventricle Combined With AI: Implications for Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) significantly compromises the functionality of the right ventricle (RV). Our recently established NFU1 mutation-based rat model spontaneously develops PAH and successfully recapitulates main features of human PAH, such as gender dimorphism, right ventricle (RV) hypertrophy and dysfunction with RV-pulmonary artery uncoupling. Objective: We aimed to discern unique transcriptional differences between in WT and NFU1 rats on the single cell level, which may shed light on potential therapeutic targets for RV hypertrophy in PAH. Methods: We performed a single-cell transcriptomics analysis of WT and NFU1 RV collected from WT and NFU1 G206C rats to determine potential targets for treating RV dysfunction. The single-cell data was processed, and cells were annotated. Differentially expressed (DE) genes in cell types between the WT and NFU1 were determined using a two-sided Wilcoxon rank sum test. Finally, PandaOmics AI was employed to select through RV transcriptomics data (Boucherat, 2022) and extract the top 300 human targets from our key gene findings in the rat model. Results: We identified several cell types in rat scRNA-seq data, among which cardiomyocytes and endothelial cells had the highest number of human-relevant rat targets. Endothelial cells had 6 targets, Hsp90aa1/b1, Fabp4, Fhl2, Tnni3, Atp2a2, Ndufa4. These genes can affect endothelial cell proliferation, vascular integrity, intracellular transport, and angiogenic phenotype. Cardiomyocytes had 24 identified targets responsible for increased mitochondrial metabolism (Ndufv1, Nme2, Mrpl15), calcium release and muscle contraction (Ryr2, S100a1, Atp2a2), and others. Conclusions: A distinct disparity is observed in the transcriptional landscape in RV in NFU1 model of PAH. This could either indicate an adaptive response by the RV to increased afterload or be tied to its distinctive embryological/developmental origin, morphology, and functional properties. Novel cell-type-specific potential targets responsible for RV hypertrophy and dysfunction in PAH were discovered.

Dissection of tumor-intrinsic and tumor-extrinsic features of MiT/TFE translocation renal cell carcinoma via single-cell RNA sequencing

Abstract Background Translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of renal cell carcinoma driven by oncogenic gene fusions involving MiT/TFE family transcription factors, most commonly TFE3. Currently, there are no molecularly tailored treatments for tRCC, and standard-of-care therapies utilized for other RCC subtypes are typically less effective in tRCC. Emerging data suggest that tRCC is molecularly distinct from more common RCC subtypes. However, an incomplete understanding of both tumor-intrinsic drivers and the tumor microenvironment (TME) features of tRCC presents barriers to developing effective therapeutics for this cancer. Methods We used single-nucleus RNA sequencing (snRNA) to profile ten samples of tRCC tumors and one adjacent normal tissue. Five of the samples also underwent multiome profiling with snATAC-seq while nine of the tumor samples underwent whole genome sequencing and RNA-sequencing. We preprocessed and obtained the raw fasta files using cellranger and extracted RNA counts and chromatin accessibility peaks using the Seurat/Signac algorithm. Scrublet was used to exclude data from droplets containing more than one cell by performing doublet detection and removal on gene-barcode matrices. Cells with fewer than 200 genes detected or more than 5% of counts attributed to mitochondrially-encoded transcripts were removed before across-sample integration. We also excluded genes detected in fewer than three cells across all samples. The combined cohort was analyzed using the MergeData function in Seurat, and cancer cells were selected based on known tRCC gene markers and inferred transcriptional copy number variations estimated via the inferCNV package and verified from WGS data. Non-tumor cell types were determined through manual annotation via known marker genes. We analyzed patterns of gene expression at the single-cell level using the Seurat V4 package and module score functions. Differential expression analysis comparing cells from different clusters or treatment exposure groups was performed using a two-sided Wilcoxon rank-sum test with Bonferroni FDR correction. Results Following quality control and integration, 71,124 single-cells were used for analysis (67,762 from tumor samples) – representing 43,214 tumor cells, 8,352 monocytes, 4,692 T cells, 4,614 endothelial/stromal cells, and normal kidney cells. The normal-adjacent sample represented multiple cell types from the normal kidney, including cells from distal connecting tubule, connecting duct, proximal tubule, thick ascending limb, podocytes, and endothelial cells. Analysis of chromatin accessibility profiles from snATAC-seq and snRNA-seq data of tumor cells was employed to identify unique cell states and a putative cell of origin for tRCCs. Tumor cell analysis also demonstrated intra- and inter-tumoral transcriptional variability in genetically similar tumor subclusters, each with distinct regulon activity. Immune subpopulation analyses revealed higher proportions of resting T cells in treatment-naive tRCC samples and higher proportions of progenitor-exhausted and terminal-exhausted populations in an immune checkpoint inhibitor (ICI) treated sample, indicating immune reprogramming in response to ICI in this mutationally quiet tumor. To further understand the role of, and factors permissive to, anti-tumor T cell responses in tRCC (which is characterized by a low tumor mutational burden) we explored the hypothesis that MiT/TFE fusions may constitute tumor neoantigens. We computationally identified fusion-associated neoantigens corresponding to these tRCC samples, as well as across a larger aggregate dataset of tRCC samples profiled by bulk RNA-Seq. We predicted binding affinities between fusion-associated neoantigens and HLA types and identified multiple peptide candidates with high HLA-binding affinity, which will be validated for their immunogenicity in vitro. Conclusions Overall, our results highlight tumor-intrinsic and tumor-extrinsic determinants of immunogenicity in tRCC and may guide the development of immunotherapeutic strategies with strong mechanistic rationale in tRCC. CDMRP DOD Funding: yes

Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

BackgroundUrothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required.MethodsIn this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings.ResultsPlasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12.ConclusionsThe measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification.As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.

A Pilot Intervention Designed to Increase Cruciferous Vegetable Intake to Reduce Bladder Cancer Recurrence and Progression

Study Purpose: Bladder cancer is one of the top 10 most common cancers in the US and is the most expensive cancer to treat. The majority of bladder cancers (70–80%) are diagnosed at early stages as non-muscle invasive bladder cancer (NMIBC), which can be removed surgically. However, 50–80% of NMIBC recurs within 5 years, and 15–30% progresses with poor survival. Current treatment is limited. Preclinical and epidemiologic evidence suggests that dietary isothiocyanates (ITCs) in cruciferous vegetables could be a non-invasive and cost-effective strategy to improve NMIBC prognosis. Thus, the purpose of our study was to develop and pilot test a cruciferous vegetable intervention designed to increase ITC exposure in NMIBC survivors. Methods: We used a blinded 2-arm randomized controlled trial (RCT) to test the preliminary efficacy of a 6-month cruciferous vegetable intervention for NMIBC survivors. The intervention consisted of mailed materials, a live phone-call to review the materials, and 11 Interactive Voice Responses calls. Three-day urine samples, 3-day dietary recalls, and survey data were collected at baseline and 6-months. Two-sided Wilcoxon rank-sum tests were used for between-group comparisons. Results: Forty-nine NMIBC patients diagnosed in 2018–2019 were randomized and 42 (22 treatment, 20 control) were retained for 6-month follow-up. Participants were mostly male (71.4%) and White (90.5%), with an average age of 67.4 years. Compared to the control, the treatment group reported 35.0 g (95% CI: −14.9, 85.0; P = 0.014) higher Cruciferae intake (treatment = 58.6 ± 54.5 g vs. control = 23.6 ± 96.1g) and increased urinary ITC levels by 11.1 μmol/g creatinine (treatment = 14.2 ± 24.5 vs. control = 3.1 ± 13.9, P = 0.027) at 6-month follow-up. Conclusion: Our behavioral cruciferous vegetable intervention is the first to significantly increase cruciferous vegetable intake and ITC levels in NMIBC survivors. Our evidence-based dietary intervention has the potential to offer an affordable, scalable option for NMIBC survivors to reduce their risk of recurrence and improve outcomes.

Morphometric analysis of tumor microvessels for detection of hepatocellular carcinoma using contrast-free ultrasound imaging: A feasibility study.

