bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of bee venom therapy in animal model of statin-induced myopathy
Authors: Kader Ann Abdel , Azmy Radwa , Maher Eman A. , El Sayed Basma Bahgat , Khalil Alshaimaa Sobhi , Ghalwash Mohammad , Mahmoud Manal
Published: November 2019

Background

Statin-induced myopathy is the most common adverse effect of statins. Bee venom provides a potential mean of controlling immune responses and inflammatory reactions; the proposed mechanisms for statin-induced myopathy.

Objective

The present study aimed at clarification of the role of the bee venom in prevention of statin-induced myopathy.

Materials and methods

It was carried out on 30 Sprague-Dawley female rats. Rats were randomly classified into 3 groups: control group, statin group which received statins for 2 weeks, and venom group that was exposed to alternate day actual bee sting concurrent to statins administration for 2 weeks. Quantitative electromyography (QEMG) was performed as well as serum creatine kinase (CK) and cholesterol levels, in addition to in vitro muscle contractility tests.

Results

QEMG and contractility tests showed significant changes in the statin group compared to both control and venom groups. Serum cholesterol level decreased with increase in CK levels in the statin and venom groups compared to controls; however, the CK level was significantly lower in the venom group as compared to the statin group.

Conclusion

Bee venom therapy offers a simple and available means of prophylaxis against the myopathic effects induced by statins in animal model. However, it partly restricts the therapeutic effect of statins.
Phylogenetic relationships of some Egyptian soybean cultivars (Glycine max L.) using SCoT marker and protein pattern
Authors: Rayan Walaa A. , Osman Samira A.
Published: November 2019

Background

Electrophoretic SDS-PAGE and SCoT-PCR techniques were used to study the fingerprints and genetic diversity of six Egyptian soybean (Glycine maxL.) genotypes (Giza111, Giza21, Giza82, Giza35, Giza22, and Giza83).

Results

SDS-PAGE revealed a total of 23 bands with a polymorphism 30.43%. The maximum number of bands (22) was recorded in Giza111 and Giza82, while the minimum number of bands (18) was recorded in Giza35. The highest similarity index for SDS- PAGE (0.909) was observed between Giza111 and Giza82, while the lowest similarity index (0.714) was recorded between Giza35 and Giza83. SCoT technique was performed by using 11 primers to generate reproducible polymorphic products. The total number of bands was 106, from them 52 polymorphic and 54 monomorphic bands with a polymorphism 49.11%. The dendrogram of both SDS-PAGE and SCoT markers revealed two main clusters; the first cluster includes the cultivars Giza111and Giza21, while the second cluster includes the cultivars Giza82, Giza35, Giza22, and Giza83. The second group was further subdivided into two subgroups; the first subgroup includes cultivars (Giza82 and Giza35) while the second subgroup includes cultivars Giza22 and Giza83.

Conclusion

The markers used in this study created a number of polymorphic bands among the different cultivars that can be utilized as molecular markers for their differentiation. The obtained data indicated that SCoT and SDS-PAGE techniques could be used efficiently for identification and differentiation of the selected genotypes.
Utility of magnetic resonance proton density fat fraction technique in quantification of liver fat in living donors for liver transplantation
Authors: Sherif Fatma Mohamed , Elmogy Sabry Alameldeen , EL-wahab Rihame Mohamed Abd , Wahab Mohamed Abdel
Published: November 2019

Background

Hepatic steatosis in living donors for liver transplantation causes morbidity of both donor and recipient. This study aims at evaluating magnetic resonance proton density fat fraction technique (MR PDFF) in quantitative evaluation of living donor’s hepatic steatosis compared to histopathology.

Results

The examined potential living liver donors’ liver biopsies revealed hepatic steatosis < 5% (grade 0) in 40 donors and 5–10% (grade 1) in 7 donors. MR PDFF technique with IDEAL sequence showed excellent results for prediction and quantitative evaluation of liver fat with sensitivity, specificity, and accuracy of 85.7%, 97.5%, and 95.7%, respectively, compared to histopathology (95% confidence interval 0.98–1.01). There was an excellent inter-reader agreement between both readers in estimation of MR liver fat fraction (r = 0.969 at 95% confidence interval 0.946–0.983).

Conclusion

Noninvasive hepatic MR PDFF technique with IDEAL sequence is a precise reliable technique for pre-operative quantitative assessment of hepatic steatosis in potential living liver donors.
The role of multidetector CT angiography in characterizing vascular compression syndromes of the abdomen
Authors: Sankaran Lakshmi , Ramachandran Rajoo , Bala Raghu Raji Venkatesh , Periasamy Varadaraju Prithiviraj , Panneerselvam Pranesh , Radhakrishnan Prabhu Radhan
Published: November 2019

Background

Various abdominal vessels can compress the adjacent structures or in turn can get compressed by them. Most of these compression syndromes present with non-specific symptoms. Unlike the common causes of acute abdomen, the various vascular compression syndromes have bizarre clinical presentations and subtle imaging findings, which can easily be missed by the physicians as well as the radiologists.

