bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole‐exome sequencing improves genetic testing accuracy in pulmonary artery hypertension
Authors: Zeng Xiaofang , Lian Tianyu , Lin Jianhui , Li Suqi , Zheng Haikuo , Cheng Chunyan , Ye Jue , Jing Zhicheng , Wang Xiaojian , Huang Wei
Published: February 2018

Sanger sequencing, the traditional “gold standard” for mutation detection, has been wildly used in genetic testing of pulmonary artery hypertension (PAH). However, with the advent of whole‐exome sequencing (WES), few studies have compared the accuracy of WES and Sanger sequencing in routine genetic testing of PAH. PAH individuals were enrolled from Fu Wai Hospital and Shanghai Pulmonary Hospital. WES was used to analyze DNA samples from 120 PAH patients whose bone morphogenetic protein receptor type 2 (BMPR2) mutation statuses had been previously studied using Sanger sequencing. The Sanger sequencing and WES agreement was 98.3% (118/120) with near‐perfect agreement (κ coefficient = 0.848). There was no significant difference between the two methods on the McNemar–Bowker test (P > 0.05). Twenty‐one BMPR2 mutation carriers and 99 non‐carriers were detected by Sanger sequencing. Among the 21 BMPR2 carriers detected by Sanger sequencing, one variant (c.1040 T > A) was not found by WES. Among the 99 BMPR2 non‐carriers, WES detected an extra mutation carrier (c.76 + 1 G > C) missed by Sanger sequencing. Both false‐positive and false‐negative results were highly conserved and were re‐analyzed by Sanger sequencing. WES improved the accuracy of Sanger sequencing and detected 1% (1/99) false‐positive and 4.8% (1/21) false‐negative results of Sanger sequencing. No false‐positive and false‐negative results of WES were identified in our analysis. WES is non‐inferior to Sanger sequencing and may play a more important role in genetic testing of PAH patients in the future.
Background and design of the ACCA–EAPCI registry on ST-segment elevation myocardial infarction of the European Society of Cardiology
Authors: Zeymer Uwe , Ludman Peter , Danchin Nicolas , Kala Petr , Maggioni Aldo P , Weidinger Franz
Published: February 2018

Treatment of patients with acute ST-segment elevation myocardial infarction has improved over past decades, with reperfusion therapy being the cornerstone in the acute phase. Based on the results of large randomised trials the current ST-segment elevation myocardial infarction guidelines of the European Society of Cardiology (ESC) recommend acute treatments and secondary prevention therapies. However, there are large variations between ESC countries in the treatment of patients presenting with ST-segment elevation myocardial infarction. Therefore the ESC has initiated a prospective registry to evaluate the current treatments and outcomes of these patients with a special focus on adherence to the ESC guidelines and on differences between countries and regions. This paper describes the methodology and design of the ST-segment elevation myocardial infarction registry conducted in collaboration of the Acute Cardiac Care Association and the European Association of Percutaneous Coronary Intervention.
Negative laparoscopy unveiled
Authors: Jarrell John , Arendt-Nielsen Lars
Published: February 2018

Introduction:

Studies indicate a variable proportion of laparoscopies done for the management of non-acute pelvic pain that do not identify visible pathology and are called negative laparoscopies. Possible explanations have included undetected endometriosis, observer error, and/or neural tissues in the endometrium acting as nociceptive input. The goal was to compare demographic and pain testing measures between women with negative laparoscopies and confirmed endometriosis in a cohort of women presenting with chronic pelvic pain.

Methods:

Women with chronic pelvic pain (n = 255) provided written consent for the study prior to entry. Data were collected at the time of clinic visit and entered contemporaneously into SPSS. Pain sensitization was identified as the presence of cutaneous allodynia. Clinical, pain, and pain sensitization variables were compared using Student’s t-test.

Results:

The frequency of negative laparoscopy was 13.7% (35 cases) and that of confirmed endometriosis was 27.1% (69 cases). There were no differences between women with a negative laparoscopy and women with confirmed endometriosis in clinical, dysmenorrhea, or pain testing measurements.

