bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Authors: Zhang Songfa , Yan Chuan , Millar David G. , Yang Qiqi , Heather James M. , Langenbucher Adam , Morton Laura T. , Sepulveda Sean , Alpert Eric , Whelton Lauren R. , Zarrella Dominique T. , Guo Mei , Minogue Eleanor , Lawrence Michael S. , Rueda Bo R. , Spriggs David R. , Lu Weiguo , Langenau David M. , Cobbold Mark
Published: December 2021

Antibody–peptide epitope conjugates (APEC) are a new class of modified antibody–drug conjugates that redirect T-cell viral immunity against tumor cells. APECs contain a tumor-specific protease cleavage site linked to a patient-specific viral epitope, resulting in presentation of viral epitopes on cancer cells and subsequent recruitment and killing by CD8+ T cells. Here we developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Using functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus (CMV) in patients with ovarian cancer, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. Each APEC was tested for in vitro cancer cell killing, and top candidates were screened for killing xenograft tumors grown in zebrafish and mice. These preclinical modeling studies identified EpCAM-MMP7-CMV APEC (EpCAM-MC) as a potential new immunotherapy for ovarian carcinoma. Importantly, EpCAM-MC also demonstrated robust T-cell responses in primary ovarian carcinoma patient ascites samples. This work highlights a robust, customizable platform to rapidly develop patient-specific APECs.

Significance:

This study develops a high-throughput preclinical platform to identify patient-specific antibody–peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma.
AMPK–mTOR–Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells
Authors: You Bo , Xia Tian , Gu Miao , Zhang Zhenxin , Zhang Qicheng , Shen Jianhong , Fan Yue , Yao Hui , Pan Si , Lu Yingna , Cheng Tianyi , Yang Zhiyuan , He Xin , Zhang Hao , Shi Muqi , Liu Dong , You Yiwen
Published: December 2021

Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer.

Significance:

Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.
The Effect of Corticosteroids on Prostate Cancer Outcome Following Treatment with Enzalutamide: A Multivariate Analysis of the Phase III AFFIRM Trial
Authors: Zhao Jimmy L. , Fizazi Karim , Saad Fred , Chi Kim N. , Taplin Mary-Ellen , Sternberg Cora N. , Armstrong Andrew J. , de Bono Johann S. , Duggan William T. , Scher Howard I.
Published: December 2021

Purpose:

The clinical impact of concurrent corticosteroid use (CCU) on enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) is unknown. We investigated the association of CCU with overall survival (OS), radiographic progression-free survival (rPFS), and time to prostate-specific antigen progression (TTPP) in post-chemotherapy, enzalutamide-treated patients with mCRPC.

Patients and Methods:

Post hoc analysis of AFFIRM (NCT00974311) with patients (n = 1,199) randomized 2:1 to enzalutamide 160 mg/day or placebo. Treatment group, CCU, and known prognostic factors were evaluated for impact on OS, rPFS, and TTPP using a multivariate Cox proportional hazards model. CCU was defined as “baseline” (use started at baseline) or “on-study” (baseline plus use that was started during the trial).

Results:

Enzalutamide significantly improved OS, rPFS, and TTPP independent of baseline CCU but was associated with inferior clinical outcomes when compared with no baseline CCU, including a shorter OS [10.8 months vs. not reached (NR); HR for use vs. no use, 2.13; 95% confidence interval (CI), 1.79–2.54], rPFS (5.2 months vs. 8.0 months; HR, 1.49; 95% CI, 1.29–1.72], and TTPP (4.6 months vs. 5.7 months; HR, 1.50; 95% CI, 1.25–1.81). These findings held in a multivariate analysis adjusting for baseline prognostic factors wherein baseline CCU was independently associated with decreased OS (HR, 1.71; 95% CI, 1.43–2.04; P < 0.0001) and rPFS (HR, 1.28; 95% CI, 1.11–1.48; P = 0.0007).

