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In the Malay archipelago, European encounters with ‘amok’, a behavioural pattern of indiscriminate, homicidal ‘tendencies’ purportedly observed among Malay-Muslim men, led to colonial discourses which posited that ‘native’ men were culturally ‘foredoomed’ to frenzied acts of violence. This chapter argues that such colonial attempts to understand ‘amok’ were founded upon an occidental analytical framework which affirmed the ‘primitive character’ of indigenous Malays. Such an interpretation offered colonial officials a moral high-ground based upon European mores, within which ‘amok’ could be used to justify colonial discourses on the civilising mission. By analysing examples and colonial interpretations of such indigenous acts of violence, this chapter explores how colonial authority instrumentalised ‘amok’ in order to assert control over indigenous societies—both on a physical and psychological level.

Objectives Maxillary sinus augmentation procedures with bone replacement grafts aimed to increase bone height in the posterior maxilla. During healing, bone particles are partially resorbed and replaced by the patient's own bone. Vitamin D plays an essential role in calcium homeostasis and is critical for bone formation and remodeling. Materials and methods This randomized, double-blind, placebo-controlled clinical investigation studied whether oral supplementation with vitamin D3 (5000 IU) combined with calcium (600 mg) impacts bone formation and remodeling after maxillary sinus augmentation compared to a placebo medication containing calcium alone (n = 10/group). Bone cores were harvested at the time of implant placement (6–8 months) for histological analysis. Results Serum 25-hydroxyvitamin D (25-OHD) levels were comparable between both groups at the baseline (P = nonsignificant [n.s.]). Vitamin D3+ calcium supplementation improved significantly serum 25-OHD levels (placebo vs. vitamin D3 group: 25-OHD ng/ml: 31.13 ± 7.06 vs. 61.11 ± 20.42, P ≤ 0.01); however, no statistically significant difference in bone formation or graft resorption was detected between groups. However, in the vitamin D3 group, a significant association was found between increased vitamin D levels and number of bone-resorbing osteoclasts around graft particles suggesting that local bone remodeling might be more pronounced when serum vitamin D levels were improved (r = 0.92, P ≤ 0.05). Conclusions Vitamin D3+ calcium supplementation improves serum vitamin D levels and potentially impacts local bone remodeling on a cellular level. However, no statistically significant difference in bone formation or graft resorption was detected between groups.

Background: Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer. Methods: This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4–22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6–11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9–25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response. Conclusion: Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.

For patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection.Between January 2011 and August of 2013, 43 patients with borderline resectable pancreatic cancer (BRPC, n = 18) or locally advanced pancreatic cancer (LAPC, n = 25) were treated with mFOLFIRINOX (no bolus 5-FU, no LV, and decreased IRI). Radiation was used based on response and intended surgery. Charts were retrospectively reviewed to assess response, toxicities, and extent of resection when possible.The most common grade 3/4 toxicity was diarrhea in six patients (14 %) with no grade 3/4 neutropenia or thrombocytopenia. Resection was attempted in 31 cases (72 %) and accomplished in 22 cases (51.1 %) including 11 of 25 LAPC cases (44 %). Vascular resection was required in 4 cases (18 %), with R0 resection in 86.4 % of the resections. Complications occurred in 6 cases (27 %), with no perioperative deaths. The median progression-free survival period was 18 months if the resection was achieved compared with 8 months if no resection was performed (p0.001).Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen for patients with advanced nonmetastatic pancreatic cancer. When mFOLFIRINOX is coupled with aggressive surgery, high resection rates are possible even when the initial imaging shows locally advanced disease. Although data are still maturing, resection appears to offer at least a progression-free survival advantage.

According to white Scoutmasters in Malaya, ‘the peculiar difficulties of locality and climate’ necessitated certain proscriptions on Scout training for Malayans. Restrictions on the physical aspects of Scouting in Malayan jungles limited opportunities for Malayans to cultivate Scouting's idealised male figure of the frontiersman. At the same time, colonial discouragement of the ‘Anglicisation’ of indigenous Scouts effectively curtailed indigenous Malayan access to those ideals of masculinity which were in many respects dominant in the colonial context. Ironically, some of these Anglicised Scouting ideals of masculinity were borrowed from ‘native cultures’ or ’martial tribes’. The exchanges and appropriations of culture and masculinities through Scouting were therefore multi-directional and more complicated than imagined. This article examines how Scouting in Malaya functioned as a vehicle for and as a product of multiple colonial exchanges. It argues that colonial Scouting in Malaya introduced but also restricted Malayan access to certain ideals of masculinity. Additionally, it argues for a more nuanced analysis of localised Malayan appropriations and negotiations of colonial/imperial concepts introduced through the Scout Movement. In particular, through considering how Malayan Scouts ‘played Indian’, this article further suggests that Scout activities of ‘make-believe’ attracted Malayan Scouts because of the liberties attached to these bodily performances of idealised Anglicised masculinities.

Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes.Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed.Sixty-two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy.Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available.

Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT.This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg/day), pasireotide (600 μg twice daily), and SIRT (SIR-Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long-acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose-limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers-angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin-like growth factor binding protein 1, insulin-like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2-were assessed. The Norfolk Quality of Life-Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL).Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well-differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver-only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment-related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression-free survival and overall survival were 18.6 and 46.3 months, respectively.The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. Cancer 2018;124:1992-2000. © 2018 American Cancer Society.

Objective: The biologic basis for gender identity is unknown. Research has shown that the ratio of the length of the second and fourth digits (2D:4D) in mammals is influenced by biologic sex in utero, but data on 2D:4D ratios in transgender individuals are scarce and contradictory. We investigated a possible association between 2D:4D ratio and gender identity in our transgender clinic population in Albany, New York. Methods: We prospectively recruited 118 transgender subjects undergoing hormonal therapy (50 female to male [FTM] and 68 male to female [MTF]) for finger length measurement. The control group consisted of 37 cisgender volunteers (18 females, 19 males). The length of the second and fourth digits were measured using digital calipers. The 2D:4D ratios were calculated and analyzed with unpaired t tests. Results: FTM subjects had a smaller dominant hand 2D:4D ratio (0.983 ± 0.027) compared to cisgender female controls (0.998 ± 0.021, P = .029), but a ratio similar to control males (0.972 ± 0.036, P =.19). There was no difference in the 2D:4D ratio of MTF subjects (0.978 ± 0.029) compared to cisgender male controls (0.972 ± 0.036, P = .434). Conclusion: Our findings are consistent with a biologic basis for transgender identity and the possibilities that FTM gender identity is affected by prenatal androgen activity but that MTF transgender identity has a different basis. Abbreviations: 2D:4D = 2nd digit to 4th digit; FTM = female to male; MTF = male to female

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

In this concluding chapter of the book, Wu discusses what it means for political discourses to be deferred to entertainment conversations. Latest developments in American politics of 2016 may make it particularly challenging to contend for entertainment’s significance in politics. Critical theories that the book revises may be especially relevant in the American public’s sense-making of Donald Trump’s presidency. Wu argues that if entertainment continues to occupy a semi-polluted position in the West, one needs to acknowledge its role in Chinese citizens’ political communication. As the author addresses in this chapter lingering concerns with the limits and threat of entertainment, the more productive task is to examine entertainment’s power for average citizens in an empirically grounded manner. The theory of an aesthetic public sphere and the empirical undertakings of this book provide a useful framework. Furthermore, scholarly efforts should look more closely for the connection between informal public spheres and the official public sphere of a country. Wu discusses latest developments in China’s entertainment and politics, and how the book’s central theoretical and empirical frameworks apply to newly emerging cases. The thesis of an aesthetic public sphere provides an informative and balanced analytical perspective for readers to contextualize new shows and new struggles in the broader framework of entertainment and politics, in China and other media systems.

In the first analytical chapter, Wu focuses on the case of Super Girl, a reality-based singing contest show, largely modeled off of American Idol, and spirited debates about political thoughts as a result of viewers’ passionate participation in Super Girl. Initially thanks to its nationwide voting element, the show garnered great success and invited much political comparison as Chinese voters cannot vote in the political sphere. As Super Girl became more popular and more politically provoking, China’s state regulators put a ban on voting. Wu closely studies public discourses in the mainstream newspapers as well as in online discussion forums, in the first season (Season 4, 2009) produced after the ban. As Super Girl producers painstakingly came up with alternative ways in which the viewers could channel their preferences and opinions to the development of the contests without direct voting, viewers frequently drew a connection between the show’s selection mechanism and political representation. They linked judges’ behaviors to broader competition in the general society and weaved discourses about Mainland China’s political culture. While newspaper contributors were more invested in the technicality of political processes, online discourses romanticized the power of the masses and harbored more explicit discussions about the political confines of Mainland China, such as the restraint on people’s freedom of speech, and the lack of systematic rules that treat all social members and situations consistently.

This chapter examines two widely popular television drama series in addition to the case of Super Girl, Dwelling Narrowness and Naked Wedding. Their titles joined a list of newly coined terms in the first decade of the twenty-first century to describe new life situations experienced by China’s young generations. On the one hand, China is suffering from enlarging wealth gaps, prevalent resentment held by ordinary citizens toward the rich, and lack of public trust in social justice. On the other hand, audience discussions about the dramas exhibited moral ambiguities. While viewers expressed deep-seated anger toward harsh consequences of China’s postsocialist developments, they also revealed sympathy toward the characters that are corrupt public officials and envy for people who take shortcuts to privileges. Such contradictions are emblematic of the despair with a lack of social mobility in contemporary China. Discussions of Super Girl echoed such sentiments. The public showed their mistrust toward the producers as suspect manipulators on the show. Newspaper contributors and online discussants alike composed an overarching thesis about today’s Chinese society and voiced genuine concerns that it is drifting away from valuing true talents, most disturbingly by such cultural institutions as TV networks. Furthermore, the public speculated and researched about the contestants’ family wealth and connections in making sense of their success on Super Girl. Overall, entertainment materials provided a platform for the viewers to voice their cynicism about frequent violations of social justice by the new rich in China and the monopoly they hold over life opportunities.