Conclusion:

The data suggest in the absence of endometriotic tissue in the pelvis, chronic visceral pain may result from a uterine origin and result in a generalized pattern of pain and pain sensitization.
Quinolone-Induced Painful Peripheral Neuropathy: A Case Report and Literature Review
Authors: Estofan Leonel J. F. , Naydin Stanislav , Gliebus Gediminas
Published: February 2018

We present a case report of a 20-year-old male with diabetes mellitus type 1, who developed severe painful peripheral neuropathy while on the second of a 10-day course with levofloxacin for the treatment of epididymitis. The intensity of the pain rapidly reached scores of 10/10 in a numeric scale 0/10, and the patient was transferred to an inpatient pain unit where he was treated aggressively with minimal improvement. A skin biopsy revealed small fiber neuropathy. Then the patient was treated with intravenous immunoglobulin, which improved the pain. Now the patient is on outpatient intravenous immunoglobulin infusions bimonthly and making a slow recovery.
Protein-Losing Enteropathy in the Setting of Severe Iron Deficiency Anemia
Authors: Yasuda Jessica Lacy , Rufo Paul A.
Published: February 2018

A 20-month-old boy presented with a 2-week history of pallor and progressive abdominal distention. Nutritional history revealed long-standing excessive cow milk intake. He was subsequently found to be profoundly iron deficient and hypoproteinemic, with an elevated fecal α-1-antitrypsin level and occult blood positive stool, consistent with protein-losing enteropathy. He was treated with cow milk restriction and oral iron supplements, which resulted in resolution of his edema and laboratory anomalies. While small numbers of previous case reports have described the potential association between excessive cow milk intake and severe iron deficiency and protein-losing enteropathy, this constellation of clinical symptoms is infrequently recognized in clinical practice. As iron deficiency is recognized as the most common nutritional deficiency in the United States, it is important to keep excessive cow milk intake in mind when evaluating young children presenting with severe iron deficiency and protein-losing enteropathy.
Screening for Diabetes Risk Using Integrated Dental and Medical Electronic Health Record Data
Authors: Acharya A. , Cheng B. , Koralkar R. , Olson B. , Lamster I.B. , Kunzel C. , Lalla E.
Published: February 2018

Undiagnosed diabetes and prediabetes present a serious public health challenge. We previously reported that data available in the dental setting can serve as a tool for early dysglycemia identification in a primarily Hispanic, urban population. In the present study, we sought to determine how the identification approach can be recalibrated to detect diabetes or prediabetes in a White, rural cohort and whether an integrated dental-medical electronic health record (iEHR) offers further value to the process. We analyzed iEHR data from the Marshfield Clinic, a health system providing care in rural Wisconsin, for dental patients who were ≥21 y of age, reported that they had never been told they had diabetes, had an initial periodontal examination of at least 2 quadrants, and had a glycemic assessment within 3 mo of that examination. We then assessed the performance of multiple predictive models for prediabetes/diabetes. The study outcome, glycemic status, was gleaned from the medical module of the iEHR based on American Diabetes Association blood test cutoffs. The sample size was 4,560 individuals. Multivariate logistic regression revealed that the best performance was achieved by a model that took advantage of the iEHR. Predictors included age, sex, race, ethnicity, number of missing teeth, percentage of teeth with at least 1 pocket ≥5 mm from the dental EHR, and overweight/obesity, hypertension, hyperlipidemia, and smoking status from the medical EHR. The model achieved an area under the receiver operating characteristic curve of 0.71 (95% confidence interval, 0.69–0.72), yielding a sensitivity of 0.70 and a specificity of 0.62. Across a range of populations, informed by certain patient characteristics, dental care team members can play a role in helping to identify dental patients with undiagnosed diabetes or prediabetes. The accuracy of the prediction increases when dental findings are combined with information from the medical EHR.