Conclusions:

Patients with mCRPC benefited from enzalutamide treatment independent of CCU, but CCU was associated with worse baseline prognostic factors and outcomes.
Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial
Authors: Cohen Ezra E.W. , Nabell Lisle , Wong Deborah J. , Day Terry , Daniels Gregory A. , Milhem Mohammed , Deva Sanjeev , Jameson Michael , Guntinas-Lichius Orlando , Almubarak Mohammed , Strother Matthew , Whitman Eric , Chisamore Michael , Obiozor Cynthia , Bagulho Teresa , Gomez-Romo Jose , Guiducci Cristiana , Janssen Robert , Gamelin Erick , Algazi Alain P.
Published: December 2021

Purpose:

To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

Patients and Methods:

Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks.

Results:

A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively.

Conclusions:

SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.
Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)
Authors: Nixon Andrew B. , Halabi Susan , Liu Yingmiao , Starr Mark D. , Brady John C. , Shterev Ivo , Luo Bin , Hurwitz Herbert I. , Febbo Phillip G. , Rini Brian I. , Beltran Himisha , Small Eric J. , Morris Michael J. , George Daniel J.
Published: December 2021

Purpose:

CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit.

Patients and Methods:

A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC).

Results:

A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P < 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P < 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0–13.8] and 34.3 (95% CI, 28.5–40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79).

Conclusions:

IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials.

See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725
Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)
Authors: Nixon Andrew B. , Sibley Alexander B. , Liu Yingmiao , Hatch Ace J. , Jiang Chen , Mulkey Flora , Starr Mark D. , Brady John C. , Niedzwiecki Donna , Venook Alan P. , Baez-Diaz Luis , Lenz Heinz-Josef , O'Neil Bert H. , Innocenti Federico , Meyerhardt Jeffrey A. , O'Reilly Eileen M. , Owzar Kouros , Hurwitz Herbert I.
Published: December 2021

Purpose:

CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.

Patients and Methods:

In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.

Results:

In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097).

Conclusions:

In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.

See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725
Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
Authors: Bergamino Milana A. , Morani Gabriele , Parker Joel , Schuster Eugene F. , Leal Mariana F. , López-Knowles Elena , Tovey Holly , Bliss Judith M. , Robertson John F.R. , Smith Ian E. , Dowsett Mitch , Cheang Maggie C.U.
Published: December 2021

Purpose:

Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor–positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs.

Experimental Design:

Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors.

Results:

The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study.

Conclusions:

Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.
Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial
Authors: Lu Yen-Shen , Im Seock-Ah , Colleoni Marco , Franke Fabio , Bardia Aditya , Cardoso Fatima , Harbeck Nadia , Hurvitz Sara , Chow Louis , Sohn Joohyuk , Lee Keun Seok , Campos-Gomez Saul , Villanueva Vazquez Rafael , Jung Kyung Hae , Babu K. Govind , Wheatley-Price Paul , De Laurentiis Michelino , Im Young-Hyuck , Kuemmel Sherko , El-Saghir Nagi , O'Regan Ruth , Gasch Claudia , Solovieff Nadia , Wang Craig , Wang Yongyu , Chakravartty Arunava , Ji Yan , Tripathy Debu
Published: December 2021

Purpose:

Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).

Patients and Methods:

Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods.

Results:

The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI.

Conclusions:

Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).
Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
Authors: Klemen Nicholas D. , Hwang Sinchun , Bradic Martina , Rosenbaum Evan , Dickson Mark A. , Gounder Mrinal M. , Kelly Ciara M. , Keohan Mary L. , Movva Sujana , Thornton Katherine A. , Chi Ping , Nacev Benjamin A. , Chan Jason E. , Bartlett Edmund K. , Richards Allison L. , Singer Samuel , Donoghue Mark T.A. , Tap William D. , D'Angelo Sandra P.
Published: December 2021

Purpose:

Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors.

Experimental Design:

We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD.

Results:

We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline.