Main body of the abstract

This is a retrospective study which was done for a period of 3 years from April 2015 to April 2018 using a 64-slice CT scanner. Among 2412 cases that came for evaluation, 114 patients were diagnosed to have one of the various vascular compression syndromes. These 114 cases were further managed either conservatively or surgically depending on the pathology and the severity of the compression. The syndromes discussed in this article include median arcuate ligament syndrome (29 cases), superior mesenteric artery syndrome (23 cases), portal biliopathy (3 cases), nutcracker syndrome (6 cases), pelvi-ureteric junction obstruction due to crossing of vessels (8 cases), and retrocaval ureter and May-Thurner syndrome (45 cases).

Conclusions

The primary goal of this article is to reinforce the knowledge of the radiologists of the various vascular compression syndromes and to make them possess a high degree of vigilance to detect them. This article elaborates the imaging findings of these syndromes and the role of multidetector CT angiography in diagnosing them.
Clinical benefit and toxicity of nivolumab plus ipilimumab in patients with advanced melanoma previously treated with checkpoint blockade inhibitors.
Authors: Friedman Claire Frances , Wolchok Jedd D. , Postow Michael Andrew , Shoushtari Alexander Noor , Callahan Margaret K. , Momtaz Parisa , Chapman Paul B.
Published: November 2019

100

Background: The combination of nivolumab and ipilimumab (nivo+ipi) prolongs progression-free survival in treatment-naïve patients (pts) with advanced melanoma. However, the efficacy and tolerability of nivo+ipi in pts previously treated with checkpoint blockade inhibitors (CPI) are unknown. Methods: 19 pts previously treated with CPI (ipi or anti-PD-1 as single agents) were treated with nivo+ipi at MSKCC. Ipi (3mg/kg) and nivo (1mg/kg) were administered q3 weeks for 4 doses with the option to continue anti-PD1 maintenance. Pts were followed for time to treatment failure (TTF), defined as the time from the date of first nivo+ipi infusion to the date of one of the following: clinical progression, new locally-directed treatment (ie surgery or radiotherapy), new systemic treatment other than anti-PD-1 monotherapy, or death. Results: 15 pts (79%) had stage M1c disease and 12 (63%) had a cutaneous primary. Pts had received a median of 2 prior systemic treatments (range 1-7). 10 pts (53%) had received prior ipi and 17 pts (89%) had received prior anti-PD-1 treatment; 8 pts (42%) had received both. The median time between anti-PD-1 monotherapy and nivo+ipi was 51 days (range 20-385). Pts received a median of 3 doses of combination therapy; 9 of 19 pts (47%) received all 4 doses. With a median follow-up time of 210 days, 8 pts (42.1%) remained on combination immune therapy, 9 pts (47%) switched systemic treatments or had a local procedure and 6 pts (31.6%) died. Median time on immunotherapy for those still alive and without treatment failure was 105 days (range 26-343). The median TTF was 78 days (range 42-220). The most common systemic treatment after nivo+ipi failure was BRAF-targeted therapy (5/9 or 56.3%). The median number of immune related adverse events (irAEs) was 1 (range 0-3). Rash (26%), Hepatitis (16%) and Colitis (16%) were the most common irAEs. Conclusions: With a short median follow-up, administration of nivo+ipi in CPI-experienced patients with advanced melanoma was associated with a short TTF. 58% of patients died or had treatment failure within the follow-up period. More research is needed to guide the utilization of combination immunotherapy in this setting.
Overcoming resistance to immune checkpoint blockade with RNA-loaded nanoparticles.
Authors: Sayour Elias Joseph , Grippin Adam , Mitchell Duane Anthony
Published: November 2019

