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Ulcerated cutaneous melanoma carries a poor prognosis, and the underlying biology driving its aggressive behavior is largely unexplored. MicroRNAs (miRs) are small, noncoding RNAs that inhibit the expression of specific genes and exhibit dysregulated expression patterns in cancer. We hypothesized that a unique miR profile exists in ulcerated relative to nonulcerated melanoma and that miR expression inversely correlates with target genes of biologic importance. Expression of miRs and mRNAs was assessed in ulcerated and nonulcerated cutaneous melanomas using the NanoString Human miRNA and Tumor Signaling 360 mRNA assays and validated in an independent cohort. Pathway enrichment and functional annotations for differentially expressed miRs and mRNAs were determined using publicly available databases. Pearson correlations were employed to predict potential miR‒mRNA binding pairs. Ulcerated melanoma tissue showed at least 1.5-fold change in relative expression of 24 miRs, including miR-206, miR-1-3p, and miR-4286 (>2.25-fold decrease, P < 0.048) and miR-146a-5p, miR-196b-5p, and miR-363-3p (>2.5-fold increase, P < 0.014). Ulcerated melanomas also had 21 differentially expressed mRNAs relative to nonulcerated tumors (P < 0.01), among which two had an inverse correlation in expression with regulatory miRs (SOCS3 and miR-218-5p and IL7R and miR-376c-5p). This miR expression profile adds to the molecular characterization of the poorly understood histopathologic phenotype of ulcerated melanoma., (Copyright © 2022. Published by Elsevier Inc.)

Detection of cancer in its early stage is a challenging task for oncologists. Inflammatory breast cancer has symptoms that are similar to mastitis and can be mistaken for microbial infection. Currently, the differential diagnosis between mastitis and Inflammatory breast cancer via nipple aspirate fluid (NAF) is difficult. Here, we report a label-free and amplification-free detection platform using an engineered nanopore of the phi29 DNA-packaging motor with biomarker Galectin3 (GAL3), Thomsen-Friedenreich (TF) binding peptide as the probe fused at its C-terminus. The binding of the biomarker in NAF samples from breast cancer patients to the probe results in the connector's conformational change with a current blockage of 32 %. Utilization of dwell time, blockage ratio, and peak signature enable us to detect basal levels of biomarkers from patient NAF samples at the single-molecule level. This platform will allow for breast cancers to be resolved at an early stage with accuracy and thoroughness., Competing Interests: Declaration of competing interest P.G. is the consultant and licensor of Oxford Nanopore Technologies; the cofounder of Shenzhen P&Z Bio-medical Co. Ltd., as well as the cofounder and the chairman of the board of ExonanoRNA, LLC., (Published by Elsevier Inc.)

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172., (© 2022 by The American Society of Hematology.)

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE)., (© 2022 by The American Society of Hematology.)

Background: Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM., Patients and Methods: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m 2 subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS)., Results: A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10 -5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR., Conclusion: These data support the use of D-Vd in Chinese patients with RRMM., Competing Interests: Disclosure MQ, SS, XG, and XY are employees of Janssen and own Johnson & Johnson stock. WeipingLiu and WenyuLiu are employees of Janssen. JL, WF, WLi, JH, GA, YW, CF, LC, JJ, XC, ZG, ZC, TN, and XH have no conflicts of interest to disclose. This study (ClinicalTrials.gov Identifier: NCT03234972) was sponsored by Janssen Research & Development, LLC, which provided support for collection, analysis, and interpretation of data; Janssen employee-authors were involved in the decision to submit the article for publication. Medical writing and editorial support were provided by Grace Wang, PharmD, of Cello Health Communications/MedErgy, and were funded by Janssen Global Services, LLC., (Copyright © 2021 Janssen Research & Development, LLC. Published by Elsevier Inc. All rights reserved.)