Conclusions:

In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.
Local Treatment of a Pediatric Osteosarcoma Model with a 4-1BBL Armed Oncolytic Adenovirus Results in an Antitumor Effect and Leads to Immune Memory
Authors: Martinez-Velez Naiara , Laspidea Virginia , Zalacain Marta , Labiano Sara , García-Moure Marc , Puigdelloses Montse , Marrodan Lucía , Gonzalez-Huarriz Marisol , Herrador Guillermo , de la Nava Daniel , Ausejo-Mauleon Iker , Fueyo Juan , Gomez-Manzano Candelaria , Patiño-García Ana , Alonso Marta M.
Published: December 2021

Osteosarcoma is an aggressive bone tumor occurring primarily in pediatric patients. Despite years of intensive research, the outcomes of patients with metastatic disease or those who do not respond to therapy have remained poor and have not changed in the last 30 years. Oncolytic virotherapy is becoming a reality to treat local and metastatic tumors while maintaining a favorable safety profile. Delta-24-ACT is a replicative oncolytic adenovirus engineered to selectively target cancer cells and to potentiate immune responses through expression of the immune costimulatory ligand 4-1BB. This work aimed to assess the antisarcoma effect of Delta-24-ACT. MTS and replication assays were used to quantify the antitumor effects of Delta-24-ACT in vitro in osteosarcoma human and murine cell lines. Evaluation of the in vivo antitumor effect and immune response to Delta-24-ACT was performed in immunocompetent mice bearing the orthotopic K7M2 cell line. Immunophenotyping of the tumor microenvironment was characterized by immunohistochemistry and flow cytometry. In vitro, Delta-24-ACT killed osteosarcoma cells and triggered the production of danger signals. In vivo, local treatment with Delta-24-ACT led to antitumor effects against both the primary tumor and spontaneous metastases in a murine osteosarcoma model. Viral treatment was safe, with no noted toxicity. Delta-24-ACT significantly increased the median survival time of treated mice. Collectively, our data identify Delta-24-ACT administration as an effective and safe therapeutic strategy for patients with local and metastatic osteosarcoma. These results support clinical translation of this viral immunotherapy approach.
Deciphering the Polygenic Basis of Racial Disparities in Prostate Cancer By an Integrative Analysis of Genomic and Transcriptomic Data
Authors: Zhang Wensheng , Nicholson Thea , Zhang Kun
Published: December 2021

Prostate cancer prevalence in African Americans (AA) is over 1.5 times the prevalence in European Americans (EA). Among over a hundred index risk SNPs for prostate cancer, only a few can be verified using the available AAs' data. Their relevance to the prevalence inequality and other racial disparities has not been fully determined. We investigated this issue by an integrative analysis of five public datasets. We categorized the datasets into two classes. The training class consisted of the datasets generated by three genome-wide association studies. The test class contained the prostate adenocarcinoma data of The Cancer Genome Atlas and the data of African and European super-populations in the 1000-Genome project. The polygenic risk scores (PRS) of test samples for cancer occurrence were calculated according to the effects of genetic variants estimated from the training samples. We obtained the following findings. Africans' PRSs are higher than Europeans' scores (P < 1 × 10−6). AA patients' PRSs are higher than EA patients' scores (P < 3×10−9). The patients with tumors presenting fusion or abnormal expression in ERG and other E26 transformation-specific (ETS) family genes have lower PRSs than the patients without such aberrations (P < 7×10−5). Five tumor progression-related genes have the expression levels being significantly correlated with PRS (FDR < 0.01). Additional simulation analysis shows that the high prostate cancer prevalence in African populations makes it challenging to identify individual risk variants using African men's data. These results implicate that the index risk SNP-based PRS is compatible with the observed racial disparity in prostate cancer prevalence and ETS abnormal cancers may be less heritable compared with other subtypes.