Knowledge Transfer Statement: Prediabetes and diabetes often go undiagnosed for many years. Early identification and care can lead to improved glycemic outcomes and prevent wide-ranging morbidity, including adverse oral health consequences, in affected individuals. Information available in the dental office can be used by clinicians to identify those who remain undiagnosed or are at risk; the accuracy of this prediction increases when combined with information from the medical electronic health record.
Customer Value Creation for Risky Products: The Role of Brand Trust and Trusting Beliefs
Authors: Carnevale Marina , Loureiro Yuliya Komarova , Kabadayi Sertan
Published: February 2018

Consumers often perceive products and services as risky. As a result, they might perceive the same products as less valuable. While past research has investigated numerous ways of reducing the negative effect of perceived product risk on customers’ perceived value, surprisingly, the role of brand trust has not been taken into account. This article aims to fill this gap by investigating how consumers’ trust in a brand, as well as their trusting beliefs about the brand’s competence, benevolence and integrity, may moderate the relationship between consumers’ perceived product risk and consumers’ perceived value. By means of two empirical studies based on a panel of smartphone users, the authors propose and demonstrate that the trust customers have for a brand can mitigate the negative effect of perceived product risk on perceived value of products with the same brand name. Importantly, findings also show that the various beliefs underlying trust have differential downstream effects. More specifically, while benevolence and integrity beliefs about a brand mitigate the negative effect of perceived product risk on customers’ perceived value, competence beliefs were found irrelevant to the effect of risk on value. These findings inform and guide marketing practitioners’ efforts to cultivate specific, rather than generic, trusting beliefs to ultimately create and maximize value for their customers who otherwise view these products as risky.
Coagulation factor XII in thrombosis and inflammation
Authors: Maas Coen , Renné Thomas
Published: February 2018

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII–driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII–driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.
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

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

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

In 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 interest

None.
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]
Performance verification of a plasma-based PD-L1 test that reliably measures mRNA expression from patients with NCSLC.
Authors: Mellert Hestia S. , Jackson Leisa , Pestano Gary Anthony
Published: February 2018

156

Background: The detection of circulating nucleic acids using non-invasive blood-draws has become highly relevant to clinical testing. In this study we report on the development of a blood-based PD-L1 test for immunotherapy selection. Methods: We have previously reported on the analytic performance of a droplet digital™ PCR (ddPCR) assay for circulating cytokeratin 19 and PD-L1. Using a variable threshold based on a logistic regression score for the blood assay and a 1% IHC (immunohistochemistry) tissue cut-off, concordance was 80% (n = 16). Positive calls for the blood-based PD-L1 assay ranged from 2 to 124 copies. In this study we focused on variables that could impact concordance of the blood assay and tissue results. Criteria included droplet counts for tissue and blood mRNA transcripts and tumor proportion score (TPS) for the tissue IHC assay (22C3 pharmDx). Results: We examined the correlation between PD-L1 in formalin-fixed paraffin-embedded (FFPE) tissue by IHC, mRNA expression in serial cut FFPE sections, and in matched plasma samples collected at the time of tissue resection. Five cases were assayed to confirm PD-L1 positivity by tissue. We successfully recovered RNA from serial tissue sections for each case and detected PD-L1 levels ranging from 6 to 1272 copies. Plasma samples were available for four of the cases for circulating RNA evaluation, and we were successful in detecting PD-L1 in all cases (copy range 32-138). While all four cases contained detectible PD-L1 mRNA in tissue and circulation, we observed little concordance between these levels in tissue and blood. Conclusions: We have developed methods to measure the dynamic range of PD-L1 from plasma. We have shown feasibility of these methods by evaluating key immune and cancer-specific RNAs. The current study demonstrates that although the development of quantitative assays for mRNA in blood is possible, concordance with traditional clinical tissue assays such as IHC may not be a useful validation measure. We have initiated prospective validation studies that will continue to evaluate PD-L1 expression by IHC and in the blood-based assay, and will also monitor patient performance measures in response to immunotherapy.
Pan-Cancer assessment of tumor mutational burden using a comprehensive genomic profiling assay.
Authors: Nichol Donna , Jones Siân , Angiouli Samuel V. , Keefer Laurel , Nesselbush Monica , Sengamalay Naomi , White James , Simmons John , Diaz Luis A. , Velculescu Victor E. , Sausen Mark
Published: February 2018