A contrast-free ultrasound microvasculature imaging technique was evaluated in this study to determine whether extracting morphological features of the vascular networks in hepatic lesions can be beneficial in differentiating benign and malignant tumors (hepatocellular carcinoma (HCC) in particular). A total of 29 lesions from 22 patients were included in this work. A post-processing algorithm consisting of clutter filtering, denoising, and vessel enhancement steps was implemented on ultrasound data to visualize microvessel structures. These structures were then further characterized and quantified through additional image processing. A total of nine morphological metrics were examined to compare different groups of lesions. A two-sided Wilcoxon rank sum test was used for statistical analysis. In the malignant versus benign comparison, six of the metrics manifested statistical significance. Comparing only HCC cases with the benign, only three of the metrics were significantly different. No statistically significant distinction was observed between different malignancies (HCC versus cholangiocarcinoma and metastatic adenocarcinoma) for any of the metrics. Obtained results suggest that designing predictive models based on such morphological characteristics on a larger sample size may prove helpful in differentiating benign from malignant liver masses.

The diagnostic utility of nanopore targeted sequencing in suspected endophthalmitis

PurposeThis paper aimed to assess the diagnostic utility of a newly developed gene-based technology-nanopore targeted sequencing (NTS) in suspected endophthalmitis patients.MethodsThis retrospective study included 43 patients (44 eyes) with suspected endophthalmitis. NTS was applied along with microbiological culture to detect unknown pathogens in intraocular fluid samples. The diagnostic utility of NTS was mainly evaluated from three aspects, including the positivity rate of bacterial/fungal presence, diagnostic turnaround time and the frequency of change in treatment based on etiology test results. Non-parametric, two-sided Wilcoxon rank sum test, the McNemar’s test and the kappa statistic were used for statistical comparisons.ResultsNTS showed significant advantages over traditional culture in positivity rates and diagnostic time (P < 0.001, kappa = 0.082; Z = −5.805, P < 0. 001). As regards antibiotic strategy, 17 patients (39.53%) and 5 patients (11.63%) underwent medication change following NTS and culture results respectively (P < 0.001, kappa = 0.335). With reasonable use of antibiotic and surgical intervention, most patients responded favorably, judged by significantly improved visual acuity (Z = −4.249, P < 0.001). The mean duration of hospitalization was 8.49 ± 2.45 days (range, 1–16 days).ConclusionThe high efficiency feature of NTS in pathogen detection renders it a valuable supplementary to traditional culture. Additionally, it has facilitated patients’ management for the early and precise diagnosis of endophthalmitis.

Prevalence and risk factors for ototoxicity after cisplatin-based chemotherapy.

Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors. Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher's exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P = 0.008), and difficulty hearing (P < .001). Tinnitus was also significantly related to age at survey completion (OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001). TC survivors with hearing loss were more likely to report diabetes (P = 0.042), hypertension (P = 0.007), hypercholesterolemia (P < 0.001), and family history of hearing loss (P = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071). Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

Relationship between body composition, insulin resistance, and hormonal profiles in women with polycystic ovary syndrome.

To investigate how body fat influences glucose metabolism and hormone profiles in women with polycystic ovary syndrome (PCOS), compared to women without PCOS. We conducted a cross-sectional study of 166 women with PCOS and 139 age-matched control women at Peking University Third Hospital (Beijing, China) from March 2016 to December 2021. All participants underwent bioimpedance rate assessment of clinical, anthropometric, hormonal, and metabolic features. In particular, body composition parameters were assessed, based on the methods used in a previous study. Homeostasis model assessment-insulin resistance (HOMA-IR) and other indices calculated from fasting glucose and insulin were used to measure insulin resistance. The hormonal profiles [follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), prolactin (PRL), total testosterone (T), and androstenedione (A2)] were assessed by using biochemical methods. Two subgroup analyses were conducted according to waist-to-hip ratio (WHR; < 0.85, non-central obesity and ≥ 0.85, central obesity) and body fat percentage (BFP; < 35% for lean and ≥35% for obesity). The indices above were analyzed using a two-sided t-test or Wilcoxon rank sum test. Linear regression was used to investigate the effects of body composition on metabolism and sex hormones in the PCOS and control groups. Compared to women without PCOS, women with PCOS and central obesity (P=0.021), PCOS and noncentral obesity (P<0.001), PCOS and high BFP (P<0.001), and PCOS and low BFP (P<0.001) had more severe glucose metabolism evaluated with HOMA-IR. Women with PCOS experienced greater insulin sensitivity impairment than did the normal population for every equal increase in BFP. LH, LH/FSH, total testosterone, and androstenedione were significantly higher in patients with PCOS than in healthy controls, regardless of WHR and BFP stratification. However, negative correlations existed between body fat indices (i.e., BFP and body mass index) and hormone indices (i.e., LH and androstenedione) in the PCOS group, but were absent in the control group. Obese and non-obese women with PCOS have more severe insulin resistance and sex-hormone disorders than women without PCOS. The effect of body fat on sex-hormone disorders is only exist in women with PCOS. These findings suggested that PCOS clinical guidelines should be more specific to body fat. https://clinicaltrials.gov/, Registration No. NCT04264832.