Background: Hepatic angiomyolipoma (HAML) may easily be misdiagnosed as a malignancy. The study aim was to assess diagnostic dilemmas, clinical management and outcome of this rare tumor., Methods: This retrospective international multicenter study included all patients with pathologically proven HAML diagnosed between 1997 and 2017. Data on patient characteristics, diagnostic work-up, management and follow-up were analyzed., Results: Thirty-eight patients were included, 32 female. Median age was 56yrs (i.q.r. 43-64) and median HAML-diameter was 57.5 mm (i.q.r. 38.5-95.3). Thirty patients had undergone CT and 27/38 MRI of the liver, diagnostic biopsy was performed in 19/38. Initial diagnosis was incorrect in 15/38 patients, of which 13 were thought to have malignancy. In 84% biopsy resulted in a correct preoperative diagnosis. Twenty-nine patients were managed with surgical resection, 4/38 with surveillance and 3/38 with liver transplantation. Recurrence after resection occurred in two cases. No HAML related deaths or progression to malignancy were documented., Conclusion: HAML diagnosis proved problematic even in hepatobiliary expertise centers. Biopsy is indicated and may provide valuable additional information when HAML diagnosis is considered on cross-sectional imaging, especially when surgical resection imposes a risk of complications. Conservative management with regular imaging follow-up might be justified when biopsy confirms (classic type) HAML., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The relationship of expenditures related to rescuing patients from complications and hospital quality has not been well characterized. We sought to examine the relationship between payments for treating post-operative complications after liver and pancreas surgery and hospital quality., Methods: A retrospective cohort study of patients who underwent hepatopancreatic surgery was performed using claims data from 2013 to 2015 in the Medicare Provider Analysis and Review (MEDPAR) database. Medicare payments for index hospitalization and readmissions, as well as perioperative clinical outcomes were analyzed. Hospitals were stratified using average payments for patients who were rescued from complications (cost-of-rescue)., Results: A total of 13,873 patients and 737 hospitals were included in the analyses. Patient characteristics were similar across hospitals. Risk-adjusted rates of overall complications were higher at the highest cost-of-rescue hospitals (relative risk [RR], 1.35, 95% confidence interval [CI] 1.16-1.58), as well as rates of serious complications (RR, 1.78, 95% CI 1.51-2.09), 30-day readmission (RR 1.21 95% CI 1.06-1.39), 90-day mortality (RR, 1.29, 95% CI 1.01-1.64), and rates of failure-to-rescue (RR, 1.50, 95% CI 1.14-1.97)., Conclusion: Highest cost-of-rescue hospitals demonstrated worse quality metrics, including higher rates of serious complications, failure-to-rescue, 30-day readmission, and 90-day mortality., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma., Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74)., Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%])., Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma., Funding: Janssen Research & Development, LLC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

An automated point-of-care (POC) immunodetection system for immunological detection of staphylococcal enterotoxin B (SEB) was designed, fabricated, and tested. The system combines several elements: (i) enzyme-linked immunosorbent assay-lab-on-a-chip (ELISA-LOC) with fluidics, (ii) a charge-coupled device (CCD) camera detector, (iii) pumps and valves for fluid delivery to the ELISA-LOC, (iv) a computer interface board, and (v) a computer for controlling the fluidics, logging, and data analysis of the CCD data. The ELISA-LOC integrates a simple microfluidic system into a miniature 96-well sample plate, allowing the user to carry out immunological assays without a laboratory. The analyte is measured in a sandwich ELISA assay format combined with a sensitive electrochemiluminescence (ECL) detection method. Using the POC system, SEB, a major foodborne toxin, was detected at concentrations as low as 0.1 ng/ml. This is similar to the reported sensitivity of conventional ELISA. The open platform with simple modular fluid delivery automation design described here is interchangeable between detection systems, and because of its versatility it can also be used to automate many other LOC systems, simplifying LOC development. This new POC system is useful for carrying out various immunological and other complex medical assays without a laboratory and can easily be adapted for high-throughput biological screening in remote and resource-poor areas., (Published by Elsevier Inc.)

Purpose: We report the results of a retrospective study of the use of tricorticocancellous iliac crest bone graft in 12 patients with acute AO type C3.2 or type C3.3 fractures of the distal radius who were followed up for at least 1 year., Methods: Twelve of 17 patients treated with the protocol were available for follow-up evaluation. All fractures were treated with open reduction and combined internal and external fixation. Five fractures were plated dorsally, 1 volarly, and 5 volarly and dorsally., Results: Five patients had AO type C3.2 fractures and 7 had AO type C3.3 fractures. Nine of 10 radiographic parameters that were restored to near-normal values during the surgery were maintained at near-normal levels at the final follow-up evaluation at a mean of 28 months after surgery. Nine fractures had less than 2 mm of articular step-off of the distal radius and 8 had less than 3 mm of total articular incongruity (gap plus step-off). In 10 patients the radial length was restored to at least 10 mm. The mean arc of flexion-extension was 67% and the mean grip strength was 57% of that of the uninjured side. According to the Gartland and Werley demerit-point system 5 of the patients had good or excellent results. According to the modified Green and O'Brien clinical rating system 2 patients had good or excellent results. Poor results for 2 patients according to the demerit-point system and for 6 patients according to the Green and O'Brien clinical rating system were associated with severe ipsilateral soft-tissue and osseous injuries of the wrist, forearm, and arm. The total articular incongruity had a moderately strong correlation with the outcome as assessed by the demerit-point system., Conclusions: Tricorticocancellous bone grafting in conjunction with combined internal and external fixation is a satisfactory treatment that can lead to a high rate of return to work and sports, a high level of patient satisfaction, and a low rate of complications., Type of Study/level of Evidence: Therapeutic, Level IV.