Search

Ming-Chao Wei,1 Yu-Min Wang,2 Da-Wei Wang3 1Department of Thoracic Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Shandong, People’s Republic of China; 2Binzhou Medical University, Shandong, People’s Republic of China; 3Department of Thoracic Surgery, Yantai Mountain Hospital, Shandong, People’s Republic of ChinaCorrespondence: Da-Wei WangDepartment of Thoracic Surgery, Yantai Mountain Hospital, Yantai, Shandong, 264001, People’s Republic of ChinaTel +86-0535-6602183Email gebizhizhang44557@163.comBackground: The role of microRNA (miR) in tumors has been reported in numerous articles. Previous studies have found that miR-130a is low expressed in lung cancer, but the related mechanism has not been fully elucidated. This study mainly explores the mechanism of miR-130a in lung cancer, so as to provide potential therapeutic targets for clinical applications.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-130a and KLF3 in the tissues of lung cancer patients. The miR-130a-mimics and miR-130a-inhibit were constructed. Cell proliferation, invasion, migration and apoptosis were determined by CCK-8, transwell, scratch test and flow cytometry. Western Blot was used to determine the expression of KLF3 protein in cells, and the dual-luciferase reporter to determine the relationship between KLF3 and miR-130a.Results: miR-130a shows low expression in NSCLC patients, while KLF3 shows high expression, exhibiting a negative correlation. The 5-year survival rate of patients with low miR-130a expression and high KLF3 expression was reduced. Cox regression analysis showed that miR-130a was an independent prognostic factor for NSCLC patients. The dual-luciferase reporter revealed that miR-130a bound to KLF3 in a targeted manner, and cell experiments showed that miR-130a could inhibit the growth of lung cancer cells by regulating the expression of KLF3.Conclusion: miR-130a shows low expression in lung cancer and predicts a poor prognosis. In addition, up-regulation of miR-130a can down-regulate KLF3 and inhibit the growth of lung cancer.Keywords: miR-130a, KLF3, lung cancer, prognosis

Chen-Hsi Hsieh,1–3 Hui-Ju Tien,1 Sheng-Mou Hsiao,4 Ming-Chow Wei,4 Wen-Yih Wu,4 Hsu-Dong Sun,4 Li-Ying Wang,5 Yen-Ping Hsieh,6 Yu-Jen Chen,3,7–9 Pei-Wei Shueng1,101Department of Radiation Oncology, Far Eastern Memorial Hospital, Taipei, Taiwan; 2Department of Medicine, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 4Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, Taipei, Taiwan; 5School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan; 6Department of Senior Citizen Service Management, National Taichung University of Science and Technology, Taichung, Taiwan; 7Department of Radiation Oncology, 8Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; 9Graduate Institute of Sport Coaching Science, Chinese Culture University, Taipei, Taiwan; 10Department of Radiation Oncology, National Defense Medical Center, Taipei, TaiwanAim: To review the experience and to evaluate the results of stereotactic body radiation therapy (SBRT) via helical tomotherapy (HT), for the treatment of brachytherapy-unsuitable cervical cancer.Methods: Between September 1, 2008 to January 31, 2012, nine cervical cancer patients unsuitable for brachytherapy were enrolled. All of the patients received definitive whole pelvic radiotherapy with or without chemotherapy, followed by SBRT via HT.Results: The actuarial locoregional control rate at 3 years was 78%. The mean biological equivalent dose in 2-Gy fractions of the tumor, rectum, bladder, and intestines was 76.0 ± 7.3, 73.8 ± 13.2, 70.5 ± 10.0, and 43.1 ± 7.1, respectively. Only two had residual tumors after treatment, and the others were tumor-free. Two patients experienced grade 3 acute toxicity: one had diarrhea; and another experienced thrombocytopenia. There were no grade 3 or 4 subacute toxicities. Three patients suffered from manageable rectal bleeding in months 11, 14, and 25, respectively. One stage IVA patient experienced fistula formation in month 3.Conclusion: SBRT via HT provides the possibility for treatment of locally advanced cervical cancer in patients who are unsuitable for brachytherapy. Long-term follow up and enrollment of more such patients to receive SBRT via the HT technique are warranted.Keywords: biological equivalent dose, complication, image guidance, intensity modulated radiation therapy, rectal bleeding

Chen-Hsi Hsieh,1,4–6 Pei-Wei Shueng,1,3 Sheng-Mou Hsiao,2 Ming-Chow Wei,2 Wen-Yih Wu,2 Hsu-Dong Sun,2 Hui-Ju Tien,1 Li-Ying Wang,7 Yen-Ping Hsieh81Division of Radiation Oncology, Department of Radiology, 2Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei City, 3Department of Radiation Oncology, National Defense Medical Center, 4Department of Medicine, 5Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 6Oriental Institute of Technology, New Taipei City, 7School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, 8Department of Senior Citizen Service Management, National Taichung University of Science and Technology, Taichung, Taiwan, ChinaBackground: The purpose of this study was to compare the efficacy of intensity-modulated radiotherapy (IMRT) and helical tomotherapy for endometrial cancer.Methods: Between November 1, 2006 and November 31, 2010, 31 patients with histologically confirmed endometrial cancer were enrolled. All enrolled patients received total abdominal hysterectomy and bilateral salpingo-oophorectomy with adjuvant whole pelvic IMRT or helical tomotherapy.Results: The actuarial 3-year overall survival, disease-free survival, locoregional control, and distant metastasis-free rates for the IMRT and helical tomotherapy groups were 87.5% versus 100%, 91.7% versus 51.7%, 91.7% versus 83.3%, and 91.7% versus 51.7%, respectively. The conformal index and uniformity index for IMRT versus helical tomotherapy was 1.25 versus 1.17 (P = 0.04) and 1.08 versus 1.05 (P < 0.01), respectively. Two of 31 patients with cervical stump failure were noted, one in the IMRT group and the other in the helical tomotherapy group. No acute or late grade 3 or 4 toxicities were noted, including proctitis, or genitourinary or gastrointestinal disturbances.Conclusion: Helical tomotherapy is as effective as IMRT and has better uniformity and conformal indices, and critical organ-sparing properties. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT versus helical tomotherapy.Keywords: endometrial cancer, helical tomotherapy, intensity-modulated radiotherapy

Background: To review the experience and to evaluate the treatment plan of using helical tomotherapy (HT) for the treatment of cervical cancer.Methods: Between November 1st, 2006 and May 31, 2009, 10 cervical cancer patients histologically confirmed were enrolled. All of the patients received definitive concurrent chemoradiation (CCRT) with whole pelvic HT (WPHT) followed by brachytherapy. During WPHT, all patients were treated with cisplatin, 40 mg/m2 intravenously weekly. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).Results: The mean survival was 25 months (range, 3 to 27 months). The actuarial overall survival, disease-free survival, locoregional control and distant metastasis-free rates at 2 years were 67%, 77%, 90% and 88%, respectively. The average of uniformity index and conformal index was 1.06 and 1.19, respectively. One grade 3 of acute toxicity for diarrhea, thrombocytopenia and three grade 3 leucopenia were noted during CCRT. Only one grade 3 of subacute toxicity for thrombocytopenia was noted. There were no grade 3 or 4 subacute toxicities of anemia, leucopenia, genitourinary or gastrointestinal effects. Compared with conventional whole pelvic radiation therapy (WPRT), WPHT decreases the mean dose to rectum, bladder and intestines successfully.Conclusion: HT provides feasible clinical outcomes in locally advanced cervical cancer patients. Long-term follow-up and enroll more locally advanced cervical carcinoma patients by limiting bone marrow radiation dose with WPHT technique is warranted. [ABSTRACT FROM AUTHOR]

