bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between immune-related adverse events and the prognosis of solid cancer patients treated with immunotherapy: a systematic review and meta-analysis
Authors: Xu Huilin , Xu Ximing , Ge Wei , Lei Jinju , Cao Dedong 
Published: December 2020

Background: Immune-related adverse events (irAEs) are common during immune checkpoint inhibitor (ICI) treatment and reported to be associated with good survival. This study evaluated the association between onset timing of irAEs and survival of cancer patients treated with ICIs. Methods: Databases including PubMed, Embase, and the Cochrane library were systematically searched to retrieve clinical studies assessing the relationship between irAEs and survival in cancer patients with ICIs. The overall response rate for treatment response and hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were calculated using RevMan 5.3. Subgroup analysis in terms of cancer type, ICIs type, region, specific irAEs, accordingly. Results: A total of 34 studies were included. The HRs for OS and PFS in cancer patients with versus without irAEs were 0.57 [95% confidence interval (CI): 0.44, 0.74; p < 0.0001], and 0.50 (95% CI: 0.37, 0.67; p < 0.00001), respectively. The odds ratio for overall response in cancer patients with irAEs was 4.72 (95% CI: 3.48, 6.40; p < 0.00001) compared with those without irAEs. Subgroup analyses suggested that the prognostic role of irAEs was associated with cancer types and region, but not irAEs types. The landmark analysis of OS revealed that there is a non-proportional (early) effect of irAEs on OS in ICI-treated cancer patients (landmark >12 weeks, HROS = 1.08; 95% CI: 0.89, 1.30; p = 0.46). Conclusion: Our findings suggest that the occurrence of irAEs could be a prognostic factor for cancer patients who were treated with ICIs.
Liquid biopsy in peritoneal fluid and plasma as a prognostic factor in advanced colorectal and appendiceal tumors after complete cytoreduction and hyperthermic intraperitoneal chemotherapy
Authors: López-Rojo Irene , Olmedillas-López Susana , Villarejo Campos Pedro , Domínguez Prieto Víctor , Barambio Buendía Javier , Cortés Guiral Delia , García-Arranz Mariano , García-Olmo Damián 
Published: December 2020

Background: Positive cytology has been identified as an independent negative prognostic factor in patients with peritoneal metastases (PM) of colorectal origin. Liquid biopsy in plasma may detect increasing levels of circulating tumor DNA (ctDNA) and could help predict systemic relapse in patients with colorectal cancer, but little is known about the role of liquid biopsy in peritoneal fluid. The aim of this study was to evaluate the prognostic value of peritoneal fluid and plasma liquid biopsy in patients undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CC-HIPEC). Methods: A longitudinal prospective study was designed in patients with KRAS-mutated colorectal or appendiceal primary tumor, including PM of colorectal origin, pseudomyxoma peritonei and patients at high risk of developing PM (selected for second-look surgery). Eleven patients were recruited according to inclusion and exclusion criteria. ctDNA from plasma and peritoneal fluid before and after HIPEC was studied by droplet digital PCR looking for KRAS mutation. A close follow-up was scheduled (mean of 28.5 months) to monitor for systemic and peritoneal recurrences. Results: All patients with positive plasma postHIPEC had systemic relapse and four patients died as a result, while those with negative plasma postHIPEC did not relapse. Patients with negative peritoneal ctDNA after CC-HIPEC did not present peritoneal relapse. Of six patients with positive peritoneal ctDNA postHIPEC, two presented peritoneal recurrence and four systemic relapses. Conclusions: Treatment with CC-HIPEC does not always neutralize ctDNA in peritoneal fluid, and its persistence after treatment may predict adverse outcome. Despite being a proof of concept, an adequate correlation between liquid biopsy in plasma and peritoneal fluid with both systemic and peritoneal relapse has been observed.
Differences and similarities among questionnaires to assess pain status in chronic widespread pain population: a quantitative analysis
Authors: Evans Valerie , Duarte Felipe CK , Linde Lukas D , Kumbhare Dinesh 
Published: December 2020