Activation region overlap visualization for image-guided cochlear implant programming

Objective. The cochlear implant is a neural prosthesis designed to directly stimulate auditory nerve fibers to induce the sensation of hearing in those experiencing severe-to-profound hearing loss. After surgical implantation, audiologists program the implant’s external processor with settings intended to produce optimal hearing outcomes. The likelihood of achieving optimal outcomes increases when audiologists have access to tools that objectively present information related to the patient’s own anatomy and surgical outcomes. This includes visualizations like the one presented here, termed the activation region overlap image, which is designed to decrease subjectivity when determining amounts of overlapping stimulation between implant electrodes. Approach. This visualization uses estimates of electric field strength to indicate spread of neural excitation due to each electrode. Unlike prior visualizations, this method explicitly defines regions of nerves receiving substantial stimulation from each electrode to help clinicians assess the presence of significant overlapping stimulation. A multi-reviewer study compared this and an existing technique on the consistency, efficiency, and optimality of plans generated from each method. Statistical significance was evaluated using the two-sided Wilcoxon rank sum test. Main results. The study showed statistically significant improvements in consistency (p < 10–12), efficiency (p < 10−15), and optimality (p < 10−5) when generating plans using the proposed method versus the existing method. Significance. This visualization addresses subjectivity in assessing overlapping stimulation between implant electrodes, which currently relies on reviewer estimates. The results of the evaluation indicate the provision of such objective information during programming sessions would likely benefit clinicians in making programming decisions.

The Impact of Hispanic Ethnicity on Disease Characteristics in Multiple Myeloma

INTRODUCTION: While the racial disparities in multiple myeloma between those of African descent and Whites are well-documented, there is a paucity of data on other racial/ethnic minorities, such as Hispanics. Most recently, Kaur, et al. (Clin Lymphoma Myeloma Leuk, 2021) found that compared to other ethnicities, Hispanics residing in New York were younger at diagnosis, had a higher proportion of early-stage disease, did not differ by cytogenetic abnormalities, and had better overall survival with equal access to treatment. However, specific FISH probes tested and treatment regimens in myeloma have substantially changed since 2018. To our knowledge, no study has characterized the biology and clinical outcomes of Hispanics since 2018, a question of import given the national drive to improve outcomes and access to cancer care in minorities. METHODS: A retrospective cohort study was conducted of all patients newly diagnosed with multiple myeloma from January 2018 to December 2021 at our institution, Columbia University Irving Medical Center (CUIMC), to determine if Hispanics differed from non-Hispanics in terms of clinical characteristics and outcomes. As CUIMC is situated in Washington Heights, NY, a neighborhood comprised predominantly of individuals of Dominican ancestry, a large proportion of its patient population self-identifies as Hispanic. Two-sided Fisher's exact tests were used to test for differences between categorical values, and two-sided Wilcoxon rank sum tests were used to compare continuous variables. Survival analysis was done using the Kaplan-Meier method; differences between survival curves were evaluated using the two-sided log-rank test and a threshold of p<0.05 for two-sided statistical significance. RESULTS: Among the 201 patients diagnosed with multiple myeloma between 2018-2021, 76 (38%) self-identified as Hispanic. Among non-Hispanic patients (n=125), 52% were non-Hispanic White, 35% were non-Hispanic Black, 11% were Asian/Pacific Islander, and 2% were other/unknown. Hispanics did not differ from non-Hispanics in terms of age at diagnosis (69 vs. 67 years, respectively, p=0.274), proportion of light-chain myeloma (24% in both, p=0.975), hypercalcemia at diagnosis (15% vs. 17%, respectively, p=0.719), or renal insufficiency at diagnosis (eGFR <60, 52% vs. 49%, respectively, p=0.659). Both ISS and R-ISS stages at presentation were comparable between ethnicities (Table 1). The median follow-up of surviving patients was 23 months. Notably, Hispanics had a more than 2.5-fold higher incidence of del(1p) compared to non-Hispanics (26% vs. 10%, p=0.026), which led to significantly greater odds of harboring expanded high-risk cytogenetics by FISH (t[4;14], t[14;16], t[14;20], del[17p] or chromosome 1 abnormalities; 74% vs. 55%, p=0.028). Additionally, Hispanics had fewer t(11;14) translocations compared to non-Hispanics (17% vs. 30%, p=0.049). The most common induction regimen was VRD (31.3%), followed by Dara-VRD (13.1%), VCD (13.1%), Dara-RD (8.6%), KRD (5.1%), and Dara-VCD (5.1%); other induction regimens were used in <5% of cases each. Upfront high-dose melphalan autologous stem cell transplantation (HDM-ASCT) was performed in 39% of all patients, with no significant difference by ethnicity. The median PFS of Hispanics was 30.3 months (95%CI 17.6- not reached) compared to 38.2 months (95%CI 33.2- not reached) in non-Hispanics (p=0.15). CONCLUSIONS: Although age at diagnosis, ISS/R-ISS stage, clinical presentation, and rates of HDM-ASCT did not differ by ethnicity, Hispanics were found to have a 2.5-fold higher incidence of del(1p) by FISH. Validated as an adverse cytogenetic prognostic marker in myeloma (Perrot et al., JCO, 2019), the significant increase in del(1p) may translate into decreased PFS, a trend seen here. Longer follow-up is needed in a larger cohort adequately powered to assess whether such cytogenetic differences in Hispanics result in significantly worse long-term outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Team-Based Approach to Radiology Resident Case Conference to Improve Camaraderie Among Trainees