Background: The primary objective of this study was to elucidate the impact of sentinel lymph node (SLN) mapping and biopsy techniques on the clinical outcomes of women with early primary cervical cancer., Methods: All consecutive women with clinically determined stage I-IIA cervical cancer who underwent lymph node assessment with either SLN mapping or conventional pelvic/para-aortic lymphadenectomy were reviewed., Results: Women in the SLN group (n=33) had fewer total dissected pelvic nodes (8.3±5.9 versus 17.4±7.7, p<0.001), less intraoperative blood loss (513±332mL versus 1228±1170mL, p<0.001), a shorter length of hospital stay (7.1±2.4 versus 10.2±6.1 days, p=0.004) and a trend toward a lower incidence of lymphocysts (3% versus 14%, p=0.090) than women in the conventional lymphadenectomy group (n=74). The rates of recurrence-free survival (3-year: 87.6% vs. 82.9%) and overall survival (3-year: 100% vs. 91.0%) did not differ between the SLN group and the conventional lymphadenectomy group (p=0.846 and p=0.254, respectively)., Conclusion: SLN biopsy does not seem to be associated with an inferior survival outcome compared with conventional lymphadenectomy in women with early primary cervical cancer. In addition, it is associated with less blood loss and a shorter length of hospital stay., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article. , (Copyright © 2024, the Chinese Medical Association.)

Purpose: Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18 F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic., Methods: Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers NCT02257567, NCT02500407; 20% holdout in ClinicalTrials.gov identifier NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review., Results: The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses., Conclusion: These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.

Purpose: We report a unique case of non-necrotizing occlusive retinal vasculitis presenting two years following chronic hypertensive uveitis., Methods: Case Report., Results: A 32-year-old Iraqi woman with a history of Posner-Schlossman Syndrome diagnosed 10 years prior presented with blurred vision and redness in her left eye. Examination demonstrated ocular hypertension, keratic precipitates, and inflammatory cells in the anterior chamber. Quantitative real-time PCR confirmed the presence of cytomegalovirus in the aqueous humor, and dilated posterior segment examination was negative for any signs of intraocular inflammation, retinitis, or vasculitis. Her uveitis workup was otherwise negative, and she was treated with valganciclovir for 6 months. Two years after her initial presentation, she was noted to have a new vitreous hemorrhage in the left eye. Fluorescein angiography demonstrated an occlusive retinal vasculitis with extensive neovascularization without retinitis. Quantitative real-time PCR again demonstrated the presence of cytomegalovirus in the anterior chamber. Her uveitis workup was repeated, which has now returned positive for HLA-B51. She otherwise did not demonstrate any systemic signs of Behcet's Disease. She was restarted on valganciclovir and oral prednisone and referred to rheumatology for consideration of adalimumab initiation. Thus far she has responded very well to treatment., Conclusion: This case highlights the importance of serial posterior segment examinations and HLA-B51 testing in individuals with cytomegalovirus anterior uveitis.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1β in the kidney. Harp was a promising anti-HUA agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate (ORR) of 80%, complete response (CR) rate of 60%, and a median progression-free survival (PFS) of 17.9 months in patients with relapsed/refractory (R/R) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for R/R FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with R/R FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching- adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. ORR (73%, 95% CI: 65-80%) and CR rates (53%, 95% CI: 45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI: 70-88%; CR=60%, 95% CI: 49-70%, respectively). PFS at 12 months was similar in the weighted LEO CReWE (60%, 95% CI: 51-69%) and the mosunetuzumab (58%, 95% CI: 47-68%) trial. Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria provide context for best practices in this setting.

Cocculus orbiculatus (L.) DC. ( C. orbiculatus ) is a medicinal herb valued for its dried roots with anti-inflammatory, analgesic, diuretic, and other therapeutic properties. Despite its traditional applications, chemical investigations into C. orbiculatus remain limited, focusing predominantly on alkaloids and flavonoids. Furthermore, the therapeutic use of C. orbiculatus predominantly focuses on the roots, leaving the stems, a significant portion of the plant, underutilized. This study employed ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) with in-house and online databases for comprehensive identification of components in various plant parts. Subsequently, untargeted metabolomics was employed to analyze differences in components across different harvest periods and plant sections of C. orbiculatus , aiming to screen for distinct components in different parts of the plant. Finally, metabolomic analysis of the roots and stems, which contribute significantly to the plant's weight, was conducted using chemometrics, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), and heatmaps. A total of 113 components, including alkaloids, flavonoids, and organic acids, were annotated across the root, stem, leaf, flower, and fruit, along with numerous previously unreported compounds. Metabolomic analyses revealed substantial differences in components between the root and stem compared to the leaf, flower, and fruit during the same harvest period. PLS-DA and OPLS-DA annotated 10 differentiating components (VIP > 1.5, P < 0.05, FC > 2 or FC < 0.67), with 5 unique to the root and stem, exhibiting lower mass spectrometric responses. This study provided the first characterization of 113 chemical constituents in different parts of C. orbiculatus , laying the groundwork for pharmacological research and advocating for the enhanced utilization of its stem.

Objective: To explore the value of optical coherence tomography (OCT) imaging system in evaluating cervical lesions in vivo. Methods: A total of 1 214 patients with cervical lesions were collected from January 2020 to December 2021 in the Third Affiliated Hospital of Zhengzhou University, Maternal and Chlid Heaith Hospital of Gushi County, Xinyang City, Henan Province, and Maternal and Chlid Heaith Hospital of Sui County, Shangqiu City, Henan Province. The age of the patients was (38.9±10.5) years (range: 16-77 years). All patients underwent in vivo cervical OCT examination and cervical biopsy pathology examination, and summarized the OCT image features of in vivo cervical lesions. Using the pathological diagnosis as the "gold standard", the accuracy, specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of OCT image interpretation results were evaluated, as well as the consistency of OCT image diagnosis and pathological diagnosis. At the same time, the in vivo cervical OCT imaging system, as a newly developed screening tool, was compared with the traditional combined screening of human papillomavirus (HPV) and Thinprep cytologic test (TCT), to assess the screening effect. Results: By comparing the OCT images of the cervix in vivo with the corresponding HE images, the OCT image characteristics of the normal cervix and various types of cervical lesions in vivo were summarized. The accuracy, sensitivity, specificity, PPV and NPV of OCT image in the diagnosis of high-grade squamous intraepithelial lesion (HSIL) and above (HSIL + ) were 93.4%, 88.5%, 95.0%, 85.0% and 96.2%, respectively. The accuracy, sensitivity, specificity, PPV and NPV of OCT for low-grade squamous intraepithelial lesion (LSIL) were 84.7%, 61.7%, 96.3%, 89.3% and 83.2%, respectively. The consistency between OCT image diagnosis and pathological diagnosis was strong (Kappa value was 0.701).The accuracy, sensitivity and specificity of OCT screening, HPV and TCT combined screening were 83.7% vs 64.9% ( χ ²=128.82, P <0.001), 77.8% vs 64.5% ( χ ²=39.01, P <0.001), 91.8% vs 65.4% ( χ ²=98.12, P <0.001), respectively. The differences were statistically significant. Conclusions: OCT imaging system has high sensitivity and specificity in the evaluation of cervical lesions in vivo, and has the characteristics of non-invasive, real-time and high efficiency. OCT examination is expected to become an effective method for the diagnosis of cervical lesions and cervical cancer screening.

