bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility and safety of total laparoscopic hysterectomy for huge uteri without the use of uterine manipulator: description of emblematic cases
Authors: Macciò Antonio , Madeddu Clelia , Kotsonis Paraskevas , Chiappe Giacomo , Lavra Fabrizio , Collu Ivan , Demontis Roberto 
Published: February 2018

Abstract
Background
Uterine manipulator is a very useful tool in performing total laparoscopic hysterectomy (TLH) for large uteri; however, in some cases, it cannot be used due to unfavorable anatomical conditions. The feasibility and safety of TLH for very large uteri without the use of uterine manipulator has not yet been established.

Results
We describe two emblematic cases of TLH for huge fibromatous uteri: the first one for a uterus weighing 5700 g, which is the largest uterus laparoscopically removed to date reported in literature, and the second one for a uterus of 3670 g associated with a severe lymph node neoplastic disease.
In both cases, TLH was successfully and safely performed even without the use of uterine manipulator, thus allowing a rapid recovery, especially in the second case, which was essential for a fast start of the most appropriate oncological treatment, the best quality of life and undoubtedly cosmetic advantages.

Conclusions
Although we believe in the great usefulness of the uterine manipulator in performing TLH for huge uteri, in the present paper, we demonstrate the feasibility and safety of such complex surgery also when the use of this tool is not possible due to unfavorable anatomical condition.
Correction to: High-fat diet or low-protein diet changes peritoneal macrophages function in mice
Authors: Santos Ed Wilson , de Oliveira Dalila Cunha , Hastreiter Araceli , de Oliveira Beltran Jackeline Soares , Rogero Marcelo Macedo , Fock Ricardo Ambrósio , Borelli Primavera 
Published: February 2018

Abstract
The original version of this article [1], published on 28 June 2016, contains a mistake. The part labels in Fig. 1 are missing. The corrected version of Fig. 1 is given below.
‘To know before hand is to freeze and kill’ Commentary on… Should psychiatrists write fiction?
Authors: Racey Daniel 
Published: February 2018

SummaryIn this article I argue that fictional accounts of mental illness should be unethically unobliged. I suggest that art is not generated with conscious ethical intent and provide evidence that art proceeding from an ethical agenda is more likely to be poor art. I also consider ways in which a writer-doctor might need to compromise what they articulate to maintain a professional ethical integrity.Declaration of interestNone.
Effect of andecaliximab (anti-MMP9) on proteolysis of IL-7 in vitro, TCR diversity in mice, and serum IL-7 in gastric cancer patients in combination with chemotherapy.
Authors: Greenstein Andrew E. , Zavodovskaya Marianna , Velasquez Maile , Weissburg Perry , Juric Vladi , Mikels-Vigdal Amanda , Brachmann Carrie 
Published: February 2018

101 Background: Andecaliximab (andeca) is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9). IL-7 selectively enhances the proliferation and survival of naïve, memory, and effector T-cells (but not regulatory T-cells) in the periphery. Previous clinical trials with systemic recombinant IL-7 therapy increased TCR diversity. In the disease setting, elevated circulating IL-7 may be due to a compensatory increase in IL-7 production as demonstrated in mice upon inhibition of IL-7 signaling. Methods: An in vitro screen, in which recombinant active human MMP9 was incubated with > 140 human recombinant folded proteins, identified IL-7 as the most efficient substrate of MMP9. Results: IL-7 proteolysis occurred between A128:L129. IL-7 proteolysis altered the global protein structure, evidenced by a loss of cooperative unfolding observed with intact IL-7 (intrinsic fluorescence, Tm = 59.3o C). Mouse MMP9 proteolyzed mouse IL-7 in vitro. In the orthotopic syngeneic NeuT mouse model, MMP9 inhibition reduced tumor growth (p = 0.0005). In a 7-day NeuT study, anti-MMP9 alone improved TCR diversity (decreased clonality) within tumor-infiltrating T-cells (Dunnett’s p = 0.0083). Further, anti-MMP9 and anti-PDL1 co-treatment promoted an increase in CD3+ cells (p = 0.01), CD4+ T cells (p = 0.006), and CD8+ T cells (p = 0.013) concomitant with a decrease in tumor-associated CD25+ FoxP3+ regulatory T cells (p = 0.04) in the tumor. In gastric cancer patient serum, pro-MMP9 (p < 0.0001), active MMP9 (p < 0.0001), and IL-7 (p < 0.0001) were higher than healthy controls. Serum IL-7 levels were normalized upon treatment with andeca plus mFOLFOX6 (N = 40; FDR-corrected p < 0.001) in a Phase I gastric cancer study. Conclusions: MMP9 proteolyzed IL-7 in vitro. Specific MMP9 inhibition in a mouse tumor model improved TCR diversity. Andeca +mFOLFOX6 therapy normalized serum IL-7 levels, which could be due to andeca, chemotherapy, or disease resolution. The functional implications of IL-7 proteolysis by MMP9 in gastric cancer are currently under investigation.
Exploration of the cGAS-STING pathway in prostate cancer.
Authors: Reilly Emma , McCavigan Andrena , Walker Steven M. , McCabe Nuala , Parkes Eileen , Harkin D. Paul , Kennedy Richard D , Knight Laura A 
Published: February 2018