117

Background: While checkpoint blockade has shown promising survival benefits in patients with solid tumors, immune escape through loss of MHCI expression juxtaposed to an immunoregulatory milieu remain significant hurdles. To overcome these limitations, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA to activate systemic immunity and re-program the intratumoral microenvironment from a regulatory into an immune activated locale. Methods: Since local vaccination strategies are mired with poor immunogenicity, we assessed if i.v. delivery of tumor-derived RNA encapsulated in lipophilic NPs could activate peripheral and intratumoral antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine melanoma models. Results: We identified a clinically translatable NP formulation that when administered intravenously, mediates release of inflammatory cytokines (i.e. CCL2, IFN-alpha) into serum, systemically activates host APCs in reticuloendothelial organs, and induces precipitous upregulation of MHCI and immune activation markers (i.e. CD86) within the tumor microenvironment. Both model-antigen encoding RNA and physiologically-relevant tumor-derived RNA, when encapsulated in NPs, could expand potent anti-tumor T-cell immunity. We demonstrated that RNA-NPs harness the anti-viral defense mechanism against tumor antigens in a type I interferon dependent manner, and can be further engineered to deliver combinatorial therapies by co-encapsulating mRNAs encoding for immunomodulatory molecules (i.e. HCV PAMPs, GM-CSF). In a pre-clinical melanoma model, RNA-NPs mediate anti-tumor efficacy and significantly enhance activity of immune checkpoint mAbs when used in combination. Conclusions: By employing a systemic RNA-NP formulation encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for delivering combinatorial therapeutics via a single treatment modality, this platform can be harnessed to simultaneously target tumor antigens and re-program the intratumoral microenvironment
Prognostic significance of professional antigen presenting cells according to morphological subtype of periampullary adenocarcinoma.
Authors: Lundgren Sebastian , Warfvinge Carl Fredrik , Elebro Jacob , Nodin Bjorn , Krzyzanowska Agnieszka , Bjartell Anders , Karnevi Emelie , Eberhard Jakob , Leandersson Karin , Jirstrom Karin
Published: November 2019

121

Background: Dendritic cells (DCs) and macrophages play vital roles in tumorigenesis and may, depending on the context, promote or inhibit tumor progression. In this study, we examined the prognostic significance of DCs and macrophages in periampullary adenocarcinoma, with particular reference to morphological type. Methods: Immune cell-specific expression of CD68, CD163 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analysis were applied to determine the impact of the investigated cells on 5-year overall survival (OS). Results: Low density of CD68+ cells or CD163 + cells was significantly associated with an improved 5-year OS in unadjusted Cox regression analysis in the entire cohort (HR = 1.66; 95% CI 1.05-2.63 and HR = 1.84; 95 % CI 1.09-3.09, respectively), but not in adjusted analysis or in strata according to subtype. CD1a+ cell density was not prognostic in entire cohort or in I-type tumours. However, in PB-type tumors, high CD1a+ cell density was significantly associated with a reduced OS in unadjusted as well as in adjusted analysis (HR = 2.09; 95% CI 1.07-4.09 and HR = 2.35; 95% CI 1.13-4.87). The prognostic value of the investigated markers did not differ in strata according to adjuvant chemotherapy, neither in the entire cohort nor according to morphological type. Conclusions: The results from study demonstrate that the prognostic significance of dendritic cells, but not macrophages, differs by morphological subtype in periampullary adenocarcinoma. Hence, morphological subtype is an important factor to consider in studies on the prognostic and predictive role of the immune microenvironment in these types of cancer.
Changes in peripheral lymphocyte subpopulations following radiation therapy.
Authors: Campostrini Franco , Zorzi M , Capodaglio G , Guizzardi E , Nicolis E , Battaglia P
Published: November 2019

128

Background: Since ionizing radiation can affect the immune system, in this research we sought to analyze the changes of peripheral blood lymphocyte subpopulations (LS) in patients undergoing Radiation Therapy (RT). Methods: In 2015 we enrolled 58 patients, 97% with no systemic cancer (breast 47%, prostate 23%,head and neck 16%, abdomen-pelvis 11%, metastases 3%). The percentages of patients with lowered LS were determined prior to RT, and at different intervals in the patients’ history.The average dose of RT was 50Gy (+/-10 ) with 2 Gy/day fractions. Results: As baseline, total T lymphocytes, T helper, T suppressor, B lymphocytes and Natural Killer cells, were reduced vs. normal range in 24%, 33%, 24%, 59% and null of patients, respectively.A second blood sample was withdrawn after 14-58 days (mean 36) from starting RT, in which we found significantly increased the patients damaged up to 66%, 65%, 62%, 88% and 7% (p=< 0,0001 for each LS ). Compared with the nadir of LS depletion, at 44 (5-180) and 153 (43-130) days from the completion of RT, all the LS raised significantly, except for a weak value of T Helper category (p=0,0145 and 0,0226 respectively). Conclusions: After common RT regimens for solid tumors, all LS can be substantially impaired, and for the T Helper the recovery is particularly slow in the following months.
Immunomodulatory pathways in both breast cancer and placental tissues: Insights from a unique clinical and genomic case report.
Authors: Hernandez Bronchud Miguel
Published: November 2019