Abstract: CD20 is an established therapeutic target in B-cell malignancies. The CD20 × CD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHLs). Because target antigen loss is a recognized mechanism of resistance, we evaluated CD20 expression relative to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial investigating mosunetuzumab monotherapy. CD20 was studied using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing performed centrally in biopsy specimens collected before treatment at predose, during treatment, or upon progression. Before treatment, most patients exhibited a high proportion of tumor cells expressing CD20; however, in 16 of 293 patients (5.5%) the proportion was <10%. Analyses of paired biopsy specimens from patients on treatment revealed that CD20 levels were maintained in 29 of 30 patients (97%) vs at progression, where CD20 loss was observed in 11 of 32 patients (34%). Reduced transcription or acquisition of truncating mutations explained most but not all cases of CD20 loss. In vitro modeling confirmed the effects of CD20 variants identified in clinical samples on reduction of CD20 expression and missense mutations in the extracellular domain that could block mosunetuzumab binding. This study expands the knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to include CD20-targeting bispecific antibodies and elucidates mechanisms of reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also confirm the utility of readily available IHC staining for CD20 as a tool to inform clinical decisions. This trial was registered at www.ClinicalTrials.gov as #NCT02500407., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: No established standard of care exists for relapsed/refractory (RR) follicular lymphoma (FL) after ≥2 prior therapies. We conducted indirect treatment comparisons (ITCs) to compare the efficacy and tolerability of mosunetuzumab with those of available treatments used in this setting., Methods: A systematic literature review (SLR) and subsequent feasibility assessments were conducted to identify the most suitable comparator studies in terms of design, available endpoints and populations. Imbalances in patient characteristics between NCT02500407 and studies featuring aggregate or patient-level data availability were accounted for using matching-adjusted indirect comparison (MAIC) and propensity score-based methodologies, respectively., Results: ZUMA-5, ELARA, DELTA, DYNAMO, UNITY-NHL, AUGMENT and NCT01897571 passed the MAIC feasibility assessment. Patient-level data were available from GADOLIN, CONTRALTO and NCT02257567. MAIC results generally favored mosunetuzumab over tazemetostat in EHZ2wild-type patients for all outcomes and over PI3K inhibitors for complete response (CR), objective response rate (ORR), discontinuations due to adverse events and progression-free survival (PFS) with umbralisib. MAICs favored CART therapies for PFS and, to a lesser extent, ORR and CR. Comparisons with anti-CD20 antibody-based regimens yielded mixed results., Conclusions: ITCs suggest that mosunetuzumab may lead to superior outcomes over tazemetostat (in EHZ2wild-type patients) and PI3K inhibitors and may be a promising alternative to re-challenging with a different anti-CD20 regimen in patients who relapse after ≥2 prior anti-CD20 lines. Although preliminary results somewhat favored CART therapies, limitations and uncertainties remain because of intrinsic differences in study design. Mosunetuzumab could thus be a promising treatment option for patients with RR FL after ≥2 prior therapies., Competing Interests: Disclosure F. Bosch: Roche, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, BeiGene (Honoraria); Roche, Celgene, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen (Consulting or advisory role); Roche, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, BeiGene (Speaker's bureau); Roche, Celgene, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen (Research funding); AbbVie (Expert testimony); AbbVie, Roche, Janssen, AstraZeneca, Celgene/BMS (Travel, accommodation, expenses). J. Kuruvilla: AbbVie, Amgen, AstraZeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics (Honoraria); AbbVie, Antengene, BMS, Gilead, Karyopharm, Medison Ventures, Merck, Roche, Seattle Genetics (Consulting or advisory role); Canadian Cancer Society Research Institute (CCSRI), Canadian Institutes of Health Research (CIHR), Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Roche, AstraZeneca, Merck (Research funding); DSMB—Karyopharm, SAB—Lymphoma Canada (Other). T.P. Vassilakopoulos: Takeda, Roche, Genesis Pharma, Merck, Novartis, Amgen, GSK, AbbVie, Integris, AstraZeneca, Gilead (Honoraria); Takeda, Roche, Genesis Pharma, Novartis, Gilead (Consulting or advisory role); Merck, Roche, Takeda, Amgen, Pfizer, Dr. Reddy's, Karyopharm, BMS, AbbVie, Mei Pharma (Research funding). D. Di Maio: Hoffman-La Roche AG (Current employment); Hoffman-La Roche AG (Stock Ownership). M. C. Wei: Genentech (Current employment); Roche (Stock ownership); Genentech/Roche (Travel, accommodation, expenses). M-H. Blanchet Zumofen: Roche Holding AG (Current employment); Roche (Leadership); Roche, Moderna (Stock ownership); Roche (Travel, accommodation, expenses). L.J. Nastoupil: ADC Therapeutics, Atara, BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Janssen, Novartis, Takeda (Honoraria); Sirpant, Interius Bio (Consulting or advisory role); BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, IGM Bioscience, Janssen, Novartis, Takeda (Research funding); Genentech/Roche (Travel, accommodation, expenses)., (Copyright © 2023. Published by Elsevier Inc.)

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 ., (© 2023. The Author(s).)

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial ( n  = 90) and a US electronic health records database ( n  = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52-2.93) and 3.18 (95% CI, 1.41-7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53-1.27) and 0.43 (95% CI, 0.19-0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.