Objective: In clinical practice, multiple questionnaires are often used as part of the diagnosis of chronic widespread pain. Body Surface Area (BSA), Visual Analogue Scale (VAS), Fibromyalgia Diagnostic Criteria (FDC) and Central Sensitization Inventory (CSI) have all been used as screening tools to assess pain status in individuals with widespread pain. However, substantial overlap can be observed among these commonly employed questionnaires. This study aimed to quantitatively determine the most independent and dependent clinical characteristics obtained through these questionnaires and to examine potential redundancies. Methods: Seventy-nine participants with widespread pain, 61 females and 18 males, from a chronic pain outpatient clinic were recruited. The FDC, BSA, VAS and the CSI were measured for all participants. A principal component analysis (PCA) using a varimax rotation was used to determine which clinical measures represented separate constructs of widespread pain. This was followed by a regression analysis to assess redundancy between the constructs and related pain characteristics. Results: The identified three-component PCA solution was characterized by (1) the FDC and CSI score, (2) the VAS score and (3) the BSA score. This indicates that the BSA and the VAS scores capture independent patient information. From the regression analysis, the FDC and CSI scores shared approximately 80% of the variance, indicative of substantial overlap between scores. Conclusion: Our findings demonstrated that BSA and VAS scores were independent clinical measures of widespread chronic pain, while the FDC and CSI scores were not independent, were highly correlated and provided redundant information. Clinicians should continue using both the BSA and VAS; however, either only FDC or CSI will be beneficial during clinical assessment of widespread chronic pain.
CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR–refractory large B-cell lymphoma
Authors: Baird John H. , Frank Matthew J. , Craig Juliana , Patel Shabnum , Spiegel Jay Y. , Sahaf Bita , Oak Jean S. , Younes Sheren F. , Ozawa Michael G. , Yang Eric , Natkunam Yasodha , Tamaresis John , Ehlinger Zachary , Reynolds Warren D. , Arai Sally , Johnston Laura , Lowsky Robert , Meyer Everett , Negrin Robert S. , Rezvani Andrew R. , Shiraz Parveen , Sidana Surbhi , Weng Wen-Kai , Davis Kara L. , Ramakrishna Sneha , Schultz Liora , Mullins Chelsea , Jacob Allison , Kirsch Ilan , Feldman Steven A. , Mackall Crystal L. , Miklos David B. , Muffly Lori 
Published: December 2020

Abstract
The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
Pneumolysin induces platelet destruction, not platelet activation, which can be prevented by immunoglobulin preparations in vitro
Authors: Jahn Kristin , Handtke Stefan , Palankar Raghavendra , Weißmüller Sabrina , Nouailles Geraldine , Kohler Thomas P. , Wesche Jan , Rohde Manfred , Heinz Corina , Aschenbrenner Axel F. , Wolff Martina , Schüttrumpf Jörg , Witzenrath Martin , Hammerschmidt Sven , Greinacher Andreas 
Published: December 2020