13

Background: some cancers might partially ectopically express intrinsic immune escape gene programs naturally developed during mammalian evolution to allow for materno-fetal immune tolerance. Methods: Genomic analysis (Nanostring Inc, Seattle, WA, USA) was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman (same patient). Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Results: Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (placenta) and pathologically ( cancer). Placenta and uterus, breast tissues (tumor and normal) and lymph node tissues (tumor and normal) formed their own RNA transcription cluster, suggesting that tissue specific gene expression patterns were well preserved during experimental procedures . We analyzed differential expression within each tissue type (i.e. matching for the analysis placenta with uterus, breast cancer with normal breast tissue and node positive with node negative tissue). Among the 583 genes analyzed, 103 genes were upregulated > 1.5 fold in placenta versus uterus, while 258 genes were downregulated at least 1.5 fold. Using the same cut-off, 258 genes were upregulated and 44 genes downregulated in breast tumor versus normal breast tissue, and 178 genes were upregulated while 146 genes downregulated in tumor bearing lymph node versus non-involved lymph node. Conclusions: A variety of complex immune regulation mechanisms seem to be shared by both placental tissues and cancer.
Safety, efficacy, and immunogenicity of autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: A phase I trial.
Authors: Sato Yasuyoshi , Matsushita Hirokazu , Mori Kazuhiko , Kakimi Kazuhiro , Seto Yasuyuki
Published: November 2019

153

Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted a phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. Methods: Patients (pts) with stage IIA (T2N0 or T3N0, UICC TNM classification 6th edition) esophageal cancer after curative (R0) resection, ECOG PS 0-2, 20 years or more and adequate organ function were eligible. We used tumor lysate for DC vaccines; the lysates potentially contain mutated proteins or neoantigens derived from somatic mutations in each patient's tumor. Patients received DC vaccines (more than 5.0×106 cells) 6 times every 2 weeks. Primary endpoint was safety and secondary endpoint were efficacy including recurrence rate and immunological responses. Results: A total of 11 pts (median age: 71 years) were enrolled until the trial stopped on March 31, 2016, because standard of therapy for objective patients had changed. No treatment related adverse events of grade 3 or 4 were reported. Recurrence rate within 2 years were 18% (n=2). We performed whole-exome sequence of tumors and adjacent normal tissues with 5 pts, and identified mutated peptide derived from their tumor specific missense mutations. To examine immune responses against those predicted candidate neoepitopes, we immunized HLA-A2 transgenic mice (HHD-II mice) with the synthesized peptides from the 2 pts harboring HLA-A2. Conclusions: This study showed that autologous tumor lysate-pulsed DC vaccination therapy is safe and have expectation of recurrence risk reduction after resection of T2N0 or T3N0 esophageal cancer. Clinical trial information: UMIN000002837.
Immunological changes following intraperitoneal administration of a formulated IL-12 plasmid in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.
Authors: Anwer Khursheed , Matsuzaki Junko , Bshara Wiam , Lugade Amit , Omilian Angela , Thaker Premal H. , Bradley William Hampton , Leath Charles A. , Gunderson Camille Catherine , Fewell Jason , Borys Nicholas , Musso Lauren , Odunsi Kunle
Published: November 2019

156

Background: The translational component of a Phase I study of weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). Our hypothesis is that the GEN-1 plus NAC treatment will reprogram the tumor immune microenvironment towards a potent antitumor immune response. Methods: Patients received GEN-1 at escalating dose levels from 36 mg/m2, 47 mg/m2, 61 mg/m2, to 79 mg/m2weekly for 8 treatments with concurrent T/C. Tumor samples collected at time of diagnostic laparoscopy and interval debulking (IDB). Blood and peritoneal ascites were collected before and after treatment. The immunological analysis included frequency of immune cell populations and cytokine levels in tumor, blood, and peritoneal ascites and cell-specific mRNA expression profile. Results: The preliminary results obtained from first two cohorts show that GEN-1 may be enhancing post-treatment changes in immune cell populations including an increase in cytotoxic CD8+ T-cells and decrease in immunosuppressive FoxP3+ T-reg cells in tumor at IDB. The CD8:Foxp3 ratio appeared to be skewing beneficially towards more cytotoxic T lymphocyte and away from suppressive cells in most patients. The analysis of circulating immune cells 21 days after first GEN-1 treatment showed a decrease in circulating CD123+ plasmacytoid dendritic cells, but no change in CD11c+ myeloid dendritic cells. There were no major changes in the frequency of circulating T-cells. Additional analyses from this study are in progress. Conclusions: Based on preliminary analyses of cohorts 1 & 2 samples analyzed, the treatment of EOC patients with GEN-1 and NAC has resulted in favorable immunological responses. Updated results to be presented at meeting. Clinical trial information: NCT02480374.
Oncolytic viruses: New era in cancer therapy.
Authors: Rasmy A. , A. Amal
Published: November 2019