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Background: Checkpoint inhibitors (CPIs) have been approved for frontline or subsequent therapies in several indications over the last few years. While patient response can be remarkably durable, many patients do not benefit. Current clinical biomarkers of response to CPIs include microsatellite instability (MSI) and PD-L1 expression. While a proportion of many solid tumors display microsatellite instability, the prevalence is often very low. Similarly, while clinically informative, PD-L1 expression alone is not sufficient to predict therapeutic outcomes with high accuracy. The lack of predictive biomarkers for response highlights the need for improved biomarkers with greater prevalence across tumor types to predict response to CPIs. Multiple clinical studies have revealed that high tumor mutational burden (TMB) is associated with improved clinical response. Methods: Here, we describe the development of a method that can be used to accurately infer mutational burden from a discrete set of targeted regions of interest across the exome. Initially, we performed an assessment of the accuracy across multiple bioinformatics methods for identification of individual sequence mutations (SBS/indels) using orthogonally validated data together with publicly available TCGA whole-exome sequencing data. The targeted regions were then isolated from these datasets to demonstrate analytical performance across several different solid tumor types. Finally, we evaluated independent non-small cell lung cancer (NSCLC) and colorectal carcinoma (CRC) cohorts to demonstrate the analytical accuracy of the assay and bioinformatics approach for determination of mutational burden when compared to whole exome sequencing. Results: In summary, high concordance was observed across a large dynamic range of mutations per megabase of coding sequence. Conclusions: Our data indicate that the assay can be used to accurately determine mutational burden in a range of tumor types, across a spectra of potential mutational burden cut-offs using automated, complex mutation identification algorithms.
Clinical significance of humoral immunity against XAGE1 cancer-testis antigen in lung adenocarcinoma.
Authors: Oka Mikio , Kurose Koji , Isobe Midori , Fukuda Minoru , Ohue Yoshihiro
Published: February 2018

162

Background: Cancer-testis antigens (CTAs) are expressed predominantly in the testis and various types of cancer. Some of CTAs are highly immunogenic and attractive targets for cancer immunotherapy. We identified XAGE1 as a dominant CTA in lung adenocarcinoma (LAD). In this study, we examined immune responses to XAGE1 and the clinical significance in LAD patients. Methods: Expression of XAGE1 and immune checkpoint molecules in LAD tissues was determined by immunohistochemistry. The XAGE1 antibody and T cell immune responses were analyzed in blood samples. Then, overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1 antibody-positive and -negative patients was analyzed. Results: The XAGE1 antigen was expressed in approximately 40% of LAD, and the expression reflected shortened OS of pStage I-IIIA LAD in two japanese cohorts. In addition, expression profiles of XAGE1 and immune checkpoint molecules of PD-L1 and galectin-9 on tumor cells efficiently predicted OS of pStage I-IIIA LAD patients. The XAGE1 antibody response was observed in 6% (9/155) of our pStage I-IIIA, and 20% (34/167) of cStage IIIB-IV LAD, respectively, showing a higher antibody response rate in more advanced stages. In the antibody-positive patients, CD4 and CD8 T cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, the OS of antibody-positive patients significantly prolonged as compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs 15.6 months, P = 0.05) or EGFRmt (34.7 vs 11.1 months, P = 0.001) LAD. Multivariate analysis showed that the XAGE1 antigen expression was a worse predictor in EGFRmt LAD (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in XAGE1 antigen positive LAD (HR: 0.18) and in either EGFRwt or EGFRmt LAD. Conclusions: The XAGE1 antigen induced strong immune responses in LAD patients with more advanced stages, and the production of XAGE1 antibody in these patients showed good prognosis. Our results indicate that the XAGE1 immunity is probably a good prognostic biomarker in LAD and a promising target for immunotherapy of LAD.
Efficacy of checkpoint inhibitors, tumor vaccines, and cellular immunotherapies in patients with advanced non-small cell lung cancer.
Authors: Yu Yunfang , Ou Qiyun , Wang Ying , Liu Zhifeng , Fu Tuping , Gao Quanlong , Lin Dagui , Yao Herui
Published: February 2018

