tbuckley/cabot-search huggingface dataset:
Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04.
Authors: Carmen Joseph Allegra, Greg Yothers, Michael J O'Connell, Mark S. Roh, Robert W. Beart, Nicholas J. Petrelli, Samia H. Lopa, Saima Sharif, Norman Wolmark
Journal: Journal of Clinical Oncology (2014)

390 Background: The primary aims were to: 1) compare capecitabine (Cape) and continuous intravenous infusion (CVI) 5-FU combined with pelvic radiation therapy (RT) given preoperatively for patients (pts) with stage II or III rectal cancer; 2) determine whether the addition of oxaliplatin (Ox) would improve pt outcomes. Preliminary results focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity were presented at ASCO 2011 (Roh: J Clin Oncol 29: 2011 Ab 3503). Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m 2 5 days/wk), with or without intravenous Ox (50mg/m 2 /wk x 5) or oral Cape (825 mg/m 2 BID 5 days/wk), with or without Ox (50mg/m 2 /wk x 5). The primary endpoint of local-regional (L-R) tumor control included L-R tumor recurrence, less than an R0 resection (complete surgical resection), and no surgery. Results: From July 2004 to August 2010, 1608 patients were randomly assigned and 99.2% were eligible. There were no significant differences in L-R tumor control, DFS, or OS between regimens for either the 5-FU-Cape (L-R p=0.98) or the Ox-none (L-R p=0.70) comparisons. The addition of Ox was associated with significantly more grade 3-4 diarrhea (p&lt;0.0001). Analysis of the primary endpoint showed 3-yr rates of L-R tumor control ranged from 87.4%-88.2%. 3-yr rates of L-R recurrence among pts who underwent R0 resection ranged from 2-4 % for stage II pts, and from 4-11% for stage III pts. 16% of stage II and 26% of stage III pts developed distant metastases by 5 yrs. From 84% to 97% of pts received &gt;80% of the ideal chemotherapy dose in combination with preoperative RT. Conclusions: CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity. Clinical trial information: NCT00058474.
Protein kinase Cϵ associates with signal transducers and activators of transcription 3, which is constitutively activated during induction and progression of prostate cancer
Authors: Moammir Aziz, Herbert Manoharan, Dawn Church, Nancy Dreckschmidt, Weizong Zhong, Terry Oberley, George Wilding, Ajit Verma
Journal: Cancer Research (2007)

118   Prostate cancer (PCa) is the second leading cause of cancer deaths in men. We now present that Protein kinase C ϵ (PKCϵ) and signals transducers and activators of transcription 3 (Stat3), two widely documented proteins with oncogenic traits, interact with each other in their signals to the development of PCa. Both PKCϵ and activated Stat3 are overexpressed in human PCa. The expression levels of PKCϵ, as determined by immunohistochemistry of human PCa tissue microarrays, correlated with the aggressiveness of PCa. To investigate the significance of the upregulation of PKCϵ and Stat3 in the induction and progression of PCa, we employed TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice, which spontaneously develop PCa. Both PKCϵ protein and activity levels were increased while Stat3 was constitutively activated in PCa specimens from TRAMP mice. Further analyses of Stat3-associated upstream and downstream signaling components revealed elevated expression of IL-6, Jak1 and Jak2, several cell cycle (p21 and p27) and anti-apoptotic (survivin, Bcl-2, Bcl-xL) regulatory proteins. A more detailed kinetic study with TRAMP mice (13, 26, 39, and 42 weeks old) elicited a parallel increase in the level of expression of PKCϵ and phosphorylated Stat3 in prostate tissue starting in 26-week old TRAMP mice. To further explore the PKCϵ signal transduction pathways to activation of Stat3, the interaction of PKCϵ with Stat3 was determined via reciprocal immunoprecipitation/blotting experiments. We found that prostate Stat3 co-immunoprecipitated with PKCϵ. PKCϵ-associated Stat3 was phosphorylated at both tyrosine 705 and serine 727. Association of PKCϵ with Stat3, as determined by double immunofluorescence staining, was observed both in the cytoplasm and nucleus of PCa specimens. Similar association of PKCϵ with Stat3 was observed in human prostate cancer cell lines. (LNCaP, PC-3, DU145) Inhibition of PKCϵ using specific siRNA in DU145 cells prevented Stat3Ser727 phosphorylation. Also, in an immunocomplex kinase assay, PKCϵ phosphorylated Stat3 at serine 727 residue. Taken together, these results indicated for the first time that PKCϵ associates with Stat3 in PCa and PKCϵ is a Stat3Ser727 kinase. PKCϵ and Stat3 may be potential molecular targets for the prevention and treatment of human PCa (Supported by NIH grants CA102431 and CA35368).
Abstract 4658: Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer
Authors: Shengmin Sang, Yingdong Zhu, Junsheng Fu, Kelly Shurlknight
Journal: Cancer Research (2015)