161

Background: Modern technology has afforded the human race with a new treatment for cancer using immunotherapy, and the Oncolytic Viruses (OVs) represent a new class of this type of therapeutic agent. Targeted therapy of cancer using OVs has generated much interest over the past few years in light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. Methods: By definition, OVs are a type of virus that infect and lyse cancer cells, but healthy cells are left intact. OVs can occur naturally or can be synthesized in the laboratory through the alteration of other viruses. The OVs immunotherapy treats cancer patients by using native or genetically modified viruses that selectively replicate within tumor cells. The mechanisms of action are not entirely understood but are likely dependent on viral replication within transformed cells, induction of primary cell death, interaction with tumor cell antiviral elements, and initiation of innate and adaptive anti-tumor immunity. Results: On 27 October 2016, the FDA approved the first genetically engineered virus called talimogene laherparepvec (T-VEC or Imlygic) to treat advanced melanoma. A treatment course with Imlygic consists of injections into the melanoma lesions. After the first injection, a second one is administered after three weeks, then additional doses every two weeks for at least six months. Conclusions: The OVs immunotherapy is a highly promising approach and introduces a new class of drugs for treating cancer patients particularly in combination approach. Additional studies are required to learn more about the mechanism of action and to understand how this new class of drug can improve the prognosis of cancer patients. As continuing work is being done to improve the OVs that are currently available, new viral species are also emerging and are worth exploring.
CD70 as a critical mediator of tumor progression and immunosuppression in gliomas.
Authors: Yang Changlin , Ge Haitao , Jin Linchun , Wang Qiong J. , Yang James C. , Long Yu , Chang Yifan(Emily) , Drake Jeffrey , Mu Luyan , Sayour Elias Joseph , De leon Gabriel , Kubilis Paul , Kresak Jesse , Lu Dunyue , Kong Yingjun , Hu Li , Sun Jiahang , Mitchell Duane Anthony , Lin Zhiguo , Huang Jianping
Published: November 2019

18

Background: For malignant gliomas, current treatment modalities are rarely curative, necessitating development of novel therapies. Cancer immunotherapy has represented one of the most promising new treatment strategies for patients with gliomas based on the evidence that patients with brain tumors are able to mount immune responses against the autologous tumors. However, very few tumor specific targets have been discovered in this malignancy. Thus, identifying clinical useful targets for immunotherapeutic approaches is desperately needed. Methods: CD70 expression was tested from primary GBM and low grade gliomas patient tissues. CD70 gene expression and clinical outcomes were culled from TCGA datasets. CD70 inducing CD8 T cells death was performed by flowcytometry. Results: We demonstrate that CD70, a member of the TNF ligand family, was constitutively overexpressed by primary IDH-wild-type LGG and GBMs with mesenchymal gene signatures. Elevated CD70 expression was also found in recurrent tumors and correlated with tumor progression and poor survival outcome in LGGs and GBMs. CD70 was shown to be directly involved in tumor-chemokine production and associated with sustained T regulatory cells in tumor. Importantly, CD70 played a role inducing CD8+T- specific cell death via engagement of the EREG-EGFR axis in glioma. Conclusions: CD70 is a multi-pronged modulator of immunosuppression in gliomas and enhances tumor progression.
Diagnostic accuracy of molecular tumor profiling in determining the tissue of origin in adult patients with cancer of unknown primary: A meta-analysis.
Authors: Inocencio Rowena Torres , Kesari Kavitha , Smith Susan
Published: November 2019

20

Background: Appropriate cancer treatment requires determination of the primary site of origin. The standard of care for diagnosing Cancer of unknown primary (CUP) based on the 2016 NCCN Guidelines is a comprehensive clinical work-up including biopsy and immunohistochemistry (IHC). However, IHC was able to identify a primary tumor in only 25% of CUP. Molecular tumor profiling (MTP) validation studies demonstrated sensitivities of 74-89% and specificities of 95-99%. Only a few studies with small sample sizes using MTP to diagnose the primary in CUP have been performed yielding variable results. This study aims to evaluate the diagnostic accuracy of MTP in determining the tissue of origin in adult patients with CUP. Methods: Literature search included articles published in any language indexed in MEDLINE and Cochrane. A Google Scholar search and a review of all published articles’ references were performed. Unpublished studies and abstracts from conference proceedings were also reviewed. Studies involving adult patients with CUP who underwent both MTP and clinical evaluation with IHC were identified. Articles were included if they had primary data sufficient to calculate both sensitivity and specificity. Methodological qualities of the included studies were evaluated using the QUADAS-2 tool. Data was analyzed using Review Manager 5.3 and MetaDiSc 1.4. Results: Seven studies with 549 patients were analyzed. MTP was found to have a pooled sensitivity of 89% (95% CI 0.85-0.92)and pooled specificity of 74% (95% CI 0.67-0.80)with pooled positive and negative likelihood ratios of 2.97 (95% CI 1.17-7.63) and 0.20 (95% CI 0.07-0.51), respectively. Area under the curve was measured to be 0.9107. Conclusions: This meta-analysis suggests that MTP could be useful in determining the tissue of origin in adult patients with CUP. With an area under the curve of 0.9107, it is an excellent diagnostic test. The results showed considerable heterogeneity as expected in meta-analyses of diagnostic test accuracy. In this case, it may be due to variability among the MTP assays used which may reflect different cutoffs.
Prognostic value of CD8+ tumor-infiltrating lymphocyte density and PD-L1 expression in tumor cells in thymic epithelial tumors.
Authors: Katsuya Yuki , Horinouchi Hidehito , Goto Yasushi , Kanda Shintaro , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Watanabe Shun-ichi , Motoi Noriko , Ohe Yuichiro
Published: November 2019