Prevention Relevance:

This study reveals the relevance of index risk SNP markers with racial disparities in prostate cancer. The findings also indicate that PRS can be used in prostate cancer subtype prediction.
Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials
Authors: Rink Lena , Adams Anne , Braun Cora , Bschor Tom , Kuhr Kathrin , Baethge Christopher
Published: December 2021

Introduction: Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. Objective: This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. Methods: A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers’ product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). Results: From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of –0.06 (–0.16 to 0.04) and –0.06 (–0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. Conclusion: Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.
Risk Factors for General Anesthesia Conversion in Anterior Circulation Stroke Patients Undergoing Endovascular Treatment
Authors: Geraldini Federico , De Cassai Alessandro , Napoli Margherita , Marini Silvia , De Bon Feliciana , Sergi Massimo , Pasin Laura , Correale Christelle , Gabrieli Joseph Domenico , Cester Giacomo , Viaro Federica , Pieroni Alessio , Causin Francesco , Baracchini Claudio , Navalesi Paolo , Munari Marina
Published: December 2021

Background and Purpose: No current consensus exists on the best anesthetic management of ischemic stroke patients undergoing mechanical thrombectomy. Both conscious sedation (CS) and general anesthesia (GA) are currently considered valid anesthetic strategies, yet patients managed under CS may require emergent conversion to GA, which has been associated with worse outcomes. The aim of this study was to analyze the conversion rate and potential risk factors for GA conversion during mechanical thrombectomy. Methods: Two-hundred and twenty-seven patients with consecutive acute anterior circulation ischemic stroke treated with mechanical thrombectomy and initiated under CS or local anesthesia were included in this retrospective analysis. Conversion rate to GA was calculated, while univariate and multivariate analysis were used to identify risk factors. Results: Twenty patients (8.8%) were switched to GA. Multivariate analysis identified procedure duration (odds ratio [OR] 1.01, 95% confidence interval [CI] 1.00–1.02, p value 0.028), tandem stroke (OR 8.57, 95% CI 2.06–35.7, p value 0.003), Sequential Organ Failure Assessment (SOFA) (OR 1.76, 95% CI 1.19–2.61, p value 0.005), and number of pharmacological agents used (OR 5.76, 95% CI 2.49–13.3, p value <0.001) as independently associated with conversion to GA. Conclusion: In our study, tandem occlusion, longer endovascular procedures, SOFA, and number of pharmacological agents used predicted the risk of emergent conversion to GA in stroke patients undergoing endovascular treatment. Prospective studies investigating optimal CS strategies are deemed necessary.
Three-Dimensional High-Resolution Temporal Bone Histopathology Identifies Areas of Vascular Vulnerability in the Inner Ear
Authors: Büki Bela , Mair Antonia , Pogson Jacob M. , Andresen Nicholas S. , Ward Bryan K.
Published: December 2021

Objectives: Hypothesized causes of vestibular neuritis/labyrinthitis include neuroinflammatory or vascular disorders, yet vascular disorders of the inner ear are poorly understood. Guided by known microvascular diseases of the retina, we developed 2 hypotheses: (1) there exist vascular vulnerabilities of artery channels in cases of hypothetical nerve swelling for the superior, inferior, and vestibulocochlear artery and (2) there are arteriovenous crossings that could compromise vascular flow in disease states. Methods: Two fully mounted and stained temporal bones were used to render three-dimensional reconstructions of the labyrinth blood supply. Using these maps, areas of potential vascular compression were quantified in 50 human temporal bones. Results: Although inner ear arteries and veins mostly travel within their own bony channels, they may be exposed (1) at the entrance into the otic capsule, and (2) where the superior vestibular vein crosses the inferior vestibular artery. At the entry into the otic capsule, the ratio of the soft tissue to total space for the superior vestibular artery was significantly greater than the inferior vestibular artery/cochleovestibular artery (median 44, interquartile range 34–55 vs. 14 [9–17], p < 0.0001). Conclusions: Three-dimensional reconstruction of human temporal bone histopathology can guide vascular studies of the human inner ear. Studies of retinal microvascular disease helped identify areas of vascular vulnerability in cases of hypothetical nerve swelling at the entrance into the otic capsule and at an arteriovenous crossing near the saccular macula. These data may help explain patterns of clinical findings in peripheral vestibular lesions.
Unicuspid Aortic Valve: A Rare Congenital Anomaly
Authors: Pan Jianhong
Published: December 2021