Intradural lumbar disk herniation (ILDH) is a rare variant and accounts for 0.33%-1.5% of lumbar disk herniations. Although clues exist on preoperative imaging, they remain subtle and most cases of ILDH are diagnosed intraoperatively. Intraoperative ultrasound is a useful adjunct in diagnosing and managing ILDH. We present a case to demonstrate the features of an intradural herniated disk on ultrasound imaging and highlight the utility of intraoperative ultrasonography in establishing diagnosis, guiding dural opening, and confirming adequate nerve root decompression following diskectomy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to or relapse after first-line therapy, highlighting the need for better treatments. Mosunetuzumab is a CD20 × CD3 bispecific antibody that engages and redirects T cells to eliminate malignant B cells. In this phase 2, open-label study (NCT03677141), 40 patients (52.5% with international prognostic index ≥3) with previously untreated DLBCL initiated 6 cycles of IV mosunetuzumab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Mosunetuzumab was administered in cycle 1 as step-up doses to mitigate cytokine release syndrome [CRS], and a dose of 30 mg was given on day 1 of cycles 2-6. Efficacy end points included objective and complete response rates, as determined by the investigator, via positron emission tomography-computed tomography, using Lugano 2014 criteria (87.5% and 85.0%, respectively). At a median follow-up of 32.0 months, the estimated 2-year progression-free survival and event-free survival rates were 65.4% (95% confidence interval [CI], 49.5-81.4) and 60.4% (95% CI, 44.7-76.1), respectively. CRS occurred in 60.0% of patients; all events were grade 1 (45.0%) or grade 2 (15.0%) and occurred primarily in cycle 1. Mosunetuzumab-related grade ≥3 neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%). Grade 5 AEs were reported in 2 patients. Neutropenia occurred in 70.0% of patients, mostly during cycle 1 and was of short duration. These findings demonstrate promising activity and a manageable safety profile for mosunetuzumab-CHOP and warrant further investigation of mosunetuzumab in first-line combination regimens for DLBCL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. The primary end point was CR rate (best response), assessed against a historical control CR rate (20%) by independent review facility. Eighty-eight patients (73.9% de novo DLBCL; 26.1% transformed follicular lymphoma) were enrolled; all had received previous anthracycline and anti-CD20 therapy. Overall response and CR rates were 42.0% (95% confidence interval [CI], 31.6-53.1) and 23.9% (95% CI, 15.4-34.1), respectively; CR rate did not reach statistical significance vs the historical control (P = .36). Median time to first response was 1.4 months. Median progression-free survival was 3.2 months (95% CI, 2.2-5.3). The CR rate in 26 patients who received previous chimeric antigen receptor T-cell (CAR-T) therapy was 12%. CRS was one of the most common adverse events (26.1% of patients); predominantly grade 1 to 2 and primarily in C1. Four patients (4.5%) discontinued mosunetuzumab owing to adverse events. Mosunetuzumab demonstrated notable efficacy and a manageable safety profile in patients with R/R DLBCL, including those previously treated with CAR-Ts. This trial was registered at www.clinicaltrials.gov as #NCT02500407., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: α-Viniferin, the major constituent of the roots of Caragana sinica (Buc'hoz) Rehder with a trimeric resveratrol oligostilbenoid skeleton, was demonstrated to possess a strong inhibitory effect on xanthine oxidase in vitro, suggesting it to be a potential anti-hyperuricemia agent. However, the in vivo anti-hyperuricemia effect and its underlying mechanism were still unknown., Purpose: The current study aimed to evaluate the anti-hyperuricemia effect of α-viniferin in a mouse model and to assess its safety profile with emphasis on its protective effect on hyperuricemia-induced renal injury., Methods: The effects were assessed in a potassium oxonate (PO)- and hypoxanthine (HX)-induced hyperuricemia mice model by analyzing the levels of serum uric acid (SUA), urine uric acid (UUA), serum creatinine (SCRE), serum urea nitrogen (SBUN), and histological changes. Western blotting and transcriptomic analysis were used to identify the genes, proteins, and signaling pathways involved., Results: α-Viniferin treatment significantly reduced SUA levels and markedly mitigated hyperuricemia-induced kidney injury in the hyperuricemia mice. Besides, α-viniferin did not show any obvious toxicity in mice. Research into the mechanism of action of α-viniferin revealed that it not only inhibited uric acid formation by acting as an XOD inhibitor, but also reduced uric acid absorption by acting as a GLUT9 and URAT1 dual inhibitor as well as promoted uric acid excretion by acting as a ABCG2 and OAT1 dual activator. Then, 54 differentially expressed (log 2 FPKM ≥ 1.5, p ≤ 0.01) genes (DEGs) repressed by the treatment of α-viniferin in the hyperuricemia mice were identified in the kidney. Finally, gene annotation results revealed that downregulation of S100A9 in the IL-17 pathway, of CCR5 and PIK3R5 in the chemokine signaling pathway, and of TLR2, ITGA4, and PIK3R5 in the PI3K-AKT signaling pathway were involved in the protective effect of α-viniferin on the hyperuricemia-induced renal injury., Conclusions: α-Viniferin inhibited the production of uric acid through down-regulation of XOD in hyperuricemia mice. Besides, it also down-regulated the expressions of URAT1 and GLUT9 and up-regulated the expressions of ABCG2 and OAT1 to promote the excretion of uric acid. α-Viniferin could prevent hyperuricemia mice from renal damage by regulating the IL-17, chemokine, and PI3K-AKT signaling pathways. Collectively, α-viniferin was a promising antihyperuricemia agent with desirable safety profile. This is the first report of α-viniferin as an antihyperuricemia agent., Competing Interests: Declaration of Competing Interest All authors have disclosed that they do not have any conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Phase I oncology clinical trials often comprise a limited number of patients representing different disease subtypes who are divided into cohorts receiving treatment(s) at different dosing levels and schedules. Here, we leverage a previously developed quantitative systems pharmacology model of the anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, to account for different dosing regimens and patient heterogeneity in the phase I study to inform clinical dose/exposure-response relationships and to identify biological determinants of clinical response. We developed a novel workflow to generate digital twins for each patient, which together form a virtual population (VPOP) that represented variability in biological, pharmacological, and tumor-related parameters from the phase I trial. Simulations based on the VPOP predict that an increase in mosunetuzumab exposure increases the proportion of digital twins with at least a 50% reduction in tumor size by day 42. Simulations also predict a left-shift of the exposure-response in patients diagnosed with indolent compared to aggressive non-Hodgkin's lymphoma (NHL) subtype; this increased sensitivity in indolent NHL was attributed to the lower inferred values of tumor proliferation rate and baseline T-cell infiltration in the corresponding digital twins. Notably, the inferred digital twin parameters from clinical responders and nonresponders show that the potential biological difference that can influence response include tumor parameters (tumor size, proliferation rate, and baseline T-cell infiltration) and parameters defining the effect of mosunetuzumab on T-cell activation and B-cell killing. Finally, the model simulations suggest intratumor expansion of pre-existing T-cells, rather than an influx of systemically expanded T-cells, underlies the antitumor activity of mosunetuzumab., (© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1 fl/fl mice and Lyz2-Cre; Arih1 fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS., (© 2022. The Author(s).)

Background: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies., Methods: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing., Findings: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred., Interpretation: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests LEB reports consulting fees from Genentech, ADC Therapeutics, Merck, AstraZeneca, and Amgen; and participation on a data safety monitoring board for Ziopharm Oncology. LHS reports research grants from Roche/Genentech and Teva; consulting fees from AbbVie, Acerta, Amgen, AstraZeneca, Celgene/Bristol-Myers Squibb (BMS), Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz, and TG therapeutics; and honoraria from AbbVie, Acerta, Amgen, AstraZeneca, Celgene/BMS, Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz, and TG therapeutics. MM reports research grants from AstraZeneca, Genentech, Janssen, Roche, Bayer, IGM Biosciences, Pharmacyclics, and Seattle Genetics; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from ADC Therapeutics, Bayer, Daiichi Sankyo, MEI Pharma, Genentech, Seattle Genetics, Epizyme, IMV Therapeutics, Janssen, Pharmacyclics, and Roche; payment from expert testimony from Bayer; and owns stock or stock options in Merck. SJS reports grants or contracts from Genentech, AbbVie, Acerta, AstraZeneca, Celgene/BMS/Juno, Incyte, Merck, Novartis, TG Therapeutics, and Theredex; consulting fees from AstraZeneca, BeiGene, Celgene/BMS/Juno, Genentech/Roche, Genmab, Incyte, Janssen, MorphoSys, Mustang Biotech, Novartis, and Regeneron; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events for Incyte, Novartis, and Takeda; participation on a monitoring board or advisory board for AstraZeneca, BeiGene, Celgene/BMS/Juno, Genentech/Roche, Genmab, Incyte, Janssen, MorphoSys, Mustang Biotech, Novartis, and Regeneron; a role in board, society, committee, or advocacy groups for Genentech, Legend Biotech, Novartis, and Nordic Nanovector; and research support for Genentech and Merck. SA reports research grants from AbbVie, Roche, Genentech, Takeda, Lilly, and Merck; speaker's bureau from Pfizer; and is chair of the haematology group (unpaid) of the Canadian Cancer Trials Group. JK reports research grants from Roche, AstraZeneca, and Merck; consulting fees from AbbVie, Antengene, BMS, Gilead, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; payment or honoraria from lectures, presentations, and educational events for AbbVie, Amgen, AstraZeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; participation in a data safety monitoring board for Karyopharm; and participation as chair, scientific advisory board, and director in the board of directors for Lymphoma Canada. MC reports consulting fees from BeiGene, BMS, Incyte, Janssen, Kite, Kyowa, Miltenyi Biotec, Novartis, Roche, and Takeda; payment from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from Amgen, Eusa Pharma, Janssen, Kite, Kyowa, Roche, and Takeda; and meeting attendance or travel support, or both, from Kite, Janssen, Roche, Sanofi, and Takeda. LN reports grants from BMS, Caribou Biosciences, Epizyme, Gilead/Kite, Janssen, IGM Biosciences, Takeda, and TG Therapeutics; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from Genentech, Gilead/Kite, and Takeda; meeting attendance or travel, or both, support from Genentech; and participation in data safety monitoring board or advisory board for ADC Therapeutics, Bayer, Epizyme, BMS, MorphoSys, Novartis, Genentech, Takeda, MEI, DeNovo, and TG Therapeutics. CYC reports payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events for Janssen, AstraZeneca, Roche, and Beigene; and participation in data safety monitoring board or advisory board for Roche, Janssen, TG Therapeutics, AstraZeneca, Lilly, and Gilead. MCW reports meeting attendance or travel support, or both, from Roche/Genentech; and stocks and stock options in Roche. SY reports meeting attendance or travel support, or both, for Genentech; patents planned, issued, or pending from Genentech; and stocks and stock options in Genentech. C-CL reports stocks and stock options in Roche; and patents planned, issued, or pending for Genentech. AK reports stocks or stock options in Roche. EP reports stocks or stock options in Genentech. NLB reports research funding from ADC Therapeutics, Affimed, Autolus, BMS, Celgene, Forty Seven, Immune Design, Janssen, Kite Pharma, Merck, Millennium, Pfizer, Pharmacyclics, Roche/Genentech, and Seattle Genetics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation., Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin)., Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 μg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 μg/L., Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wei, Zhang, Chen, Chen, Lau and Peng.)