21

Background: The prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in thymic epithelial tumors (TETs; thymoma [TM] and thymic carcinoma [TC]) is unknown. We examined whether the density of CD8+ TILs and the PD-L1 expression level in TETs were correlated with patient outcome. Methods: Immunohistochemistry and a semi-automated software quantification analysis were used to examine formalin-fixed paraffin-embedded specimens from patients with TET who had been treated with chemotherapy. The density of CD8+ TILs was evaluated at two representative sites: within the tumor nest (intratumoral CD8), and at the invasive margin (stromal CD8, if evaluable). The average density of CD8+ TILs was used as the cut-off value, while an H-score of 5% was used as the cut-off for PD-L1 expression. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate prognostic factors. Results: Twenty-six patients (TM/TC 9/17) were evaluated. A high intratumoral CD8 density was correlated with a superior outcome in terms of both PFS (median, 7.6 vs 27.7 months; P = 0.002) and OS (median, 54.3 months vs not reached; P = 0.022) among the patients with TM, and a similar tendency was seen among the patients with TC, although the correlations were not statistically significant. PD-L1 expression was not significantly correlated with patient outcome in the TM and TC groups. Univariate and multivariate analyses demonstrated that a high intratumoral CD8 density was a significant predictive factor for PFS (Hazard ratio, 0.25 [95%CI 0.08–0.75]; P = 0.014) and OS (Hazard ratio, 0.06 [95%CI 0.007–0.44]; P= 0.006), whereas PD-L1 expression was not. The tendency for a change in the intratumoral CD8 density in pre/post-chemotherapy TM specimens was not consistent. The proportion of stromal CD8 density to intratumoral CD8 density in the TC specimens was not correlated with survival. Conclusions: A high intratumoral CD8 density had a positive prognostic impact for patients with TETs, especially those with TMs. The impact of this immune-related factor should be validated in a larger cohort.
Neutrophil lymphocyte ratio (NLR) as a predictor of outcomes with immune checkpoint inhibitor (ICI) therapy in genitourinary cancer and melanoma.
Authors: Jeyakumar Ghayathri , Bumma Naresh , Kim SeongHo , Landry Craig , Weise Amy , Flaherty Lawrence E. , Heath Elisabeth I. , Silski Cynthia , Zechar Erich , Vaishampayan Ulka N.
Published: November 2019

37

Background: Immunotherapy, such as PD-1 and PD L1, has been recently approved in melanoma and genitourinary cancers (GU) such as renal cell carcinoma and urothelial carcinoma. There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR (ratio of absolute values of neutrophils to lymphocytes) as predictors of response, progression free survival (PFS) and overall survival (OS) in patients treated with PD1 or PD L1 inhibitors. We extrapolated from renal cell data with NLR and used a value of 4 as cutoff. Other known prognostic clinical factors assessed were age, race, and smoking status. Methods: Regulatory approval was obtained. A retrospective chart review of melanoma and genitourinary cancer patients at Karmanos Cancer Institute, treated with ICI was conducted. Data were collected on demographics, smoking status, pretherapy NLR, and post 4 doses of ICI. Association with clinical outcomes (response rate, PFS and OS) was conducted by univariable and multivariable analyses. A log-rank test was used to compare PFS and OS. Results: 143 pts, (59 GU and 84 Melanoma) were evaluated with median age of 61yrs (range, 24-87). 11 pts (19%) and 5 (6%) were African American (AA) in GU and melanoma respectively. 61 pts (43%) were smokers in total. Pretherapy NLR<4 and ≥4 was seen in 97(68%) and 46 (32%) pts. The table summarizes the results of the analysis. Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in GU and melanoma cancers. NLR is an easily applicable predictive factor, however validation of this observation is required in a larger sample size. [Table: see text]
The pan-cancer, pan-biomarker landscape for precision immuno-oncology.
Authors: McLeod Howard L. , Berglund Anders E. , Yao Jiqiang , Avedon Melissa , Teer Jamie K.
Published: November 2019