Unicuspid aortic valve (UAV) is a rare congenital aortic valve anomaly. It has 2 subtypes and often is associated with aortic valve dysfunction and corresponding clinical presentations. Echocardiography is the first choice of diagnostic method for UAV. Three-dimensional echocardiography has played an increasingly important role in diagnosis, intraprocedural guidance, and post-procedural assessment in recent years. There remain challenges in distinguishing UAV from bicuspid aortic valve or tricuspid aortic valve. Misdiagnosis is most resulted from raphes or leaflet calcifications. Multi-modality imaging has obvious advantages over single-modality imaging and is crucial for UAV diagnosis. Accurate identification of aortic valve morphology is important to choose the best treatment. Aortic balloon valvoplasty, surgical valvotomy, commissurotomy, Ross procedure, surgical valve repair, and surgical replacement are most common treatment modalities of UAV. In this review, we aim to discuss UAV including epidemiology, definition, classification, diagnostic importance and necessity, valvular function, clinical presentation, associated disorders, noninvasive diagnostic modalities, and therapeutic approaches.
Surgery versus Radiofrequency Ablation for Small Hepatocellular Carcinoma: A Randomized Controlled Trial (SURF Trial)
Authors: Takayama Tadatoshi , Hasegawa Kiyoshi , Izumi Namiki , Kudo Masatoshi , Shimada Mitsuo , Yamanaka Naoki , Inomata Masafumi , Kaneko Shuichi , Nakayama Hisashi , Kawaguchi Yoshikuni , Kashiwabara Kosuke , Tateishi Ryosuke , Shiina Shuichiro , Koike Kazuhiko , Matsuyama Yutaka , Omata Masao , Makuuchi Masatoshi , Kokudo Norihiro
Published: December 2021

Introduction: It remains unclear which surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group). Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤7, largest HCC diameter ≤3 cm, and ≤3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing. Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range [IQR], 1.5–2.2 cm) in the surgery group and 1.8 cm (IQR, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 vs. 40 min, p < 0.01) and the median duration of hospital stay (17 days vs. 10 days, p < 0.01) were longer in the surgery group than in the RFA group. RFS did not differ significantly between the groups as the median RFS was 3.5 (95% confidence interval [CI], 2.6–5.1) years in the surgery group and 3.0 (95% CI, 2.4–5.6) years in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; p = 0.58). Discussion/Conclusion: Our study did not show which surgery or RFA is the better treatment option for small HCC.
First-in-Human Experience and Acute Procedural Outcomes Using a Novel Pulsed Field Ablation System: The PULSED AF Pilot Trial
Authors: Verma Atul , Boersma Lucas , Haines David E. , Natale Andrea , Marchlinski Francis E. , Sanders Prashanthan , Calkins Hugh , Packer Douglas L. , Hummel John , Onal Birce , Rosen Sofi , Kuck Karl-Heinz , Hindricks Gerhard , Wilsmore Bradley
Published: December 2021

Background:

Pulsed field ablation (PFA) is a novel form of ablation using electrical fields to ablate cardiac tissue. There are only limited data assessing the feasibility and safety of this type of ablation in humans.

Methods:

PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF;
https://www.clinicaltrials.gov
; unique identifier: NCT04198701) is a nonrandomized, prospective, multicenter, global, premarket clinical study. The first-in-human pilot phase evaluated the feasibility and efficacy of pulmonary vein isolation using a novel PFA system delivering bipolar, biphasic electrical fields through a circular multielectrode array catheter (PulseSelect; Medtronic, Inc). Thirty-eight patients with paroxysmal or persistent atrial fibrillation were treated in 6 centers in Australia, Canada, the United States, and the Netherlands. The primary outcomes were ability to achieve acute pulmonary vein isolation intraprocedurally and safety at 30 days.

Results:

Acute electrical isolation was achieved in 100% of pulmonary veins (n=152) in the 38 patients. Skin-to-skin procedure time was 160±91 minutes, left atrial dwell time was 82±35 minutes, and fluoroscopy time was 28±9 minutes. No serious adverse events related to the PFA system occurred in the 30-day follow-up including phrenic nerve injury, esophageal injury, stroke, or death.