Abstract In more than a century of use, the benefits of aspirin have been exploited in different therapeutic areas, from inflammation to cardiovascular diseases and cancer prevention. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. The present study found that resveratrol, a natural chemopreventive agent from grapes and berries, and its methylated derivatives can react with acetylsalicyloyl chloride to form resveratrol aspirinate (RAS) and related derivatives. Among all the synthesized derivatives, we found that RAS is the most active component and have much stronger growth inhibitory effect on human colon cancer cells (HCT-116 and HT-29) than resveratrol and aspirin along, as well as the combination of resveratrol and aspirin. In addition, we found that RAS can be hydrolyzed to regenerate resveratrol and aspirin in mice and in human colon cancer cells. Therefore they serve as prodrugs of aspirin and resveratrol and its derivatives. Compared to simply combining aspirin and resveratrol, RAS has not only greater growth inhibitory effects on human colon cancer cells, but also can prevent the damage of gastric epithelial cells caused by direct contact between aspirin and gastric mucosa. Further mechanistic studies found that RAS inhibited cell growth through regulating cell cycle arrest via down-regulation of cyclins D1 and E, and inducing cancer cell apoptosis via mitochondrial pathway. In addition, two stable RAS analogues, for the first time, were successfully synthesized to demonstrate the importance of the scaffold composed of resveratrol and aspirin in the anti-cancer activity of RAS. Our results demonstrated for the first time that resveratrol based aspirin derivatives represent a brand-new, safer and improved alternative to aspirin in anti-cancer and anti-inflammatory therapies. Note: This abstract was not presented at the meeting. Citation Format: Shengmin Sang, Yingdong Zhu, Junsheng Fu, Kelly Shurlknight. Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4658. doi:10.1158/1538-7445.AM2015-4658
Polymorphisms in cancer-related pathway genes and lung cancer
Authors: Shin Yup Lee, Hyo-Gyoung Kang, Jin Eun Choi, Deuk Kju Jung, Won Kee Lee, Hyun Chul Lee, So Yeon Lee, Seung Soo Yoo, Jaehee Lee, Yangki Seok, Eung Bae Lee, Seung Ick Cha, Sukki Cho, Chang Ho Kim, Myung Hoon Lee, Jae Yong Park
Journal: European Respiratory Journal (2016)

We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication.Among the 68 SNPs, three SNPs (corepressor interacting with RBPJ 1 (CIR1) rs13009079T>C, ribonucleotide reductase M1 (RRM1) rs1465952T>C and solute carrier family 38, member 4 (SLC38A4) rs2429467C>T) consistantly showed significant associations with lung cancer in the replication study. In combined analysis, adjusted odds ratio for CIR1 rs13009079T>C, RRM1 rs1465952T>C and SLC38A4 rs2429467C>T were 0.69, 0.71 and 0.73, respectively (p=4×10-5, 0.01 and 0.001, respectively) under the dominant model. The relative mRNA expression level of CIR1 was significantly associated with rs13009079T>C genotypes in normal lung tissues (ptrend=0.03).These results suggest that the three SNPs, particularly CIR1 rs13009079T>C, may play a role in the pathogenesis of lung cancer.
Bioterrorism and Public Health Law
Authors: Jane M. Orient
Journal: JAMA (2002)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Bacterial biofilm in chronic lesions of hidradenitis suppurativa
Authors: H.C. Ring, L. Bay, M. Nilsson, K. Kallenbach, I.M. Miller, D.M. Saunte, T. Bjarnsholt, T. Tolker-Nielsen, G.B. Jemec
Journal: British Journal of Dermatology (2016)