43

Background: Precision medicine has the opportunity to also change medical practice. However, there are many cancer treatments for which there are few tools for individualized selection based on patient-specific attributes. This is especially the case for the immune check point inhibitors, where a subset of patients receive almost unimaginable benefit, there is a significant incidence of severe, life threatening, and persistent autoimmune oriented toxicities, and the financial burden is real for patients. At least 3 distinct predictive immunooncology biomarkers (IOMark) have been proposed. This includes tumor mutation analysis, expression of PD-L1, and tumor-specific t cell subset (Weber Predictor). However, there is little data on the intrapatient relationship of these putative response markers. Methods: Analysis of individual patient IOMark status was determined in TCGA patients that had cancers for which immunotherapy is FDA approved (n = 2039; bladder, colorectal, kidney, lung, melanoma, stomach). Patients were categorized as putative high/low predicted responders for each biomarker [neoantigen burden (whole exome cutpoint = 225), PD-L1 (median), Weber predictor (upper 50% for each of CD8/Ki67/EOMES)]. Results: A high neoantigen burden was detected in 1%-60% of the tumors (median 31%; range kidney to melanoma). There was less variance for high PD-L1 (26%-78%, median 49%; colorectal to lung). The Weber predictor ranged from 2% to 41% (kidney to stomach). A subset of each cancer type were positive for each of the response markers (0% to 12%; median 6%; renal to stomach). There is not a high association between the IOMarks. Conclusions: Immuno-oncology is in need of robust IOMark, to allow more informed patient treatment. Analysis of the currently most promising IOMarks show high variation across tumor types and within tumor types. Only a subset of patients has high response predicted for all 3 IOMarks. The IOMarks are independent and identify distinct patient features.
Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.
Authors: Barros e Silva Milton Jose , Salgado Boneti Bianca , de Moares Rafael
Published: November 2019

48

Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent. Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected. Results: 54 patients with histologiacally confirmed MM were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.
Single-cell cytokine profiling of tumor-infiltrating T cells to measure patient responses to anti-PD-1 therapy.
Authors: Mackay Sean , Flynn Brianna , Morse Kevin , Paczkowski Patrick , Bacchiocchi Antonella , Fan Rong , Halaban Ruth , Zhou Jing
Published: November 2019

49

Background: Functional alteration of tumor-infiltrating T lymphocytes (TILs) may serve as a predictor for clinical outcome in cancer patients receiving immunotherapy.To evaluate TILs function unleashed by anti-PD-1 blocking, we employed a single-cell technology integrated with automated bioinformatics to simultaneously measure 17 cytokines secreted by single TILs, permitting the full spectrum delineation of anti-tumor T cell functions in patients with metastatic melanoma. Methods: TILs were enriched from biopsied melanoma tissues digested with enzymes, stimulated with anti-CD3 at 37°C, 5% CO2 for 24 hrs and loaded into a single-cell barcode chip (SCBC) containing ~12000 microchambers. Each chamber (~1.2 nl) was pre-patterned with a complete copy of a 17-plex antibody array. Cells on the SCBC were imaged and incubated for 16 hrs at 37°C, 5% CO2; single-cell cytokine signals were captured with a microarray scanner. The polyfunctional expression (2+ cytokines per cell) of single TILs was evaluated across 4 groups: Effector (Granzyme B, IFN-γ, MIP-1α, Perforin, TNF-α), Stimulatory (GM-CSF, IL-2, IL-5, IL-8, IL-9), Regulatory (IL-4, IL-10, IL-13, IL-22), and Inflammatory (IL-6, IL-17A, MCP-1). Results: Single-cell TILs analysis revealed significant increase of polyfunctional cytokines in patients who responded to anti-PD-1 therapy, compared to those resistant to therapy or in the control group. It was further revealed that the major contributions to enhanced polyfunctional strength are dominated by effector and stimulatory cytokines – both associated with anti-tumor immunity. Notably, TILs of patients responding to therapy exhibited polyfunctional secretions containing a subset of cells co-secreting Granzyme B, IFN- γ, MIP-1 α, and IL-8, which upon further validation is potentially a biomarker to predict clinical outcome of melanoma patients treated by checkpoint immunotherapy. Conclusions: Single-cell multiplexed cytokine profiling is capable of dissecting the full spectrum of immune functions associated with anti-tumor T cell immunity and more accurately measuring the function of TILs for predicting the response of patients receiving anti-PD-1 blocking therapy.
A radiosensitivity gene signature and PD-L1 status to predict clinical outcome of patients with invasive breast carcinoma in the cancer genome atlas (TCGA) dataset.
Authors: Kim In Ah , Jang Bum Sup
Published: November 2019