Conclusions:

In this first-in-human clinical study, 100% pulmonary vein isolation was achieved using only PFA with no PFA system–related serious adverse events.

Graphic Abstract:

A graphic abstract is available for this article.
Early Pregnancy Blood Pressure Patterns Identify Risk of Hypertensive Disorders of Pregnancy Among Racial and Ethnic Groups
Authors: Gunderson Erica P. , Greenberg Mara , Nguyen-Huynh Mai N. , Tierney Cassidy , Roberts James M. , Go Alan S. , Tao Wei , Alexeeff Stacey E.
Published: December 2021

Background:

Hypertensive disorders of pregnancy are a leading cause of severe maternal morbidity and mortality and confer 4-fold higher perinatal mortality in Black women. Early pregnancy blood pressure patterns may differentiate risk of hypertensive disorders of pregnancy.

Methods:

This study identified distinct blood pressure trajectories from 0 to 20 weeks’ gestation to evaluate subsequent pregnancy-related hypertension in a retrospective cohort of 174 925 women with no prior hypertension or history of preeclampsia, prenatal care entry ≤14 weeks, and a stillborn or live singleton birth delivered at Kaiser Permanente Northern California hospitals in 2009 to 2019. We used electronic health records to obtain clinical outcomes, covariables, and longitudinal outpatient blood pressure measurements ≤20 weeks’ gestation (mean 4.1 measurements). Latent class trajectory modeling identified 6 blood pressure groups: ultra-low-declining(referent), low-declining, moderate-fast-decline, low-increasing, moderate-stable, and elevated-stable. Multivariable logistic regression evaluated trajectory group-associations with the odds of preeclampsia/eclampsia and gestational hypertension‚ and effect modification by race-ethnicity and prepregnancy body size.

Results:

Compared with ultra-low-declining, adjusted odds ratios (95% confidence intervals [CIs]) for low-increasing, moderate-stable, and elevated-stable groups were 3.25 (2.7–3.9), 5.3 (4.5–6.3), and 9.2 (7.7–11.1) for preeclampsia/eclampsia‚ and 6.4 (4.9–8.3), 13.6 (10.5–17.7), and 30.2 (23.2–39.4) for gestational hypertension. Race/ethnicity, and prepregnancy obesity modified the trajectory-group associations with preeclampsia/eclampsia (interaction
P
<0.01), with highest risks for Black, then Hispanic and Asian women for all blood pressure trajectories, and with increasing obesity class.

Conclusions:

Early pregnancy blood pressure patterns revealed racial and ethnic differences in associations with preeclampsia/eclampsia risk within equivalent levels and patterns. These blood pressure patterns may improve individual risk stratification permitting targeted surveillance and early mitigation strategies.
Outcome of Aneurysmal Subarachnoid Hemorrhage in a Population‐Based Cohort: Retrospective Registry Study
Authors: Iversen Mathilde V. , Ingebrigtsen Tor , Totland Jon A. , Kloster Roar , Isaksen Jørgen G.
Published: December 2021

Background

Studies of aneurysmal subarachnoid hemorrhage report an association between higher patient volumes and better outcomes. In regions with dispersed settlement, this must be balanced against the advantages with shorter prehospital transport times and timely access. The aim of this study is to report outcome for unselected aneurysmal subarachnoid hemorrhage cases from a well‐defined rural population treated in a low‐volume neurosurgical center.

Methods

This is a retrospective, population‐based, observational cohort study from northern Norway (population 486 450). The University Hospital of North Norway provides the only neurosurgical service. We retrieved data for all aneurysmal subarachnoid hemorrhage cases (n=332) admitted during 2007 through 2019 from an institution‐specific register. The outcome measures were mortality rates and functional status assessed with the modified Rankin scale.