In light of increasing concerns regarding resident burnout, we developed a team-based approach (TBA) to radiology resident case conference to foster wellness by cultivating camaraderie and a positive learning environment. Teaching faculty provided both a traditional hot-seat and a TBA format case conference. Resident perceptions of each conference format were assessed using a 16-item questionnaire, with 14 of the items utilizing a 7-point Likert scale to assess the learning environment, including measures related to wellness. A two-sided Wilcoxon rank-sum test was used to compare responses between the 2 formats of teaching conferences. Four paired teaching sessions were performed by 4 individual faculty. Sixty-six individual resident responses were received for the hot-seat and TBA conferences in aggregate. Residents responded "strongly agree" to positive statements more often for the TBA format compared with hot-seat for 13 out of the 14 items used to assess perceptions of the learning environment, including measures of wellness and camaraderie. The level of agreement on a 7-point Likert scale pertaining to the statement "The format of this case conference improves camaraderie among my co-residents" had a median value of 4.5 for the hot-seat format and 7 for the TBA format (P=0.002). A TBA format for resident case conference may foster a sense of camaraderie among trainees. Residency programs may consider supplementing hot-seat conferences with the TBA method to address increasing burnout among trainees and promote resident wellbeing.

A multi‐omics analysis for the prediction of neurocognitive disorders risk among the elderly in Macao

BackgroundDue to the increasing ageing population, neurocognitive disorders (NCDs) have been a global public health issue, and its prevention and early diagnosis are crucial. Our previous study demonstrated that there is a significant correlation between specific populations and NCDs, but the biological characteristics of the vulnerable group predispose to NCDs are unclear. The purpose of this study is to investigate the predictors for the vulnerable group by a multi‐omics analysis.MethodsMulti‐omics approaches, including metagenomics, metabolomic and proteomic, were used to detect gut microbiota, faecal metabolites and urine exosome of 8 normal controls and 13 vulnerable elders after a rigorous screening of 400 elders in Macao. The multi‐omics data were analysed using R and Bioconductor. The two‐sided Wilcoxon's rank‐sum test, Kruskal–Wallis rank sum test and the linear discriminant analysis effective size were applied to investigate characterized features. Moreover, a 2‐year follow‐up was conducted to evaluate cognitive function change of the elderly.ResultsCompared with the control elders, the metagenomics of gut microbiota showed that Ruminococcus gnavus, Lachnospira eligens, Escherichia coli and Desulfovibrio piger were increased significantly in the vulnerable group. Carboxylates, like alpha‐ketoglutaric acid and d‐saccharic acid, and levels of vitamins had obvious differences in the faecal metabolites. There was a distinct decrease in the expression of eukaryotic translation initiation factor 2 subunit 1 (eIF2α) and amine oxidase A (MAO‐A) according to the proteomic results of the urine exosomes. Moreover, the compound annual growth rate of neurocognitive scores was notably decreased in vulnerable elders.ConclusionsThe multi‐omics characteristics of disturbed glyoxylate and dicarboxylate metabolism (bacteria), vitamin digestion and absorption and tricarboxylic acid cycle in vulnerable elders can serve as predictors of NCDs risk among the elderly of Macao. Intervention with them may be effective therapeutic approaches for NCDs, and the underlying mechanisms merit further exploration.

Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis.

Molecular subtyping of bladder cancer has revealed luminal tumors generally have a more favourable prognosis. However, some aggressive forms of variant histology, including micropapillary, are often classified luminal. In previous work, we found long non-coding RNA (lncRNA) expression profiles could identify a subgroup of luminal bladder tumors with less aggressive biology and better outcomes. In the present study, we aimed to investigate whether lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancer with differential outcome. LncRNAs were quantified from RNA-seq data from a HGT1 bladder cancer cohort that was enriched for primary micropapillary cases (15/84). Unsupervised consensus clustering of variant lncRNAs identified a three-cluster solution, which was further characterised using a panel of micropapillary-associated biomarkers, molecular subtypes, gene signatures, and survival analysis. A single-sample genomic signature was trained using lasso-penalized logistic regression to classify micropapillary-like gene-expression, as characterised by lncRNA clustering. The genomic classifier (GC) was tested on luminal tumors derived from the TCGA cohort (N = 202). Patient and tumor characteristics were compared between subgroups by using X2 tests and two-sided Wilcoxon rank-sum tests. Primary endpoints were overall, progression-free and high-grade recurrence-free survival, calculated as the date of high-grade T1 disease at TURBT till date of death from any cause, progression, or recurrence, respectively. Survival rates were estimated using weighted Kaplan-Meier (KM) curves. Primary micropapillary HGT1 showed decreased FGFR3, SHH, and p53 pathway activity relative to tumors with conventional urothelial carcinoma. Many bladder cancer-associated lncRNAs were downregulated in micropapillary tumors, including UCA1, LINC00152, and MALAT1. Unsupervised consensus clustering resulted in a lncRNA cluster 1 (LC1) with worse prognosis that was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Interestingly, LC1 appeared to better identify aggressive HGT1 disease, compared to stratifying outcomes using primary histologic characteristics. A signature trained to identify LC1 cases showed good performance in the testing cohort, identifying seven cases with significantly worse survival (p < 0.001). Limitations include the retrospective nature of the study and the lack of a validation cohort. Using the lncRNA transcriptome we identified a subgroup of aggressive HGT1 bladder cancer that was enriched with micropapillary histology. These data suggest that lncRNAs can facilitate the identification of aggressive micropapillary-like tumors, potentially improving patient management.

Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages. © 2021 International Parkinson and Movement Disorder Society.

Impact of Light Chain Isotype on Clinical Features and Outcomes in Systemic AL Amyloidosis