Background: The primary objective of this study was to elucidate the predictors for cancer recurrence in women with clinically uterine-confined endometrial cancer in the era of sentinel lymph node (SLN) mapping., Methods: All consecutive women with clinically determined uterine-confined endometrial cancer who had lymph node assessment by either SLN mapping or traditional pelvic lymphadenectomy were reviewed., Results: Women in the SLN mapping group had lower total dissected pelvic nodes, lower incidence of para-aortic lymph node dissection, less intraoperative blood loss and lower complication rates, but a longer operation time compared to the traditional lymphadenectomy group. Para-aortic lymph node metastasis (hazard ratio = 7.60, p = 0.03) was the sole independent predictor for recurrence-free survival. In addition, the utilization of cytokeratin immunohistochemistry stain detected more lymph node metastases (adjusted odds ratio = 3.04, p = 0.03). Recurrence-free survival did not differ between SLN mapping and traditional lymphadenectomy groups ( p = 0.24)., Conclusions: Para-aortic lymph node metastasis is an important predictor of cancer recurrence. Women with negative hematoxylin and eosin stain should undergo cytokeratin immunohistochemistry stain to increase the detection rate of positive lymph node metastasis. Besides, the probabilities of recurrence seem to be similar between SLN mapping and traditional lymphadenectomy groups in women with clinically uterine-confined endometrial cancer.