Chronic nonhealing or recurrent inflammatory lesions, reminiscent of infection but recalcitrant to antibiotic therapy, generally characterize biofilm-driven diseases. Chronic lesions of hidradenitis suppurativa (HS) exhibit several characteristics, which are compatible with well-known biofilm infections.To determine and quantify the potential presence of bacterial aggregates in chronic HS lesions.In 42 consecutive patients with HS suffering from chronic lesions, biopsies were obtained from lesional as well as from perilesional skin. Samples were investigated using peptide nucleic acid-fluorescence in situ hybridization in combination with confocal laser scanning microscopy. In addition, corresponding histopathological analysis on haematoxylin and eosin slides was performed.Biofilms were seen in 67% of the samples of chronic lesions and in 75% of the perilesional samples. The mean diameter of aggregates in lesional skin was significantly greater than in perilesional skin (P = 0·01). Large biofilms (aggregates > 50 μm in diameter) were found in 42% of lesional samples and in only 5% of the perilesional samples (P = 0·009). The majority of the large biofilms were situated in sinus tracts (63%) or in the infundibulum (37%). The majority of the sinus tract samples (73%) contained active bacterial cells, which were associated with inflammation.This study suggests that biofilm formation is associated with inflammation of chronic HS lesions. The aggregates most likely occur as a secondary event, possibly due to predisposing local anatomical changes such as sinus tracts (tunnels), keratinous detritus and dilated hair follicles.
Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study
Authors: Khalid A. Jadoon, Stuart H. Ratcliffe, David A. Barrett, E. Louise Thomas, Colin Stott, Jimmy D. Bell, Saoirse E. O’Sullivan, Garry D. Tan
Journal: Diabetes Care (2016)

Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes.In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated.Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = -1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function [ETD = -44.51 points; P < 0.01]), adiponectin (ETD = -5.9 × 10(6) pg/mL; P < 0.01), and apolipoprotein A (ETD = -6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (-898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated.THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.
Sulindac suppressed beta-catenin expression in human malignant cell lines
Authors: Anjia Han, Zibo Song, Chang Tong, Tianhong Li, Barbara Heerdt, Leonard Augenlicht, Wancai Yang
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3 

Sulindac, a nonsteroidal anti-inflammatory drug, has been reported to be effective in suppressing tumor growth through the induction of p21WAF1/cip1 in human, animal models of colon cancer and colon cancer cells. In this study, we treated human breast cancer cell line MCF-7, lung cancer cell line A549 and colon cancer cell line SW620 with sulindac to observe the effects of sulindac in other tissue sites. In all three cell lines, proliferation was significantly inhibited by sulindac after 24 hours of treatment. The apoptosis was induced by sulindac in both lung cancer cells and colon cancer cells but the induction of apoptosis was not observed in the breast cancer cells. To further explore the role of p21WAF1 in these actions, the cell lysate was collected after the treatment of 8, 24 and 48 hours with sulindac. Protein expression was assayed by western blot. As documented previously, p21WAF1 was induced by sulindac in colon cancer cell line. However, p21 was not induced by sulindac in the breast or lung cancer cell lines. Unexpectedly, the suppression of beta-catenin, a key regulator of Wnt-pathway was seen in all the three cell lines with sulindac administration. Subsequently, cyclin D1 and cdk 4 were dramatically suppressed by sulindac. In conclusion, our data demonstrated that the efficiency of sulindac in the inhibition of cell proliferation (other than the induction of apoptosis) may be through the suppression of beta-catenin pathway in human breast and lung cancer cell lines.
Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses
Authors: Thomas Kirkegaard, James Gray, David A. Priestman, Kerri-Lee Wallom, Jennifer Atkins, Ole Dines Olsen, Alexander Klein, Svetlana Drndarski, Nikolaj H. T. Petersen, Linda Ingemann, David A. Smith, Lauren Morris, Claus Bornæs, Signe Humle Jørgensen, Ian Williams, Anders Hinsby, Christoph Arenz, David Begley, Marja Jäättelä, Frances M. Platt
Journal: Science Translational Medicine (2016)

Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.
Особливості змін біохімічних показників шлункового соку в пацiєнтiв iз гастроезофагеальною рефлюксною хворобою
Authors: L.M. Mosiichuk, O.I. Hrabovska, K.V. Paramonova, A.I. Rudenko, I.A. Klenina, I.V. Kuchnirenko, O.P. Petishko
Journal: GASTROENTEROLOGY (2016)

У дослідженні були вивчені особливості змін факторів агресії та захисту у вмісті шлункового соку в 91 пацiєнта iз гастроезофагеальною рефлюксною хворобою (ГЕРХ) у поєднанні з дисфункцією сфінктера Одді. Визначали рН, концентрацію пепсину, глікопротеїнів, жовчних кислот, сіалових кислот, фукози, гексозамінів, рівень метаболітів оксиду азоту. Встановлено, що підвищення рівня метаболітів оксиду азоту та жовчних кислот у шлунковому соку призводить до посилення запальних процесів у слизовій оболонці шлунка незалежно від функціонального стану сфінктера Одді. Збільшення агресивних властивостей шлункового вмісту спостерігалось у пацієнтів із ГЕРХ як із гіпертонусом, так і гіпотонусом сфінктера Одді. Дефіцит та диспропорція факторів захисту в більшості хворих в усіх групах проявлялись у вигляді зменшення концентрації вуглеводних термінальних залишків глікопротеїнів відносно показників контрольної групи.
Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy
Authors: Yongxian Hu, Jie Sun, Zhao Wu, Jian Yu, Qu Cui, Chengfei Pu, Bin Liang, Yi Luo, Jimin Shi, Aiyun Jin, Lei Xiao, He Huang
Journal: Journal of Hematology & Oncology (2016)

Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in CD19+ malignancies. However, the etiological nature of neurologic complications remains a conundrum. In our study, the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed. A patient with acute lymphocytic leukemia developed sustained pyrexia with tremors about 6 h after CART19 infusion, followed by a grade 2 cytokine release syndrome (CRS) and neurological symptoms in the next 3 days. Contrast-enhanced magnetic resonance showed signs of intracranial edema. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF) contained 20 WBCs/μL with predominant CD3+ T cells. qPCR analysis for CAR constructs showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels including IFN-γ and IL-6 in CSF were extremely higher than those in the serum. Methyprednisone was administrated and the symptoms relieved gradually. The predominance of CART19 in CSF and the huge discrepancies in cytokine distributions indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. For the first time, we reported the development of cerebral CRS triggered by BBB-penetrating CAR T cells. Trial registration: ChiCTR-OCC-15007008 .
Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan
Authors: Kohei Yamaguchi, Kazunori Murai, Shigeki Ito, Tomoaki Akagi, Kazuei Ogawa, Kuniaki Meguro, Mitsue Inomata, Reiko Watanabe, Takuto Miyagishima, Kentaro Wakasa, Motohiro Shindo, Yasuhiko Tsukushi, Kohmei Kubo, Yoji Ishida
Journal: Blood (2013)
Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker-based results from a randomized clinical trial.
Authors: Toni K. Choueiri, Mayer N. Fishman, Bernard J. Escudier, Jenny J. Kim, Harriet M. Kluger, Walter Michael Stadler, Jose Luis Perez-Gracia, Douglas G. McNeel, Brendan D. Curti, Michael Roger Harrison, Elizabeth R. Plimack, Leonard Joseph Appleman, Lawrence Fong, Charles G. Drake, Lewis J. Cohen, Shivani Srivastava, Maria Jure-Kunkel, Quan Hong, John F. Kurland, Mario Sznol
Journal: Journal of Clinical Oncology (2014)

5012 Background: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) inhibitor antibody, has shown encouraging activity in mRCC. This trial assessed the immunomodulatory and clinical activity, and safety of nivolumab in patients (pts) with mRCC. Methods: Ninety-one pts received nivolumab IV Q3W: pretreated pts (1–3 prior therapies; ≥1 anti-angiogenic agent) received 0.3 (n=22), 2 (n=22), or 10 mg/kg (n=23); 24 treatment-naïve pts received 10 mg/kg. Fresh biopsies and serum were obtained at baseline (BL) and nivolumab cycle 2 day 8 (C2D8; biopsy) and cycle 4 day 1 (C4D1; serum). Primary objective was to assess the immunomodulatory activity of nivolumab on serum chemokines (CXCL9, CXCL10) and tumor T cell infiltrates from BL to post treatment. Secondary/exploratory objectives included safety and tolerability, antitumor activity (ORR; RECIST 1.1), BL and treatment-induced changes in PD-1 ligand (PD-L1) expression (Dako immunohistochemistry assay; PD-L1 positivity: >5% tumor membrane staining at any intensity) and association of clinical activity with BL PD-L1 expression. Results: Mean increase from BL to C4D1 was 191% for CXCL9 and 90% for CXCL10. T cell infiltrates increased by a median of 70% (CD3+; range 53–220%) and 88% (CD8+; 61–257%) from BL to C2D8. Of 56 evaluable fresh pretreatment biopsies, 18 (32%) were PD-L1+. ORR was 22% (4/18) for PD-L1+ pts vs 8% (3/38) for PD-L1–. In 5/27 (19%) matched biopsy pairs PD-L1 expression increased >5% by C2D8. For evaluable pts ORR was 16% (14/90); 16% in previously treated pts, 13% in untreated pts. Median duration of response was 15 months; 6 (43%) responses are ongoing. 14/91 (15%) pts had grade 3–4 related AEs, most commonly colitis and elevated AST (n=2 each), diarrhea and pneumonitis (n=1 each), all grade 3. Conclusions: In this prospective biomarker-based study, nivolumab showed clinical activity and manageable safety in pts with previously treated and untreated mRCC. Responses were numerically higher in PD-L1+ pts but also seen in PD-L1– pts. Changes in biomarkers were consistent with PD-1 inhibition and provided evidence of immunomodulatory effects in serum and in the tumor microenvironment. Clinical trial information: NCT01358721.