Results

The mean annual number of cases was 26 (range, 16–38) and the mean crude incidence rate 5.4 per 100 000 person‐years. Two hundred seventy‐nine of 332 (84%) cases underwent aneurysm repair, 158 (47.5%) with endovascular techniques and 121 (36.4%) with microsurgical clipping, while 53 (15.9%) did not. The overall mortality rate was 16.0% at discharge and 23.8% at 12 months. The proportion with a favorable outcome (modified Rankin scale scores 0–2) was 36.1% at discharge and 51.5% at 12 months. In subgroup analysis of cases who underwent aneurysm repair, the mortality rate was 4.7% at discharge and 11.8% at 12 months, and the proportion with a favorable outcome 42.3% at discharge and 59.9% at 12 months.

Conclusions

We report satisfactory outcomes after treatment of aneurysmal subarachnoid hemorrhage in a low‐volume neurosurgical department serving a rural population. This indicates a reasonable balance between timely access to treatment and hospital case volume
Exploring the Unmet Need in Acute Ischemic Stroke Patients Not Treated With Intravenous Alteplase: The Get With The Guidelines‐Stroke Registry
Authors: Mac Grory Brian , Xian Ying , Solomon Nicole C. , Matsouaka Roland A. , Decker‐Palmer Marquita R. , Fonarow Gregg C. , Smith Eric E. , Schwamm Lee H.
Published: December 2021

Background

Early administration of intravenous tissue plasminogen activator (IV alteplase) improves functional outcomes in patients with acute ischemic stroke, yet many patients are not treated with IV alteplase. There is a need to understand the reasons for nontreatment and the short‐ and long‐term outcomes in this patient population.

Methods

We analyzed patients ≥65 years old with a primary diagnosis of acute ischemic stroke presenting within 24 hours of time last known well (LKW) but not treated with IV alteplase from 1630 Get With The Guidelines‐Stroke hospitals in the United States between January 2016 and December 2016. We report clinical characteristics, reasons for withholding treatment, in‐hospital mortality, and 90‐day and 1‐year outcomes including costs, stratified by time from LKW to presentation (≤4.5, >4.5–6, and >6–24 hours).

Results

Of 39 760 patients (median age 80 [25th–75th quartiles: 73–87], 56.7% female), 19 391 (48.8%) presented within 4.5 hours of LKW. In those with documented reasons for withholding IV alteplase, the most common reasons were rapid improvement of symptoms (3985/14 782, 27.0%) and mild symptoms (3791/14 782, 25.6%). In 1100 out of 1174 (93.7%) patients presenting in the >3.0‐ to 4.5‐hour time window, the most common reason for not treating was a delay in patient arrival. The most common discharge location for those presenting ≤4.5 hours since LKW was home (8660/19 391, 44.7%). The 90‐day mortality and readmission rates were 18.9% and 23.0% in those presenting ≤4.5 hours since LKW, 19.0% and 22.2% in those presenting between 4.5 and 6 hours, and 19.1% and 23.2% in those presenting between 6 and 24 hours. Median 90‐day total in‐hospital costs remained relatively high at $9471 (Q25–Q75: $5622–$21 356) in patients presenting ≤4.5 hours since LKW.

Conclusions

Patients within the Get With The Guidelines‐Stroke registry not treated with IV alteplase have a high risk of readmission and mortality and have high total in‐hospital and postdischarge costs. This study may inform future efforts to address the unmet need to improve the scope of IV alteplase delivery along with other aspects of acute ischemic stroke care and, consequently, outcomes in this patient population.
Developmental & Ecological Perspective on the Intergenerational
Transmission of Trauma & Violence
Authors: Keels Micere
Published: December 2021

The focus of this essay is on understanding the development and maintenance of patterns of violent behavior for the purpose of identifying points of prevention and intervention. Close attention is paid to using person-centered language that does not conflate exhibiting violent behaviors with being a violent person. There is a meaningful perceptual difference between discussing the behaviors of a violent person versus discussing a person who engaged in violent behaviors: the former is more likely to be associated with immutable characteristics of a person and the latter is more likely to be associated with attempts at understanding social and contextual causes of the behavior.
Lu Märten: An Introduction to Four Texts
Authors: Nachtigall Jenny , Stakemeier Kerstin
Published: December 2021