Background: Novel therapies for relapsed or refractory follicular lymphoma are commonly evaluated in single-arm studies without formal comparison with other treatments or historical controls. Consequently, rigorously defined treatment outcomes informing expectations for novel therapeutic strategies in this population are sparse. To inform outcome expectations, we aimed to describe treatment patterns, survival outcomes, and duration of response in patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy., Methods: In this multicentre cohort study, we developed a database of patients with relapsed or refractory follicular lymphoma from eight academic centres in the USA using data collected in the LEO Cohort study (NCT02736357) and the LEO Consortium. For this analysis, eligible patients were aged at least 18 years, had non-transformed grade 1-3a follicular lymphoma, and were receiving systemic therapy in the third line or later after previous therapy with an anti-CD20 antibody and an alkylating agent. Clinical data and patient outcomes were abstracted from medical records by use of a standard protocol. The index therapy for the primary analysis was defined as the first line of systemic therapy after the patient had received at least two previous systemic therapies that included an alkylating agent and an anti-CD20 therapy. The main endpoints of interest were overall response rate, progression-free survival, and overall survival. Outcomes were also evaluated in subsets of clinical interest (index therapy characteristics, patient and disease characteristics, treatment history, and best response assessment)., Findings: We screened 933 patients with follicular lymphoma, of whom 441 were included and diagnosed between March 6, 2002, and July 20, 2018. Index therapies included immunochemotherapy (n=133), anti-CD20 antibody monotherapy (n=53), lenalidomide with or without anti-CD20 (n=37), and phosphoinositide 3-kinase inhibitors with or without anti-CD20 (n=25). 57 (13%) of 441 patients received haematopoietic stem-cell transplantation and 98 (23%) of 421 patients with complete data received therapy on clinical trials. After a median follow-up of 71 months (IQR 64-79) from index therapy, 5-year overall survival was 75% (95% CI 70-79), median progression-free survival was 17 months (15-19), and the overall response rate was 70% (65-74; 280 of 400 patients evaluable for response). Patients who were refractory to therapy with an alkylating agent had a lower overall response rate (170 [68%] of 251 patients vs 107 [77%] of 139 patients) and a significantly lower 5-year overall survival (72%, 95% CI 66-78 vs 81%, 73-89; hazard ratio 1·60, 95% CI 1·04-2·46) than patients who were not refractory to therapy with an alkylating agent., Interpretation: Patients with relapsed or refractory follicular lymphoma receive heterogeneous treatments in the third-line setting or later. We observed high response rates to contemporary therapies that were of short duration. These data identify unmet needs among patients with follicular lymphoma, especially those who are refractory to alkylating agents, and might provide evidence by which clinical trials evaluating novel treatments could be assessed., Funding: Genentech and the National Cancer Institute., Competing Interests: Declaration of interests CC reports research funding from Gilead Sciences, Bristol Myers Squibb, Verastem, and GNE. ISL is on advisory boards for Seattle Genetics, Janssen Scientific, and Verastem. YW reports that research funding has been provided to his institution from Incyte, InnoCare, LOXO Oncology, Novartis, and Genentech, and advisory board membership for Lilly Oncology, Incyte/MorphoSys, and TG Therapeutics (but was not personally compensated for his participation). LJN reports honorarium from ADC Therapeutics, Bayer, Bristol Myers Squibb/Celgene, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, Morphosys, Novartis, Pfizer, Takeda, and TG Therapeutics, and research funding from Bristol Myers Squibb/Celgene, Caribou Biosciences, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, IGM Biosciences, Novartis, Pfizer, Takeda, and TG Therapeutics. CS reports honorarium from Bristol Myers Squibb. DC reports honorarium from AstraZeneca. PM reports research funding from Karyopharm and consultancy for ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Cellectar, Epizyme, Gilead Sciences, Incyte, Janssen, Karyopharm, Regeneron, Takeda, Teneobio, and Verastem. JBC reports research funding and advisory board membership for Genentech. BSK reports research funding and consultancy for F. Hoffmann-La Roche and Genentech. JLK reports research funding from the American Association for Cancer Research (underwritten by Pharmacyclics, an AbbVie Company, and Janssen Biotech), the Lymphoma Research Foundation (underwritten by Celgene), Oncternal Therapeutics, and Viracta Therapeutics, and advisory board membership for Janssen Biotech. YM, AM, MW, MCW, AS, and JL report employment by Genentech and ownership of shares in F. Hoffmann-La Roche. JC reports research funding from GNE, NanoString, and Celgene/Bristol Myers Squibb, and advisory board membership for Celgene/Bristol Myers Squibb. CRF reports research funding from 4D, AbbVie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech, F. Hoffmann-La Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, the Eastern Cooperative Oncology Group, the National Cancer Institute, the V Foundation, and Cancer Prevention and Research Institute of Texas Scholar in Cancer Research, and consultancy for AbbVie, Bayer, BeiGene, Celgene, Denovo Biopharma, Genentech, F. Hoffmann-La Roche, Genmab, Gilead Sciences, Karyopharm, Pharmacyclics/Janssen, SeaGen, and Spectrum. BKL is a consultant for Genentech. MJM reports research funding from Morphosys, Genentech, Bristol Myers Squibb, and Nanostring, and is an advisory board member for Pfizer, Morphosys, and Kite Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs)., Methods: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response., Results: Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively., Conclusion: Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study., Competing Interests: Lihua E. BuddeConsulting or Advisory Role: Roche/Genentech, Kite/Gilead, Novartis, BeiGeneResearch Funding: Merck, Amgen, MustangBio, AstraZenecaPatents, Royalties, Other Intellectual Property: CCR4 CAR T cells for treatment of patients with CCR4-positive cancer. CD33CAR for treatment of patients with CD33+ acute myeloid leukemiaTravel, Accommodations, Expenses: Roche/Genentech, Kite/Gilead, AstraZeneca Sarit AssoulineStock and Other Ownership Interests: Knight PharmaceuticalsHonoraria: Janssen Oncology, Pfizer, AbbVie, Novartis Canada Pharmaceuticals Inc, AstraZeneca, BMSConsulting or Advisory Role: Roche/Genentech, BeiGeneResearch Funding: Roche Canada (Inst), Takeda (Inst), Astex Pharmaceuticals (Inst), BeiGene (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Roche Canada Laurie H. SehnHonoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite, a Gilead company, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda, Teva, TG Therapeutics, AstraZeneca, Acerta Pharma, morphosys, Incyte, Debiopharm Group, Sandoz-Novartis, Verastem, GenmabConsulting or Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Lundbeck, Amgen, apobiologix, Karyopharm Therapeutics, Kite, a Gilead company, Merck, Takeda, Teva, TG therapeutics, AstraZeneca, Acerta Pharma, MorphoSys, Incyte, Debiopharm Group, Sandoz-Novartis, Genmab, VerastemResearch Funding: Roche/Genentech (Inst), Teva (Inst) Stephen J. SchusterConsulting or Advisory Role: Celgene, Nordic Nanovector, Novartis, AbbVie, Acerta Pharma/AstraZeneca, Alimera Sciences, BeiGene, Juno Therapeutics, Loxo Oncology, Tessa Therapeutics, Genentech/RocheResearch Funding: Novartis (Inst), Pharmacyclics (Inst), Adaptive Biotechnologies (Inst), Merck (Inst), Genentech/Roche (Inst), Celgene (Inst), Juno Therapeutics (Inst), AbbVie (Inst), Incyte (Inst), TG Therapeutics (Inst), DTRM (Inst)Patents, Royalties, Other Intellectual Property: Patent Combination Therapies of CAR and PD-1 Inhibitors (via University of Pennsylvania with royalties to Novartis) Sung-Soo YoonHonoraria: NovartisConsulting or Advisory Role: Janssen, Takeda, Amgen, Celgene/JazzResearch Funding: Kyowa Kirin, Roche/Genentech, Yuhan Dok Hyun YoonHonoraria: Celltrion, Roche, Janssen, Amgen, Celgene, Samyang, Kirin Pharmaceuticals, TakedaConsulting or Advisory Role: Roche, Janssen, Amgen, Celgene, Green Cross, NovartisResearch Funding: Samyang, Abclone, Roche/Genentech, Janssen Oncology, Amgen, Genmab, Boryung, Eutilex Matthew J. MatasarStock and Other Ownership Interests: MerckHonoraria: Genentech, Roche, Bayer, Pharmacyclics, Seattle Genetics, Takeda, Immunovaccine, ADC Therapeutics, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, TakedaResearch Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM Biosciences , IGM BiosciencesTravel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer Francesc BoschConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Janssen-Cilag, Lilly, AbbVie, Kite, a Gilead company, BeiGene, NovartisSpeakers' Bureau: AbbVie, Janssen, Roche, AstraZenecaResearch Funding: Janssen, AstraZeneca Loretta J. NastoupilHonoraria: Celgene, Gilead Sciences, Novartis, Bayer, Janssen Oncology, Pfizer, Gamida Cell, TG Therapeutics, Bristol Myers Squibb, ADC Therapeutics, Morphosys, Epizyme, GenmabResearch Funding: TG Therapeutics, Janssen Biotech, Celgene, Genentech/Roche, LAM Therapeutics, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Ian W. FlinnConsulting or Advisory Role: AbbVie (Inst), Seattle Genetics (Inst), TG Therapeutics (Inst), Verastem (Inst), Roche (Inst), Gilead Sciences (Inst), Kite, a Gilead company (Inst), Janssen (Inst), BeiGene (Inst), Takeda (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Nurix (Inst), Shanghai Yingli Pharmaceuticals (Inst), Genentech (Inst), Great Point Partners (Inst), Iksuda Therapeutics (Inst), Novartis (Inst), Pharmacyclics (Inst), Century Therapeutics (Inst), Hutchison MediPharma (Inst), SERVIER (Inst), Vincerx Pharma (Inst), Genmab (Inst), InnoCare Pharma (Inst)Research Funding: Acerta Pharma (Inst), Agios (Inst), Calithera Biosciences (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst), Genentech (Inst), Gilead Sciences (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Janssen (Inst), Karyopharm Therapeutics (Inst), Kite, a Gilead company (Inst), Novartis (Inst), Pharmacyclics (Inst), Portola Pharmaceuticals (Inst), Roche (Inst), TG Therapeutics (Inst), Trillium Therapeutics (Inst), AbbVie (Inst), ArQule (Inst), BeiGene (Inst), Curis (Inst), FORMA Therapeutics (Inst), Forty Seven (Inst), Merck (Inst), Pfizer (Inst), Takeda (Inst), Teva (Inst), Verastem (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Seattle Genetics (Inst), IGM Biosciences (Inst), Loxo (Inst), Rhizen Pharmaceuticals (Inst), Triact Therapeutics (Inst) Mazyar ShadmanConsulting or Advisory Role: AbbVie, Genentech, AstraZeneca, Sound Biologics, Cellectar, Pharmacyclics, BeiGene, Bristol Myers Squibb/Celgene, MorphoSys, Innate Pharma, Kite, a Gilead company, Adaptive Biotechnologies, EpizymeResearch Funding: Pharmacyclics (Inst), Acerta Pharma (Inst), Merck (Inst), TG Therapeutics (Inst), BeiGene (Inst), Celgene (Inst), Genentech (Inst), MustangBio (Inst), AbbVie (Inst), Sunesis Pharmaceuticals (Inst), Bristol Myers Squibb/Celgene Catherine DiefenbachStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Seattle Genetics, Bayer, Bristol Myers Squibb, Genentech/Roche, Merck, Janssen, Celgene, MorphoSysResearch Funding: Seattle Genetics (Inst), Genentech (Inst), Incyte (Inst), LAM Therapeutics (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Millennium (Inst), Roche/Genentech (Inst), Janssen (Inst), MEI Pharma (Inst), Trillium Therapeutics (Inst), Astex Pharmaceuticals (Inst)Expert Testimony: Jim Harmon Carol O'HearEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/RochePatents, Royalties, Other Intellectual Property: Antibody bufferingTravel, Accommodations, Expenses: Genentech/Roche Huang HuangEmployment: Roche Canada Antonia KwanEmployment: Genentech/RocheStock and Other Ownership Interests: Roche/Genentech Chi-Chung LiEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechPatents, Royalties, Other Intellectual Property: Patent applications pertaining to the development and dosing of bispecific antibodies Emily C. PiccioneEmployment: GenentechStock and Other Ownership Interests: Roche/Genentech Michael C. WeiEmployment: Genentech/RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Genentech/Roche Shen YinEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: Genentech Nancy L. BartlettConsulting or Advisory Role: Seattle Genetics, Roche/Genentech, ADC Therapeutics, BTG, Acerta PharmaResearch Funding: Seattle Genetics (Inst), Kite, a Gilead company (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Immune Design (Inst), Forty Seven (Inst), Janssen (Inst), Pharmacyclics (Inst), Millennium (Inst), ADC Therapeutics (Inst), Autolus (Inst), Roche/Genentech (Inst), Pfizer (Inst), Affimed Therapeutics (Inst)No other potential conflicts of interest were reported.