103 Background: Recent studies have demonstrated limited success of immune checkpoint therapies in unselected prostate cancer. We therefore assessed an immune based DNA Damage Repair Deficiency (DDRD) assay, that we have previously reported represents activation of the cGAS STING pathway, in the TCGA prostate cancer dataset to investigate the presence of targetable immune biology in prostate cancer. In addition we applied a second assay (the prostate cancer metastatic signature-PCM) that predicts the risk of metastatic recurrence for early prostate cancer, in order to assess if immune therapy could have a role in treating high risk disease. Methods: 498 samples with RNA sequencing data were scored with the PCM and DDRD assays. Integrative analysis was performed on 488 samples with RNA sequencing, promoter site methylation, somatic mutation and somatic copy number variation. Gene expression of n = 6 immune checkpoint targets was investigated with the subgroups identified using T-tests. The prevalence of immune infiltration in each subgroup was tested by applying a cut off to the leukocyte fraction. Cox proportional hazards regression analysis of 441 patients was assessed for biochemical recurrence. Results: Integrative analysis identified four patient subgroups characterised primarily by variances in copy number and genomic mutation. One of these subgroups ‘Metastatic-like DDRD’ had significantly higher PCM scores and DDRD immune scores compared to the other subgroups (p < 2E-12). This subgroup of patients showed elevated leukocyte fraction and expression of immune checkpoint genes: CD274 (PDL1), CTLA4, ICOS, IDO1, HAVCR2 (TIM3) & LAG3 (p < 2E-6). Genomic instability with amplification of 8q and a larger prevalence of somatic mutations including that of TP53 was also detected in this subgroup. These patients had an increased risk of biochemical relapse in both univariate (p < 2E-5) and multivariate (p < 0.008) analysis. Conclusions: We identified a poor prognostic subgroup, representing 17% of early prostate cancer patients that are at increased risk of developing metastatic disease and present with targetable immune biology. These patients may represent a viable target population for immune checkpoint and DNA damaging therapies in prostate cancer.
Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R/R aggressive B-NHL (TRANSCEND NHL 001 study).
Authors: Siddiqi Tanya , Abramson Jeremy S. , Palomba Maria Lia , Gordon Leo I. , Lunning Matthew Alexander , Arnason Jon E. , Wang Michael , Forero-Torres Andres , Maloney David G. , Heipel Mark , Smith Jeffrey , Brown William , Karimi Mandana , Xie Benhuai , Li Daniel , Albertson Tina , Garcia Jacob , Dave Kedar , DeVries Todd , Sutherland Claire 
Published: February 2018

122 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Ph1 pivotal trial of R/R B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Blood samples were collected for biomarker analyses at protocol-defined time points. PK (CAR T cell expansion and persistence) was measured using flow cytometry. Cytokines were measured on a Luminex platform. Additional analytes will be presented. All reported p-values are 2-sided without multiplicity adjustment. Results: Safety (n = 59) and efficacy (n = 54) outcomes were analyzed for correlations with patient (pt) characteristics and biomarkers. Dose level did not correlate with cytokine release syndrome (CRS) or neurotoxicity (NT) despite higher median Cmax and median AUC0-28 at DL2. In pts with NT or ≥Gr 2 CRS, CD4 and CD8 CAR T cell levels were 5-10 fold and 3-5 fold higher, respectively, than median DL2 levels. Pt factors that correlated with any grade CRS and NT were ECOG 2 (p = 0.03) and high disease burden (p < 0.05). Higher levels of IL-8, IL-10, and CXCL10 before CART cell infusion were associated with Gr 3-4 NT (each p< 0.05), suggesting that inherent pt factors may result in higher CAR T expansion and associated CRS and NT. Lower pre-CAR T cell ferritin, LDH, CXCL10, G-CSF, and IL-10 were associated with CR/PR, and lower pre-CAR T cell ferritin, CRP, LDH, CXCL10, IL-8, IL-10, IL-15, MCP-1, MIP-1β, TNF-α were associated with 3-month durable response (each p< 0.05). Median Cmax and AUC0-28 of CD8 CAR T cells were higher in responding patients and with durable response at Month 3 (CD8 Cmax median = 20.8 vs 5.5; CD8 AUC median = 235 vs 55 in CR/PR vs PD at Month 3). Of pts evaluable for persistence at 3 months (n = 29), 90% and 93% had detectable CD8+ and CD4+ CAR+ T cells; of those with available PK results at time of relapse (n = 11), 82% had persistence at time of relapse. Conclusions: JCAR017 demonstrated increased CAR T cell expansion and persistence and higher durability of response at higher dose levels, with manageable toxicities. CAR T cells were also detected at time of relapse, suggesting potential opportunities for future combination clinical trials. Clinical trial information: NCT02631044.
Single agent and combination checkpoint inhibitors therapy: A post marketing safety analysis.
Authors: Elias Rawad , Rider Jennifer , Tan Xainming , Rahma Osama E. 
Published: February 2018