AbstractCommunity-acquired pneumonia by primary or superinfections with Streptococcus pneumoniae can lead to acute respiratory distress requiring mechanical ventilation. The pore-forming toxin pneumolysin alters the alveolar-capillary barrier and causes extravasation of protein-rich fluid into the interstitial pulmonary tissue, which impairs gas exchange. Platelets usually prevent endothelial leakage in inflamed pulmonary tissue by sealing inflammation-induced endothelial gaps. We not only confirm that S pneumoniae induces CD62P expression in platelets, but we also show that, in the presence of pneumolysin, CD62P expression is not associated with platelet activation. Pneumolysin induces pores in the platelet membrane, which allow anti-CD62P antibodies to stain the intracellular CD62P without platelet activation. Pneumolysin treatment also results in calcium efflux, increase in light transmission by platelet lysis (not aggregation), loss of platelet thrombus formation in the flow chamber, and loss of pore-sealing capacity of platelets in the Boyden chamber. Specific anti-pneumolysin monoclonal and polyclonal antibodies inhibit these effects of pneumolysin on platelets as do polyvalent human immunoglobulins. In a post hoc analysis of the prospective randomized phase 2 CIGMA trial, we show that administration of a polyvalent immunoglobulin preparation was associated with a nominally higher platelet count and nominally improved survival in patients with severe S pneumoniae–related community-acquired pneumonia. Although, due to the low number of patients, no definitive conclusion can be made, our findings provide a rationale for investigation of pharmacologic immunoglobulin preparations to target pneumolysin by polyvalent immunoglobulin preparations in severe community-acquired pneumococcal pneumonia, to counteract the risk of these patients becoming ventilation dependent. This trial was registered at www.clinicaltrials.gov as #NCT01420744.
Prognostic and predictive performance of R-ISS with SKY92 in older patients with multiple myeloma: the HOVON-87/NMSG-18 trial
Authors: Kuiper Rowan , Zweegman Sonja , van Duin Mark , van Vliet Martin H. , van Beers Erik H. , Dumee Belinda , Vermeulen Michael , Koenders Jasper , van der Holt Bronno , Visser-Wisselaar Heleen , Hansson Markus , van der Velden Annette W. G. , Beverloo H. Berna , Stevens-Kroef Marian , Levin Mark-David , Broijl Annemiek , Waage Anders , Sonneveld Pieter 
Published: December 2020

Abstract
The standard prognostic marker for multiple myeloma (MM) patients is the revised International Staging System (R-ISS). However, there is room for improvement in guiding treatment. This applies particularly to older patients, in whom the benefit/risk ratio is reduced because of comorbidities and subsequent side effects. We hypothesized that adding gene-expression data to R-ISS would generate a stronger marker. This was tested by combining R-ISS with the SKY92 classifier (SKY-RISS). The HOVON-87/NMSG-18 trial (EudraCT: 2007-004007-34) compared melphalan-prednisone-thalidomide followed by thalidomide maintenance (MPT-T) with melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R). From this trial, 168 patients with available R-ISS status and gene-expression profiles were analyzed. R-ISS stages I, II, and III were assigned to 8%, 75%, and 7% of patients, respectively (3-year overall survival [OS] rates: 80%, 65%, 33%, P = 8 × 10−3). Using the SKY92 classifier, 13% of patients were high risk (HR) (3-year OS rates: standard risk [SR], 70%; HR, 28%; P &lt; .001). Combining SKY92 with R-ISS resulted in 3 risk groups: SKY-RISS I (SKY-SR + R-ISS-I; 15%), SKY-RISS III (SKY-HR + R-ISS-II/III; 11%), and SKY-RISS II (all other patients; 74%). The 3-year OS rates for SKY-RISS I, II, and III are 88%, 66%, and 26%, respectively (P = 6 × 10−7). The SKY-RISS model was validated in older patients from the CoMMpass dataset. Moreover, SKY-RISS demonstrated predictive potential: HR patients appeared to benefit from MPR-R over MPT-T (median OS, 55 and 14 months, respectively). Combined, SKY92 and R-ISS classify patients more accurately. Additionally, benefit was observed for MPR-R over MPT-T in SKY92-RISS HR patients only.
“We’re in good hands there.” - Acceptance, barriers and facilitators of a primary care-based health coaching programme for children and adolescents with mental health problems: a qualitative study (PrimA-QuO)
Authors: Decke Siona , Deckert Karina , Lang Martin , Laub Otto , Loidl Verena , Schwettmann Lars , Grill Eva 
Published: December 2020

Abstract
Background
11.5 % of girls and 17.8 % of boys are affected by a mental health problem (MHP). The most prevalent problem areas are behavioural problems (girls/boys in %: 11.9/17.9), emotional problems (9.7/8.6) and hyperactivity problems (4.8/10.8). Primary care paediatricians are the first in line to be contacted. Nevertheless, even for less severely affected patients, referral rates to specialised care are constantly high. Therefore, a major statutory health insurance fund introduced a Health Coaching (HC) programme, including a training concept for paediatricians, standardised guidelines for actions and additional payments to strengthen primary care consultation for MHP and to decrease referrals to specialised care. The aim of this study was to examine how the HC is perceived and implemented in daily practice to indicate potential strengths and challenges.