A procedure combining supercritical CO 2 and ultrasound-assisted (USC-CO 2 ) extraction was developed to obtain rosmarinic acid (RA)-rich extracts from Perilla frutescens. Based on extraction yields and efficiencies, USC-CO 2 was considered the best extraction method among the methods studied for obtaining RA from P. frutescens. The constant extraction rate period and the falling extraction rate period for USC-CO 2 extraction of P. frutescens were 45 and 96 min long, respectively, and they were significantly shorter than those of traditional SC-CO 2 (TSC-CO 2 ) extraction. Furthermore, mass transfer coefficients were derived using the Sovová model for the fluid and solid phases from USC-CO 2 extraction, with values of 9.752 × 10 -3 and 4.203 × 10 -3  min -1 , respectively, which were obviously higher than those for TSC-CO 2 extraction. Consequently, the theoretical solubilities of RA in the supercritical solvents used in dynamic USC-CO 2 and TSC-CO 2 extractions were estimated and found to be well correlated using three density-based models., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Increasing the vertical dimension of occlusion (VDO) is a common procedure in complicated prosthodontic treatment. The swallowing technique had been verified as a functional method to determine the VDO. The purpose of this study was to investigate the association between increasing VDO and mandibular movement during swallowing., Methods: 26 females and 14 males were enrolled (age range: 21 to 30 year-old). Under different increased VDO (3, 5, and 8 mm), the mandibular trajectory during swallowing was measured by K7 Evaluation System (Myotronics®). When the subjects were instructed to salivary swallowing, the range of mandibular movement in vertical, anteroposterior and lateral directions were recorded., Results: Increasing VDO significantly impacted the range of mandibular movement in lateral direction during swallowing (p < 0.0001, F value = 40.09). The average variance of the mandibular movement distance in lateral direction during swallowing raise 1.58 (p = 0.001); 3.59 (p = 0.0001) and 2.01 (p = 0.001) when th VDO was raised from 3 mm to 5 mm; from 3 mm to 8 mm and from 5 to 8 mm respectively. The range of mandibular movement was significantly correlated to the increasing VDO (p ≤ 0.05) under the analysis of the Post Hoc test., Conclusions: VDO was closely correlated to the trajectory of mandibular motion during swallowing. The increase in VDO could change the extent of mandibular trajectory during swallowing if the increase was more than 3 mm. The range of mandibular motion when swallowing had positive correlative tendency as the VDO was increased., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Purpose: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA -mutant cancers with the isoform-specific PI3K inhibitor taselisib., Patients and Methods: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed., Results: A total of 166 patients with PIK3CA -mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront ( TP53 and PTEN ) and postprogression through reactivation of the PI3K pathway ( PTEN, STK11 , and PIK3R1 ). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index., Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA -mutant tumors., (©2020 American Association for Cancer Research.)

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115 -/- organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115 -/- cells compared to the wild-type counterparts. Consequently, the Rnf115 -/- mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.

Background: to elucidate the predictors of progression-free survival (PFS) and overall survival (OS) in high-risk endometrial cancer patients. Methods: the medical records of all consecutivewomen with high-risk endometrial cancer were reviewed. Results: among 92 high-risk endometrial cancer patients, 30 women experienced recurrence, and 21 women died. The 5-year PFS and OS probabilities were 65.3% and 75.9%, respectively. Multivariable Cox regression revealed that body mass index (hazard ratio (HR) = 1.11), paraaortic lymph node metastasis (HR = 11.11), lymphovascular space invasion (HR = 5.61), and sandwich chemoradiotherapy (HR = 0.15) were independently predictors of PFS. Body mass index (HR = 1.31), paraaortic lymph node metastasis (HR = 32.74), non-endometrioid cell type (HR = 11.31), and sandwich chemoradiotherapy (HR = 0.07) were independently predictors of OS. Among 51 women who underwent sandwich ( n = 35) or concurrent ( n = 16) chemoradiotherapy, the use of sandwich chemoradiotherapy were associated with better PFS (adjusted HR = 0.26, 95% CI = 0.08-0.87, p = 0.03) and OS (adjusted HR = 0.11, 95% CI = 0.02-0.71, p = 0.02) compared with concurrent chemoradiotherapy. Conclusion: compared with concurrent chemoradiotherapy, sandwich chemoradiotherapy was associated with better PFS and OS in high-risk endometrial cancer patients. In addition, high body mass index, paraaortic lymph node metastasis, and non-endometrioid cell type were also predictors of poor OS in high-risk endometrial cancer patients.

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis ( S. suis ) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates ( n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log 10 CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection.

An ultrasound-assisted supercritical carbon dioxide (USC-CO 2 ) procedure was developed for the extraction of ursolic acid, oleanolic acid and oridonin from Rabdosia rubescens, with yields that were 9.84-10.46 and 15.43-21.10% higher than those of the conventional SC-CO 2 and heat-reflux extractions, respectively. USC-CO 2 uses a shorter extraction time (1.83-2.09 times) and less organic solvent (3.39-173.25 times) to operate at a lower extraction temperature (5-16 °C). The dominant component in the extract was oridonin, which may indicate that the kinetic behavior in the extraction system is predominated by that of oridonin. Furthermore, the USC-CO 2 and conventional SC-CO 2 dynamic extraction kinetics of oridonin from R. rubescens were well described by the second-order rate and Fick's second law models. The extraction rate constant, energy of activation for diffusion, Biot number and thermodynamic parameters were deduced from the data obtained. These results provide valuable insights into the USC-CO 2 and conventional SC-CO 2 procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We aimed to determine the influence of osteoporosis and stress urinary incontinence in women. We hypothesized that women with osteoporosis had an increased risk of stress urinary incontinence. This retrospective study used data from the Taiwan Longitudinal Health Insurance database from 2005-2009. The study population was screened to identify women (age ≥ 40 years) newly diagnosed with osteoporosis (ICD-9-CM code = 733.0, 733.1). The osteoporosis cohort included 6125, and the non-osteoporosis cohort included 12,250 participants. The newly diagnosed stress urinary incontinence incidence was calculated to determine the influence of osteoporosis and stress urinary incontinence. We used the Cox proportional hazards model to predict the effects of stress urinary incontinence and the Kaplan-Meier analysis to estimate the cumulative incidence of stress urinary incontinence in women. Participants with osteoporosis experienced a 1.79 times higher risk than that of the non-osteoporosis group (95% CI = 1.28-2.51) for stress urinary incontinence, regardless of age. We did not observe a higher risk of stress urinary incontinence in participants with pathological fractures compared to those with simple osteoporosis. Our data emphasized that physicians and nurses should conduct urinary incontinence screening in women with osteoporosis to recommend proper treatment, medical help or to bring the disorder to light.