125 Background: Immune Checkpoint Inhibitors (ICIs) are used to treat patients with a wide spectrum of malignancies. Individuals enrolled in clinical trials are usually more fit compared to patients seen in everyday practice. Therefore, it is important to evaluate the safety profile of these agents in real-world data. In addition, it is not clear if the safety of these agents is similar across all age groups. Methods: We reviewed the FDA Adverse Event Reporting System (FAERS) for adverse events associated with the use of PD-1 inhibitors (nivolumab and pembrolizumab); PD-L1 inhibitor (atezolizumab); and CTLA-4 inhibitor (ipilimumab). Our analysis was restricted to reports that included only an ICI as a suspect agent. For each agent, we performed a descriptive analysis of hospitalization (HO) and death (DE) outcomes, as well as select adverse events of special interest (AESI). We compared the distribution of each outcome within age groups ( < 65 years; 67-75; > 75) using Mantel-Haenszel chi -quare test for trend. Results: A total of 23,586 safety reports were included in our analysis. 415 for atezolizumab, 10,026 for nivolumab, 4,808 for pembrolizumab, 6,339 for ipilimumab, and 1,988 for the combination nivolumab plus ipilimumab. Increased age was associated with a statistically significant trend of more hospitalizations for all drugs except for the combination nivolumab plus ipilimumab where hospitalization rate was high ( > 80%) but similar across all age groups. Prevalence of any of the AESI was higher as age increased for all drugs (p < 0.0001) except for atezolizumab (p 0.12) and combination nivolumab plus ipilimumab (p 0.488). Proportion of older patients who experienced death was higher for pembrolizumab (p < 0.001), ipilimumab (p 0.002), and combination nivolumab plus ipilimumab (p < 0.001). Conclusions: Our analysis suggests that among patients treated with ICI, older individuals receiving pembrolizumab, Nivolumab or ipilimumab were more likely to develop immune related AEs, and to be hospitalized. An increased rate of death with higher age was seen with the use of pembrolizumab, ipilimumab, and combination nivolumab + ipilimumab. Older patients treated with ICIs should be monitored carefully for treatment-related AEs.
Plinabulin, a novel small molecule clinical stage IO agent with anti-cancer activity, to prevent chemo-induced neutropenia and immune related AEs.
Authors: Mohanlal Ramon W. , LLoyd Ken , Huang Lan 
Published: February 2018