Methods
During a one-year period starting in November 2017, a series of guideline-based interviews were conducted by phone with HC-developers, HC-qualified paediatricians, parents and patients (≥14 years) treated according to the HC programme. Paediatricians were selected from a Bavarian practice network with a total of 577 HC qualified paediatricians. Parents of patients with the four most common MHP diagnoses were approached by their health insurance: [World Health Organization, 2013] developmental disorder of speech and language [Wille N, et al., 2008] head/abdominal pain (somatoform) [Holling H, et al., 2003-2006 and 2009-2012] conduct disorder [Plass-Christl A, et al., 2018] non-organic enuresis. 23 paediatricians, 314 parents and 10 adolescents consented to be interviewed. Potential participants were selected based on purposeful sampling, according to principles of maximum variance. All interviews were recorded and transcribed verbatim. Two researchers analysed the transcripts independently of each other. Structuring content analysis derived from Mayring was used for analysis.

Results
11 paediatricians, 3 co-developers, 22 parents and 4 adolescents were included. Families were generally satisfied with paediatric care received in the programme’s context. The HC supported paediatricians’ essential role as consultants and improved their diagnostic skills. Lack of time, financial restrictions and patients’ challenging family structures were reported as major barriers to success.

Conclusion
The HC programme is perceived as a facilitator for more patient-centred care. However, structural barriers remain. Starting points for improvement are further options to strengthen families’ resources and expanded interdisciplinary networking.
Community care coordination for stroke survivors: results of a complex intervention study
Authors: Deutschbein Johannes , Grittner Ulrike , Schneider Alice , Schenk Liane 
Published: December 2020

Abstract
Background
Outpatient follow-up care for stroke survivors is often inadequate and mostly self-organized by the patients themselves. In the German health care system, there are no standard care programs for patients after they are discharged from the hospital to support them with their multifaceted and heterogeneous health care needs. The objective of this complex intervention study was to evaluate the effectiveness of a post-stroke care coordination program in comparison to standard care in the first year after a stroke.

Methods
Patients aged 55 and older who had survived a stroke or a transient ischemic attack (TIA) within the last 6 months before enrollment were included. Participants received care coordination either by telephone or face-to-face for up to 1 year. Patients’ health insurance claims data were used to measure outcomes. The control group consisted of stroke survivors receiving standard care and was constructed by exact matching based on six criteria. Outcome measures were health services utilization, rate of recurrent events, readmissions and accompanying costs, and mortality. Outcomes were tested using different multiple models.

Results
In total, N = 361 patients were included in the analyses. Intervention participants had seen an outpatient neurologist more often (OR = 4.75; 95% CI: 2.71–8.31) and were readmitted to a hospital less frequently (IRR = 0.42; 95% CI: 0.29–0.61), resulting in lower hospital costs (IQR = €0–1910 in the intervention group, IQR = €0–4375 in the control group). There were no substantial group differences in the rate of recurrent events and mortality.

Conclusion
This study showed the beneficial potential of care coordination for a vulnerable patient population: the utilization rate of important health services was increased, and the rate of hospital readmissions decreased as a result. Future research should focus on the risk of recurrent strokes and the long-term effects of improved care.