Background: We aimed to compare the clinical outcomes between intraperitoneal chemotherapy and dose-dense chemotherapy for the frontline treatment of advanced ovarian, fallopian tube and primary peritoneal cancer in women not receiving bevacizumab. Methods: All consecutive women with stage II~IV cancer treated with either frontline intraperitoneal or dose-dense platinum/paclitaxel chemotherapy and not receiving bevacizumab between March 2006 and June 2019 were reviewed. Results: A total of 50 women (intraperitoneal group, n = 22; dose-dense group, n = 28) were reviewed. Median progression-free survival (32.6 months versus 14.2 months; adjusted hazard ratio = 0.38; 95% CI = 0.16 to 0.90, p = 0.03) and overall survival (not reached versus 30.7 months; adjusted hazard ratio = 0.23, 95% CI = 0.07 to 0.79, p = 0.02) were significantly higher in the intraperitoneal group than in the dose-dense group. A multivariable Cox proportional-hazards model also indicated that the number of frontline chemotherapy cycles (adjusted hazard ratio = 0.66, 95% CI 0.47 to 0.94, p = 0.02) was a predictor of better overall survival. Nausea/vomiting and nephrotoxicity occurred more frequently in the intraperitoneal group ( p = 0.02 and <0.0001, respectively). Conclusions: Intraperitoneal chemotherapy seems to be superior in progression free survival and overall survival to dose-dense chemotherapy in the frontline treatment of women with optimally resected advanced ovarian, fallopian tube or primary peritoneal cancer and not receiving bevacizumab.

Blood pressure (BP) control is crucial for minimizing the risk of mortality and hematoma growth in patients with acute intracranial hemorrhage (ICH). We aimed to determine the optimal BP range associated with improved patient outcomes. From the Medical Information Mart for Intensive Care-III database, we identified 1493 patients (age, 18-99 years) admitted to the intensive care unit (ICU) with non-traumatic ICH. The 3-day and 14-day mortality of ICU admissions were compared at different BP ranges. Generalized additive models were used to assess the optimal range of initial mean arterial pressure, systolic blood pressure (SBP), and diastolic blood pressure, and these were identified to be 70-100, 120-150, and 60-100 mmHg, respectively. The 3-day or 14-day mortality showed U-shaped correlations with BP ranges. Our results show that an initial SBP between 120 and 150 mmHg is associated with minimal risk of mortality risk. This recommendation can assist physicians to achieve better outcomes for patients with ICH., Competing Interests: The authors declare no conflict of interest.

Purpose: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC)., Methods: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment., Results: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m 2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m 2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents., Conclusions: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Chromosomal rearrangements involving the mixed lineage leukemia ( MLL ) gene, also known as KMT2A , are often observed in human leukemias and are generally associated with a poor prognosis. To model these leukemias, we applied clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL chromosomal rearrangements in human hematopoietic stem and progenitor cells purified from umbilical cord blood. Electroporation of ribonucleoprotein complexes containing chemically modified synthetic single guide RNAs and purified Cas9 protein induced translocations between chromosomes 9 and 11 [t(9;11)] at an efficiency >1%. Transplantation of gene-edited cells into immune-compromised mice rapidly induced acute leukemias of different lineages and often with multiclonal origins dictated by the duration of in vitro culture prior to transplantation. Breakpoint junction sequences served as biomarkers to monitor clonal selection and progression in culture and in vivo. High-dimensional cell surface and intracellular protein analysis by mass cytometry (CyTOF) revealed that gene-edited leukemias recapitulated disease-specific protein expression observed in human patients and showed that MLL -rearranged ( MLLr ) mixed phenotype acute leukemias (MPALs) were more similar to acute myeloid leukemias (AMLs) than to acute lymphoblastic leukemias (ALLs). Therefore, highly efficient generation of MLL chromosomal translocations in primary human blood stem cells using CRISPR/Cas9 reliably models human acute MLLr leukemia and provides an experimental platform for basic and translational studies of leukemia biology and therapeutics., (© 2019 by The American Society of Hematology.)

Objectives: The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes., Methods: To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs)., Results: Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs., Conclusions: The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph + acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR + ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR + ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR + ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL. Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg Cancer Res; 78(22); 6497-508. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer. Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1. Results: Median treatment duration was 4.6 (range: 0.9-40.5) months. All patients experienced ≥1 AE, 30 (50.0%) had grade ≥3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9-68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9-68.4)], PIK3CA -MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0-36.3); CBR: 23.8% (5/21; 95% CI, 8.2-47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5-55.6); CBR: 30.0% (3/10; 95% CI, 6.7-65.2)]. Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA -mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380-7. ©2018 AACR ., (©2018 American Association for Cancer Research.)

This study compared the use of ultrasound-assisted supercritical CO 2 (USC-CO 2 ) extraction to obtain apigenin-rich extracts from Scutellaria barbata D. Don with that of conventional supercritical CO 2 (SC-CO 2 ) extraction and heat-reflux extraction (HRE), conducted in parallel. This green procedure yielded 20.1% and 31.6% more apigenin than conventional SC-CO 2 extraction and HRE, respectively. Moreover, the extraction time required by the USC-CO 2 procedure, which used milder conditions, was approximately 1.9 times and 2.4 times shorter than that required by conventional SC-CO 2 extraction and HRE, respectively. Furthermore, the theoretical solubility of apigenin in the supercritical fluid system was obtained from the USC-CO 2 dynamic extraction curves and was in good agreement with the calculated values for the three empirical density-based models. The second-order kinetics model was further applied to evaluate the kinetics of USC-CO 2 extraction. The results demonstrated that the selected model allowed the evaluation of the extraction rate and extent of USC-CO 2 extraction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: All Singaporean males undergo medical screening prior to compulsory military service. A history of possible food allergy may require referral to a specialist Allergy clinic to ensure that special dietary needs can be taken into account during field training and deployment., Objective: To study the pattern of food allergy among pre-enlistees who were referred to a specialist allergy clinic to work up suspected food allergy., Methods: Retrospective study of all pre-enlistees registered in the Clinical Immunology/Allergy New Case Registry referred to the Allergy Clinic from 1 August 2015 to 31 May 2016 for suspected food allergy., Results: One hundred twenty pre-enlistees reporting food allergy symptoms other than rash alone were referred to the Allergy Clinic during the study period. Of these, 77 (64.2%) had food allergy. Among those with food allergy, mean age was 19.1 ± 1.5 years. They comprised predominantly Chinese (66.2%) and Malays (20.8%). The most commonly reported foods were shellfish/crustaceans (78%), peanut (15.6%), and egg (6.5%). Self-limiting oral allergy syndrome, OAS (itchy lips and throat with/without lip angioedema) was the most common manifestation (n = 33, 42.9%) followed by anaphylaxis (n = 23, 29.9%). Majority of OAS was from shellfish/crustacean (90.6%); of which shrimp (30.3%), crab (15.2%), and lobster (3.0%) were the most common. Mild childhood asthma (69.7%), allergic rhinitis (6.3%), and eczema (6.1%) were the most common atopic conditions among individuals with shellfish/crustacean OAS. This pattern was similar for shellfish/crustacean anaphylaxis. Skin prick tests were most commonly positive for shrimp (OAS 87.1% vs. anaphylaxis 100%), crab (OAS 95.8% vs. 90.9%), and lobster (OAS 91.7% vs. 63.6%)., Conclusion: OAS to shellfish/crustaceans was more common than anaphylaxis among this study population of young males referred for food allergy symptoms other than rash alone.

Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR + ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Medulla oblongata dysplasia is an extremely rare form of neurodevelopmental immaturity in premature infants. Intracranial hemorrhage in premature infants may be closely related to neurodevelopmental immaturity., Diagnoses: We report a female premature infant who succumbed to intracranial hemorrhage caused by medulla oblongata dysplasia., Patient Concerns: The infant was born at 31 weeks gestation. The onset manifestation was symptomatic epilepsy associated with subependymal hemorrhage., Interventions: Levetiracetam and sodium valproate were administered. During the hospitalization, hydrocephalus developed and the intracranial hemorrhage aggravated., Outcomes: The infant died on day 171 after birth., Lessons: Early identification and prompt treatment should be emphasized. Clinicians should be aware of this condition, as it can potentially cause neonatal intracranial hemorrhage.