126 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects by targeting Dendritic Cells (DCs). In preclinical studies, Plin induces DC maturation and the production of MHCII, CD40, CD80 and CD86 and related antigen-specific T-cell activation. Plin had synergistic anticancer efficacy with PD1+CTLA4inhibitors in animal models. In addition, Plin increases expression of IL-1β, IL-6, IL-12 in DC cell, which cytokines protect neutrophils against apoptosis. In a Phase 2 (Ph2) trial, the addition of Plin to Docetaxel (Plin+Doc; n = 38) in NSCLC patients (pts) with a measurable lesion, improved mOS with 4.6 mo vs Doc alone (n = 38). DOR (a marker of immune effect) was ~1 yr longer (P < 0.05) with Plin+Doc vs Doc alone. Plin exerted immune-enhancing effects (DOR), without increasing Immune-Related AEs (IR-AEs). This may suggest that Plin exerts immune-enhancing and anti-inflammatory effects. Methods: Prospective, randomized Ph2 clinical trial (NCT00630110) and non-clinical studies. Results: In-vitro screens showed that Plin is a PDE4-inhibitor, and clinical evidence (p < 0.03; n = 90) of PDE4-inhibition with Plin was observed in Ph2. PDE4-inhibitors have steroid-like effects and are approved for the treatment of Inflammatory disorders, and thus have the potential to prevent IR-AEs. In addition, Plin prevented chemo-induced Neutropenia (CIN), through a mechanism, different from G-CSF, in non-clinical (with various chemotherapies) and Ph2. In Ph2, Gr 4 Neutropenia occurred in 5% with Plin+Doc vs 33 % off pts with Doc (p < 0.0003) in Cycle 1, day 8. Plin is given 30 min after chemo (on the same day of chemo), and does not cause bone pain. G-CSF is given 24 hr after chemo, and causes bone pain in most pts. Conclusions: Plin exerts anticancer immune-enhancing effects, combined with anti-inflammatory effects, due to PDE4-inhibition. Plin holds the promise of an agent with anti-cancer efficacy, while also mitigating IR-AEs and CIN. Therefore, Plin is an attractive candidate for combination therapy with PD1-inhibitors (or PD-L1 inhibitors), PD1+CTLA-inhibitor, or PD1-inhibitor/chemotherapy.
Risk factors for and characteristics of pneumonitis in patients treated with anti-programmed death-1 therapy.
Authors: HU YI , Cui Pengfei , Zhang Jing 
Published: February 2018

128 Background: Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1) monoclonal antibodies (mAbs), but its prevalence, risk factors and clinical features are poorly described. Methods: The medical records of 234 patients with advanced cancer who underwent anti–PD-1mAbs therapies between September 2015 and September 2017 at the Cancer Center of the Chinese PLA (People’s Liberation Army) General Hospital were analyzed with regard to patient background and clinical features. Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Univariate and multivariate analyses were performed to identify independent predictive factors for pneumonitis. Clinical features, management and prognosis of pneumonitis were also collected. Results: A total of 55 patients (23.5%) developed pneumonitis. Anti–PD-1mAbs induced pneumonitis was significantly associated with male sex, a history of prior thoracic radiotherapy, combination therapy and underlying lung condition (odds ratios 3.380, 3.081, 2.538 and 2.559, respectively). Time to onset of pneumonitis ranged from 2 days to 277days (median time was 85days). 85.4% (47 of 55) of cases were grade 1 to 2, 25.5% (14 of 55) were treated with steroid therapy, of which 85.7% (12 of 14) resolved/ improved. Nine (16.4%) patients worsened clinically and one died during the course of pneumonitis treatment. Conclusions: Pneumonitis associated with anti–PD-1 mAbs is a serious adverse effect in the clinical setting that cannot be ignored. However, patient selection based on sex, history of prior thoracic radiotherapy, combination therapy and underlying lung condition can minimize pneumonitis risk. Most events are low grade and resolved/ improved with steroid therapy. Rarely, pneumonitis worsens despite steroid therapy, and may result in death.
The impact of PD-L1 on survival and values of nivolumab, atezolizumab, and pembrolizumab compared with docetaxel in second-line non-small cell lung cancer.
Authors: Guirgis Helmy M. 
Published: February 2018

141 Background: The impact of programmed death receptor-ligand1 (PD-L1) on values of the immune check point inhibitors (ICPI) has received minimal attention. Objectives: Grade survival and weigh values of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2nd-line non-squamous non-small-cell lung cancer (NSCLC). Methods: Previously reported median overall survival (OS), adverse events and prices posted by the parent companies were utilized. The OS gains in days over controls were graded (gr) from A to D. Docetaxel costs x 6 -12 cycles and ICPI x one year were calculated separately from adverse events treatment costs (AEsTC). Costs/life-year gain (C/LYG) were computed as drug C/OS gain x 360. Relative Values were expressed as $100,000/C/LYG. Results: Docetaxel costs of 9 cycles were $35,802, OS/gr 87/C, AEs gr ¾ > 20%, AEsTC $4,940 and C/LYG $148,146. Nivo, Atezo and Pembro gr ¾ < 20% were at $1,480 costs. In non-squamous NSCLC, Nivo OS/gr were 84/C and C/LYG $545,754. The results improved in PD-L1 > 10% to 264/A and $177,645 respectively. Atezolizumab demonstrated OS/gr 99/C and C/LYG $551,407 improving in PD-L1 50% to 348/A and $151,193. Pembrolizumab in PD-L1 > 1.0%, the OS/gr were 57/C and C/LYG $659,059 improving in > 50% to 201/A and $186,897. PD-L1 enrichment increased relative values of Nivo from 0.19 to 0.56, Atezo from 0.19 to 0.66 and Pembro from 0.15 to 0.53. Conclusions: In 2nd-line non-squamous NSCLC, the OS of Doc, Nivo, Atezo and Pembro were limited. In PD-L1 enriched, the ICPI resulted in unprecedented OS, improved grades and enhanced values at justifiable costs.
Effect of the tumor-shed antigen CA125 on humoral immune responses of IgG1, IgG3, and IgM-type antibodies.
Authors: Kline J Bradford 
Published: February 2018