Trial registration
DRKS00017526 on DRKS – German Clinical Trials Register (retrospectively registered: 21 June 2019).
11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool
Authors: Barnard Lise , Schiffer Lina , Louw du-Toit Renate , Tamblyn Jennifer A , Chen Shiuan , Africander Donita , Arlt Wiebke , Foster Paul A , Storbeck Karl-Heinz 
Published: December 2020

Abstract
Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β and that 11β-hydroxy-17β-estradiol and the classic androgen pathway-derived active estrogen, 17β-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo.
Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin
Authors: Riggs Arthur D 
Published: December 2020

Abstract
In the mid- to late 1970s, recombinant deoxyribonucleic acid methods for cloning and expressing genes in E. coli were under intense development. The important question had become: Can humans design and chemically synthesize novel genes that function in bacteria? This question was answered in 1978 and in 1979 with the successful expression in E. coli of 2 mammalian hormones, first somatostatin and then human insulin. The successful production of human insulin in bacteria provided, for the first time, a practical, scalable source of human insulin and resulted in the approval, in 1982, of human insulin for the treatment of diabetics. In this short review, I give my personal view of how the making, cloning, and expressing of human insulin genes was accomplished by a team of scientists led by Keiichi Itakura, Herbert W. Boyer, and myself.
Salvage Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) for T4b Esophageal Cancer After Definitive Chemoradiotherapy
Authors: Defize I. L. , van der Horst S. , Bülbul M. , Haj Mohammad N. , Mook S. , Meijer G. J. , Brosens L. A. A. , Ruurda J. P. , van Hillegersberg R. 
Published: December 2020

Abstract
Background
Patients with esophageal cancer that invades adjacent structures (cT4b) are precluded from surgery and usually treated with definitive chemoradiotherapy (dCRT). dCRT might result in sufficient downstaging to enable a radical resection, possibly improving survival. This study aimed to assess the perioperative and oncologic outcomes of a salvage robot-assisted minimally invasive esophagectomy (RAMIE) in patients with cT4b esophageal cancer after dCRT.

Methods
Between June 2012 and November 2019, patients who underwent a RAMIE with a gastric conduit reconstruction after completion of dCRT for cT4b esophageal carcinoma were identified from a prospectively maintained surgical database at the University Medical Center Utrecht.

Results
In total, 24 patients with a histopathologically confirmed T4b adenocarcinoma or squamous cell carcinoma of the esophagus were included. The adjacent organs involved were the tracheobronchial tree (67%), aorta (21%) or both (13%). No conversions or major intraoperative complications were observed. A radical resection was achieved in 22 patients (92%), and a pathologic complete response was observed in 13 (54%) patients. Postoperative grade 2 or higher complications occurred in 20 patients (83%). The disease-free survival at 24 months was 68% for the patients in whom a radical resection was achieved.

Conclusion
In patients with cT4b esophageal cancer treated with dCRT followed by a salvage RAMIE, a radical resection rate of 92% was achieved, with acceptable complications and promising survival rates. These results demonstrate the feasibility of a curative surgical treatment for patients with initially irresectable esophageal cancer but underscore the importance of a proper preoperative patient selection.
ASPECTOS GERAIS DOS PRECEDENTES JUDICIAIS E A DOGMÁTICA DO NOVO CÓDIGO DE PROCESSO CIVIL
Authors: Cruz Paulo Márcio , Faria Barbiero Victória 
Published: December 2020

A presente pesquisa tem o objetivo de fazer um paralelo entre os precedentes judiciais da common law e como estes são inseridos no contexto brasileiro. Para isso, faz-se uma análise dos elementos constitutivos e práticos dos precedentes judiciais no sistema common law, como também a perspectiva histórica que culminou seu surgimento. Ademais, verifica-se os novos enquadramentos judiciários e atividades do juiz a partir dessa nova lógica vinculante no direito processual brasileiro. O precedente se torna um instrumento adequado para resolver os problemas de duração dos processos judicias e segurança jurídica do judiciário, e sua efetividade só poderá ser medida com a sua prática.PALAVRAS-CHAVE:‌ Common law; Precedentes judiciais; Processo Civil.