Purpose: In systemic AL amyloidosis, light chain (LC) isotype has been shown to predict outcome in patients undergoing upfront autologous transplantation. However, less than one-third of newly diagnosed AL patients are transplant-eligible. The objective of our study was to characterize the relationship between LC isotype, organ involvement, response, and survival in patients with newly diagnosed AL amyloidosis irrespective of transplant-eligibility.Methods: We performed a retrospective cohort study on 112 patients with AL amyloidosis who had treatment records at Columbia University Irving Medical Center (CUIMC) between 2015-2019. Two-sided Fisher's exact test was used for categorical variables and two-sided Wilcoxon rank sum test was used for continuous variables. Survival analysis was done using Kaplan Meier method. Overall survival (OS) was the time from randomization to death due to any cause. Event-free survival (EFS) was the time to initiation of a subsequent line of therapy or death due to any cause, whichever was earlier. Two-sided log-rank test was used to test differences between survival curves.Results: Kappa LC isotype was seen in 26% of patients. The proportion of patients with Mayo 2004 stage IIIA or IIIB disease in kappa and lambda isotype was 33% and 35% respectively (p=0.91). Bortezomib-based and daratumumab-based initial therapy was administered in 70% and 8% of patients respectively, with 36% having auto-transplant as part of first-line therapy. Patients with kappa LC isotype had a significantly higher baseline difference in free light chain (dFLC) and involved/uninvolved serum free light chain ratio (sFLCr) compared to lambda (median dFLC, 61.5 vs 21.6 mg/dl respectively, p=0.02; and median sFLCr, 63.5 vs 10.6 respectively; p<0.01). Kappa LC isotype was also associated with a near-significant higher bone marrow plasma cell (BMPC) burden at baseline (median BMPCs, 20% vs 10% respectively; p=0.06). Patients with lambda LC isotype had a significantly higher incidence of kidney involvement compared to kappa (64% vs 38% respectively, p=0.02). There was no significant difference in the incidence of t(11;14) between the two groups. The incidence of hematologic very good partial response or better (≥VGPR), involved free light chain less than 20 mg/dl (iFLC<20), and dFLC less than 10 mg/dl (dFLC<10) at the end of first-line therapy was similar in the two groups (Table in Figure 1). There was no difference in cardiac or renal response rates between the two groups. The proportion of patients requiring a subsequent line of therapy in kappa and lambda isotype was 41.4% and 39.8% respectively (p=0.88). At a median follow-up of 43 months for surviving patients, there was no significant difference in event-free survival (hazard ratio (HR) [kappa/lambda]: 0.76 [0.43-1.38]; p=0.37). However, there was a non-significant trend toward superior OS (HR [kappa/lambda]: 0.47 [0.18-1.23], p=0.12; 4-year OS: 86% vs 67% respectively) in patients with kappa LC isotype. Achievement of hematologic ≥VGPR, iFLC<20 mg/dl, and dFLC<10 mg/dl at end of first-line therapy was associated with a superior OS in our cohort irrespective of light chain isotype.Conclusion: Lambda AL amyloidosis is associated with significantly higher renal involvement compared to kappa. Despite a higher baseline disease burden (dFLC, sFLCr, and percent BMPC) in kappa compared to lambda, there was a trend toward superior OS in the former, which may imply decreased tissue toxicity of kappa FLCs. Further studies should investigate proteomic signatures and immunoglobulin gene usage according to light chain isotype and correlation with clinical phenotype. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dynamic lung compliance imaging from 4DCT-derived volume change estimation

Background. Lung compliance (LC) is the ability of the lung to expand with changes in pressure and is one of the earliest physiological measurements to be altered in patients with parenchymal lung disease. Therefore, compliance monitoring could potentially identify patients at risk for disease progression. However, in clinical practice, compliance measurements are prohibitively invasive for use as a routine monitoring tool. Purpose. We propose a novel method for computing dynamic lung compliance imaging (LCI) from non-contrast computed tomography (CT) scans. LCI applies image processing methods to free-breathing 4DCT images, acquired under two different continuous positive airway pressures (CPAP) applied using a full-face mask, in order to compute the lung volume change induced by the pressure change. LCI provides a quantitative volumetric map of lung stiffness. Methods. We compared mean LCI values computed for 10 patients with idiopathic pulmonary fibrosis (IPF) and 7 non-IPF patients who were screened for lung nodules. 4DCTs were acquired for each patient at 5 cm and 10 cm H20 CPAP, as the patients were free breathing at functional residual capacity. LCI was computed from the two 4DCTs. Mean LCI intensities, which represent relative voxel volume change induced by the change in CPAP pressure, were computed. Results. The mean LCI values for patients with IPF ranged between [0.0309, 0.1165], whereas the values ranged between [0.0704, 0.2185] for the lung nodule cohort. Two-sided Wilcoxon rank sum test indicated that the difference in medians is statistically significant (p value = 0.009) and that LCI -measured compliance is overall lower in the IPF patient cohort. Conclusion. There is considerable difference in LC scores between patients with IPF compared to controls. Future longitudinal studies should look for LC alterations in areas of lung prior to radiographic detection of fibrosis to further characterize LCI’s potential utility as an image marker for disease progression.