54

Background: A radiosensitivity gene signature that included 31 genes was identified using microarray data from NCI-60 cancer cells; however, this has not been validated in independent datasets for breast cancer patients. We investigated the link between the radiosensitivity gene signature and programmed cell death ligand 1 (PD-L1) status and clinical outcome to identify a group of patients that would possibly receive clinical benefit of radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. Methods: We validated the identified gene signature related to radiosensitivity and analyzed the PD-L1 status of invasive breast cancer in The Cancer Genome Atlas (TCGA) dataset using bioinformatic tools. To validate the gene signature, 1,065 patients (or samples) were selected and divided into two clusters using a consensus clustering algorithm based on their radiosensitive (RS) or radioresistant (RR) designation according to their prognosis. Patients were also stratified as PD-L1-high or PD-L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. The relationship between the RS/RR groups and PD-L1 status was also assessed. The prognostic value was evaluated by Kaplan-Meier analysis and Cox proportional hazard models. Results: Patents assigned to the RS group had better 5-year recurrence-free survival (RFS) rate than patients in the RR group by univariate analysis (89% vs. 75%, p = 0.017) only when treated with RT. The RS group was independently associated with the PD-L1-high group, and CD274 mRNA expression was significantly higher in the RS group (p<0.001) than the RR group. In the PD-L1-high group, the RS group had better 5-year RFS rate compared to the RR group (89% vs. 72%, p = 0.015), and this difference was also significant by Cox-hazard proportional analysis. Conclusions: The radiosensitivity gene signature and PD-L1 status were important factors for prediction of the clinical outcome of RT in patients with invasive breast cancer and may be used for selecting patients who will benefit from RT combined with anti-PD1/PDL1 therapy.
Correlation of circulating PD-L2 levels with outcomes of therapy with the anti-PD-1 antibody pembrolizumab (P) in patients (pts) with advanced soft tissue sarcomas (STS): Biomarker analysis of SARC028.
Authors: Burgess Melissa Amber , Roszik Jason , Van Tine Brian Andrew , Hu James , Schuetze Scott , D'Angelo Sandra P. , Attia Steven , Priebat Dennis A. , Okuno Scott H. , Riedel Richard F. , Davis Lara Emily , Movva Sujana , Reed Damon R. , Baker Laurence H. , Reinke Denise K. , Maki Robert G. , Patel Shreyaskumar , Tawbi Hussein Abdul-Hassan , Butterfield Lisa Helene
Published: November 2019

60

Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.
Response to nivolumab in radiation induced, BRCA-2 N372H variant, programed death ligand-1 negative, pleomorphic undifferentiated sarcoma.
Authors: Foster Yevgeniya Gora , Cecchini Michael , Slater Dennis , Neumeister Veronique , Walther Zenta , Husain Zain , Judson Benjamin , Deshpande Hari Anant
Published: November 2019

61

Background: Early results from recent studies using immune checkpoint blockade targeting programmed death 1 (PD-1) have suggested that pleomorphic undifferentiated sarcomas may have response rates of over 40%. As of now predictive biomarkers for response and resistance have been incompletely characterized. Methods: A 58-year-old man who received radiation for a head and neck squamous cell cancer, developed a radiation-induced undifferentiated pleomorphic sarcoma (UPS) in his neck in 2014. His sarcoma was resected but recurred in 2015. He received adjuvant radiation after surgical debulking in September 2015 and was found on radiation simulation scan to have new widespread metastatic disease involving liver, lung, and bone. He started treatment on nivolumab in November 2015 and has had a sustained near complete response in all lesions. Results: All sites had a near complete response to nivolumab treatment. Pre treatment tissue analysis revealed no mutations or amplifications in 134 cancer-related genes, on the Oncomine Assay (Life Technologies, Inc.). Normal tissue was noted to be heterozygous for BRCA2 N372H, while the allelic fraction of the 372H variant in the tumor was found to be 85%. Programmed death ligand-1 (PDL-1) immunohistochemistry staining of the tumor tissue was negative. Tumor infiltrating lymphocytes were not noted in the tumor tissue specimen. Conclusions: This patient exhibited a near complete response to all sites of disease, with remaining PET avidity in a single hilar node. The role of the BRCA2 variant and radiation just prior to starting nivolumab is unknown. BRCA2 N372H is a common single nucleotide polymorphism (SNP) in the population with a minor allele frequency of 0.25. Although the effect of the 372H variant on BRCA2 protein structure is predicted to be minimal, population studies have suggested a slightly increased risk of breast and ovarian cancer in homozygotes. It is possible that the radiation treatment to the site of recurrence in the head and neck, resulted in an abscopal effect enhancing the therapeutic effect of nivolumab therapy. Additional testing on his tissue is being done to further investigate the response.