This article presents an introduction to four texts that the German feminist-materialist art historian Lu Märten (1879–1970) published between 1903 and 1928. It outlines some of the major concepts of and contexts for this unduly neglected thinker. Her writings covered a wide terrain that spanned studies on the labor conditions of female artists, polemics against “proletarian art,” and a monist, rather than dialectical, view on film, art, and what she called the “full life-work of a human.” At the core of her multiple endeavors was the demand for remaking the history of art as a history of form that is more capacious than art's institutionalized Western field. Situating Märten's work in historical debates (e.g., on Marxist aesthetics in the 1930s), the introduction also points to the new legibility that her nonaligned materialism gains with the material turn in the humanities.
Art Communities at Risk: On Cuba
Authors: Fusco Coco ,   27N
Published: December 2021

The article discusses the political actions of Cuban artist group 27N, including a conversation with some of its members and one of its manifestoes.
The Four Books of Shiʿi Hadith: From Inception to Consolidation
Authors: Ehteshami Amin
Published: December 2021

Since their compilations in the tenth and eleventh centuries ce, the four hadith books, al-Kāfī, al-Faqīh, al-Tahdhīb, and al-Istibṣār, have left an indelible mark on Shiʿi religiosity. The present study takes as its starting point the earliest instance in which these four compilations were collectively referred to as the Four Books (al-kutub al-arbaʿa). I investigate the major developments in the period between the inception of this phrase in the fifteenth century and its consolidation as the demarcator of a unique Imami hadith corpus in the seventeenth century. Following the introduction, each section of the article focuses on a figure whose ideas contributed to this consolidation process. In the conclusion I summarize the findings of the previous sections and reflect on the notion of hadith canonicity within the context of Imami jurisprudence during the period under study.
Understanding and Incorporating the Contradictions around the Book
Authors: Johnson Miriam
Published: December 2021

This article sets out to critically examine how the idea of what a book can be is changing in relation to the growth of digitally social communities and the writers and readers who congregate in these spaces, and to identify how this connectivity is altering the balance of power between the traditional industry and those who choose to write and share their work in a global village. By offering a succinct consideration of the role of social media, citizen authors, communities, gender, and genre, it can potentially help publishers determine if they need to alter the way they provide access to the industry, conventionally through the hierarchical author–agent–publisher gatekeeping system, in order to take advantage of new authors who are writing in digital communities and building a following there.
Publishers and Others Who Publish
Authors: Ungure Elza
Published: December 2021

The objective of the article is to deconstruct the notion of publisher through the lens of the episteme of professionalism and provide a statistical overview of mainstream and marginal book publishers in Latvia. The statistical overview is based on an alternative, experimental approach, in which publishers are grouped by the legal register they are registered in as juridical persons and the output of each group is analysed. This approach is selected to profile publishers in a context where economic indicators or other means by which to analyse publishers are not available. The results provide an insight into the diversity of those who publish books in Latvia as well as give an overview of the characteristics and patterns of their publishing practices.
Writing Africa, Righting America: An Experience of Otherness in J. P. Clark’s America, Their America
Authors: Ayodeji Adewuyi Aremu
Published: December 2021

In this article, I examine one of the finest first-generation Nigerian writers, John Pepper Clark-Bekederemo, who passed away on 13 October 2020, and who has been categorised as a Eurocentric writer. By critiquing his America, Their America, this work investigates the authenticity of this perception of J. P. Clark as a Eurocentric Nigerian writer. By analysing his autobiography vis-à-vis the notion of the Self and the Other, a theoretical concern in contemporary travel writing, the researcher establishes that every culture has its positive and negative aspects. It must not feel too proud to change as time and situation demand. It is clear that Clark vehemently rejects the US claim of the sophistication and superiority of their culture over African culture. The paper concludes that contemporary travel writing should be a rightful site for negotiating cultural compromises between the Self and the Other, since the gap may be difficult to close altogether.