The effect of the implementation of the Affordable Care Act in the early diagnosis of type I endometrial cancer

Objectives: The objective of this study was to determine the effect of the Affordable Care Act (ACA), implemented in 2014, on the stage at which Type I Endometrial Cancer (EC) was diagnosed. Methods: Patients with Type I Endometrial cancer diagnosed based on surgical pathology at University Hospital between 2008 and 2018 were included in this study. We had complete data regarding age, race, insurance status, race and ethnicity, stage, grade, and year of diagnosis. The patients were split into those diagnosed prior to 2014 (pre-ACA), and those diagnosed in or after 2014 (post-ACA). Numerical variables were compared using a two-sided t-test or Wilcoxon rank-sum test as appropriate. Categorical variables were compared using Chi-square test or Fischer's exact test as appropriate. Results: There were 547 women that were included in our study. 232 (42.4%) women were diagnosed pre-ACA and 315 (57.6%) diagnosed post-ACA. The median ages were 54 (22-91) years and 59 (27-87) years in the pre-ACA and post-ACA groups respectively. Mean body mass index (BMI) was 38.9 kg/m2 (SD 9.95 kg/m2) in the pre-ACA women and was 39.2 kg/m2 (SD 9.81 kg/m2) in the post-ACA women (P=0.011). A Chi-square test was used to compare insurance coverage including private insurance, Medicare, Medicaid, local community payment plans (Carelink), or uninsured in the pre-ACA and post-ACA that was statistically significant (χ2 (5, 547) = 22.304, p= Download : Download high-res image (147KB) Download : Download full-size image Conclusions: Patient's diagnosed with Type I Endometrial Cancer were more likely to have insurance and be diagnosed at an earlier stage of disease after the implementation of the Affordable Care Act.

Impact of the COVID-19 pandemic on staging at presentation of patients with invasive melanoma.

e21579 Background: The COVID-19 pandemic has impacted cancer care beyond the direct implications of viral infection. Delays in presentation and diagnosis may lead to more advanced disease and worse patient outcomes. We evaluated the impact of the pandemic on patients (pts) with melanoma (mel). Methods: A single-institution, retrospective comparison of pts with newly diagnosed invasive mel or metastatic recurrence prior to (pre-cohort, n = 246) and after (post-cohort, n = 246) declaration of the COVID-19 pandemic on March 11, 2020. 492 pts were evaluated between March 1, 2019 and January 12, 2021. Key variables collected included demographics, pathology, stage at diagnosis, surgical management, receipt of adjuvant or systemic therapy, and follow up. Categorical variables were compared using the two-sided Fisher’s exact test, continuous variables were compared using the two-sided Wilcoxon rank sum test, and survival endpoints were evaluated with the Kaplan-Meier method. This study was exempt from review by the IRB. Results: 200 (81.3%) pts presented with early-stage disease and 46 (18.7%) pts presented with metastatic disease in the post-cohort, compared to 209 (85%) and 37 (15%) pts in the pre-cohort, respectively. In the post-cohort there was a significant decrease in stage I pts (28.5% vs 40.7%, p = 0.006), a significant increase in stage III pts (30.5% vs 21.1%, p = 0.023), and a significant increase in pts with metastatic recurrence (7.7% vs 3.3%, p = 0.046) compared to the pre-cohort. There was also a significant increase in pts with brain metastases (BM) in the post-cohort (6.5% vs 1.6%, p = 0.010). For pts with early-stage disease, there was a significant increase in median Breslow depth (2.0 vs 1.4 mm, p = 0.047) and mitotic rate &gt; 1 (78.1% vs 66%, p = 0.008) in the post-cohort. There were trends toward increased ulceration, lymphovascular/perineural invasion, and microsatellite presence. Pts receiving adjuvant therapy in the post-cohort were significantly more likely to receive oral targeted therapy (37.6% vs 27.5%) compared to IV immunotherapy (62.4% vs 72.5%), p = 0.034, perhaps reflecting an attempt to minimize in-person visits. There was not a significant difference between the 2 groups in the type of systemic therapy administered in the metastatic setting. Median progression-free and overall survival were not reached due to a limited number of events in each arm. Conclusions: There was a significant decrease in pts with stage I mel along with a significant increase in pts with stage III mel, metastatic recurrence, and BMs presenting to our institution during the pandemic. Findings are likely related to delays from both the patient (to avoid interaction with the healthcare system - including primary care, dermatology, and oncology) and from the system itself, with some clinics potentially evaluating pts in a limited capacity. These data reaffirm the importance of early detection and evaluation of melanoma.