165

Background: Checkpoint inhibitors, tumor vaccines or cellular immunotherapies demonstrated prolonged survival versus placebo or observation in several randomized clinical trials (RCTs) of patients with advanced non-small-cell lung cancer (NSCLC). We aimed to clarify the benefits of imunotherapy by a meta-analysis of RCTs data. Methods: We searched for RCTs investigating immunotherapy versus placebo or observation in patients with advanced NSCLC. Overall survival (OS) and progression-free survival (PFS) were calculated as combined hazard ratios (HRs). The quality of the evidence was evaluated with the GRADE framework. Results: Overall, 23 RCTs including a total of 8,956 patients were identified (5,142 patients in the immunotherapy group and 3,814 in the placebo or observation group). High- to moderate-quality evidence indicated that immunotherapy prolonged OS (HR = 0.79, 95% confidence interval (CI) 0.75 to 0.84, P < 0.0001) and PFS (HR = 0.80, 95% CI 0.73 to 0.88, P < 0.0001). In subgroup analysis, high- to moderate-quality evidence revealed immunotherapy extended NSCLC survival and PFS in tumor vaccines (HR, 0.84, 95% CI 0.76 to 0.92 and 0.86, 95% CI 0.78 to 0.94 for OS and PFS, respectively), checkpoint inhibitors (0.77, 95% CI 0.72 to 0.83 and 0.78, 95% CI 0.68 to 0.90, respectively), maintenance therapy (0.77, 95% CI 0.71 to 0.83 and 0.78, 95% CI 0.66 to 0.91, respectively), first-line therapy (0.89, 95% CI 0.80 to 0.98 and 0.76, 95% CI 0.64 to 0.91, respectively), previous definitive chemotherapy (0.72, 95% CI 0.67 to 0.78 and 0.87, 95% CI 0.79 to 0.95, respectively), and concurrent chemotherapy (0.87, 95% CI 0.80 to 0.95 and 0.84, 95% CI 0.77 to 0.91, respectively). There was a benefit of immunotherapy in previous definitive chemotherapy compared with chemoradiotherapy and with concurrent administration of chemotherapy (OS as HR: P = 0.002 and P = 0.006, respectively). Conclusions: This analysis provides strong evidence for OS and PFS benefit of immunotherapy in patients with advanced NSCLC, particularly in those receiving tumor vaccines, checkpoint inhibitors, maintenance and first-line therapy, previous definitive chemotherapy, and with concurrent chemotherapy.
Comprehensive immune and mutational profile of melanoma.
Authors: Conroy Jeffrey M. , Pabla Sarabjot , Ernstoff Marc S. , Puzanov Igor , Nesline Mary , Glenn Sean T. , Papanicolau-Sengos Antonios , Burgher Blake , Andreas Jonathan , Giamo Vincent , Qin Maochun , Lenzo Felicia L. , Gardner Mark , Morrison Carl
Published: February 2018

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Background: The association between tumor mutational profiles and immune signatures has not been well-characterized. Methods: 306 melanoma samples were tested by NGS using a comprehensive cancer panel for mutational status and an immune response panel which interrogates the expression profile of 54 validated immune-related genes. The ranking of gene expression, mutational burden and 7 immune phenotypes was compared to a reference population. 38% cases were positive for activating BRAF mutations, 12% for RAS, and 6% for NF1. The remaining 44% were considered triple wild type. Principal component analysis (PCA) followed by hierarchical clustering was performed to determine association of BRAF/RAS/NF1 mutations and triple wild type with immune phenotypes, mutational burden and gene expression as measured by the NGS panels. Results: PCA showed that the first and second dimension explain 86% of the variation in the mutation profiles of the 306 melanomas. The first principal component highly correlated with BRAF positive status (pval < 0.001), the second highly correlated with RAS positive status (pval < 0.001), and the third principal component, although not informative, highly correlated with NF1 status (pval < 0.001) and Mutation Burden (pval < 0.001). Hierarchical clustering of the samples resulted in 4 distinct clusters: RAS positive, BRAF Positive, NF1 positive and triple wild type. The RAS positive cluster demonstrated significantly lower expression of ICOSLG, ICOS, CD4, C10orf54, CD40 and CD244 genes. Similarly, the BRAF positive cluster under-expresses immune escape and proinflammatory immune phenotypes, but over-expressed OX40L. The NF1 positive cluster had significantly higher mutational burden than other clusters. On the contrary, the triple wild type cluster over-expressed 6 out of 7 immune phenotypes. Conclusions: BRAF/RAS/NF1 mutation status are immunophenotypically distinct and do not associate with a typical immune phenotype in the tumor microenvironment. Triple wild type samples present with an overall activated immune phenotype, representative of an inflamed tumor. Additional studies are necessary to include additional activating or loss of function mutations to expand these findings.