15 Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of CA125 on suppressing humoral immune responses of naturally occurring and therapeutic antibodies (Abs). These data stem from prespecified subgroup analysis of a Ph3 trial testing farletuzumab, a monoclonal Ab (mAb) to folate receptor alpha, plus standard-of-care carboplatin-taxane (CT) chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low CA125 serum levels treated with farletuzumab plus CT demonstrated improvements in PFS (HR 0.49, p = 0.0028) and OS (HR 0.44, p = 0.0108) compared to placebo plus CT. Farletuzumab utilizes Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with the aim to kill target bound tumor cells. These functions were analyzed in patient samples to determine if CA125 negatively impacts mAb-mediated humoral responses. Methods: Molecular and cell based assays tested the effects of CA125 on humoral immune activity mediated by mAbs on ovarian cancer patient serum samples. Results: Here we show that CA125 inhibits ADCC and CDC by directly binding to a subset of mAbs and perturbing engagement with Fc-γ activating receptors CD16a and CD32a and the C1q complement initiating protein. The effects occur via CA125 binding to the mAb variable domain, which alters the structure of the CH2 motif leading to suppressed binding by CD16a/CD32a and C1q. The lack of inhibition by the high affinity CD64a Fc-γ receptor as well as lack of FcRn inhibition suggests a conformational change occurs within the CH2 motif that perturbs the binding of low affinity CD16a, CD32a and C1q proteins. The effect appears to involve a subset of Abs composed of IgG1, IgG3 and IgM isotypes. Conclusions: CA125 has an immunosuppressive effect on Ab-mediated humor immunity in a subset of tested Abs of varied isotypes including IgG1, IgG3, and IgM. The effects have implications in monitoring therapeutic mAbs that may be negatively affected by CA125 binding as well as potential implications for identifying patients who may be at risk for developing certain types of cancer, including ovarian.
Changes in the use of commercial and lab-developed IVD assays in the clinical setting for PD-L1 expression testing in NSCLC in the United States.
Authors: Levent Ayse , De Richter Pieter , Angel William H , Edathanal Ciny , Homer Christophe 
Published: February 2018

154 Background: In 2016 we observed a lack of standardization in the use of cut-off points to define positivity when testing for PD-L1 expression in NSCLC, despite these being specified by assay manufacturers or recommended based on trial data. One year on we look at how clinical practice has changed in light of new approvals for PD-(L)1 inhibitors, availability of new IVD assays and changes in clinical practice guidelines recommending the use of immunotherapy for stage IV NSCLC. Here we explore how the variety of test brands and cut-off points used in the US has changed since 2016 by examining real-world clinical usage data. Methods: Between June and August 2016 and June and August 2017, a panel of pathologists in the US (n = 21 in 2016 and n = 28 in 2017) was asked to report on their practices relating to PD-L1 expression testing in NSCLC, through the submission of online de-identified record forms (n = 167 and n = 224 PD-L1-tested samples in 2016 and 2017 respectively). Results: Of the 224 samples gathered in 2017, 187 (84%) were tested with the Dako 22C3 pharmDx assay (vs 67% in 2016), 16 (7%) with the Dako 28-8 pharmDx assay (vs 22% in 2016) and 11 (5%) with a lab-developed test (LDT). An increase in the use of 1% staining as the cut-off was observed for both 22C3 and 28-8 pharmDx. The full distribution of cut-offs used is shown in the table below. Conclusions: Following initial fragmentation of clinical practices in 2016, PD-L1 expression testing has seen consolidation towards greater use of the Dako 22C3 assay and higher conformity in testing at the recommended cut-off points. While greater standardization simplifies testing, the choice of assay has potential implications on subsequent treatment: current PD-L1 assays allow physicians to confirm whether a specific PD-(L)1 inhibitor is appropriate for a patient, but there is no single PD-L1 expression test that supports oncologists in making treatment decisions for the PD-(L)1 inhibitor class as a whole.[Table: see text]