This chapter discusses cultural concerns around entertainment production in China. Shows like Super Girl and If You Are the One, a reality-based matchmaking show, inspired much critical reflection on culture and cultural production. While the Chinese state often justifies its regulations of the cultural industry through such critical public discourses, viewers interpreted the state authorities’ heavy hand in entertainment production as deeply political. In the case of If You Are the One, while viewers celebrated the open and quick-fire exchanges among the participants about what they seek in an ideal match, many viewers along with state regulators were troubled by scandals constantly visiting the show and potential manufacturing of controversies on the show to shore up viewership. As the state took measures to rein in the show, producers re-framed it as a “large-scale public service program,” instead of a “pure entertainment show.” However, viewers continued to evaluate the show’s cultural value in regard to its authenticity. Wu discusses this connection in particular from the angle of the show’s spotlight on the pervasive narrative about China’s “leftover women” problem. Because Super Girl was largely inspired by the global Idol series, Chinese audience also used the show to compare between the Chinese and the Western production fields, especially where China is lacking. The online community constructed more developed arguments about the artistic aspects of the show than the newspapers. Wu argues that such aesthetic critiques provided the basis of bonding among the discussants and deeper reflections on the show’s political implications.

This chapter offers an updated review of the cyberspace carved out by the Chinese state for its citizen-audience, which is at the same time connected to a globalizing world and disconnected from it. As one becomes more aware of the mechanism in which Internet censorship works in China, theoretical revisions by the notions of cultural citizenship and an aesthetic public sphere will prove useful to their understanding not only about the civic significance of entertainment, but also that of the Internet. As the Internet provides a fertile ground where audience discourses organically percolate, Wu reviews literature that has taken an evaluative approach to the civic potential of the new digital media based off of the traditional notion of politics and citizenship. Wu proposes that we break free of such confines, whether the conclusions are optimistic or pessimistic, and closely examine how entertainment converges with political reflections through the communicative channel of new digital media. To take on such an empirical enterprise of examining how ordinary citizens actually interact with the entertainment media as part of their civic life, this book samples broadly from both China’s mainstream media discourses about its entertainment and online discussions, both in traditional Internet forums and on newer social media platforms. Wu details empirical framework of the book, including sampling process and analytical methods.

Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF.Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology.Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p 0.05; and IGFBP-3, 3,880 ± 934 versus 1,935 ± 862 ng/ml in HF, p = 0.05). The GH/IGF-1 ratio, a marker of GH resistance, was elevated in HF (0.002 ± 0.002 versus 0.048 ± 0.1 pre-VAD; p 0.0039). After VAD support, skeletal muscle expression of IGF-1 and IGFBP-3 increased (10-fold and 5-fold, respectively; p 0.05) accompanied by enhanced oxidative gene expression (CD36, CPT1, and PGC1α) and increased oxidation rates (+1.37-fold; p 0.05). Further, VAD implantation increased the oxidative muscle fiber proportion (38 versus 54 %, p = 0.031), fiber cross-sectional area (CSA) (1,005 ± 668 versus 1,240 ± 670 μm(2), p 0.001), and Akt phosphorylation state in skeletal muscle. Finally, hand grip strength increased 26.5 ± 27.5 % at 180 days on-VAD (p 0.05 versus baseline).Our data demonstrate that VAD implantation corrects GH/IGF-1 signaling, improves muscle structure and function, and enhances oxidative muscle metabolism in patients with advanced HF.

Combinations of fluoropyrimidines with oxaliplatin or irinotecan plus a biologic agent are standard treatments for metastatic colorectal cancer (mCRC). Recent approvals of first-line cetuximab, second-line ziv-aflibercept, and regorafenib as salvage therapy have increased the complexity of the treatment armamentarium. To define optimal regimens, we systematically reviewed combination chemotherapy trials (N=83). Descriptive analyses focusing on fluoropyrimidine formulation, oxaliplatin vs irinotecan combinations, and compatibility with biologics indicated the following: infusional 5-fluorouracil (5-FU) yielded better efficacy and safety than bolus 5-FU. Capecitabine had similar outcomes and better safety than 5-FU with oxaliplatin but not irinotecan. First-line oxaliplatin and irinotecan appeared equivalent. Antiangiogenics, such as bevacizumab and ziv-aflibercept, and epidermal growth factor receptor-targeted monoclonal antibodies cetuximab and panitumumab further improved efficacy. The treatment landscape for mCRC has become complex, and we are approaching individualized therapy based on predictive factors, including KRAS mutational status. Appropriate administration of chemotherapy/biologic combinations is critical.

Heart failure (HF) is associated with the derangement of muscle structure and metabolism, contributing to exercise intolerance, frailty, and mortality. Reduced handgrip strength is associated with increased patient frailty and higher morbidity and mortality. We evaluated handgrip strength as a marker of muscle function and frailty for prediction of clinical outcomes after ventricular assist device (VAD) implantation in patients with advanced HF.Handgrip strength was measured in 72 patients with advanced HF before VAD implantation (2.3 ± 4.9 days pre-VAD). We analyzed dynamics in handgrip strength, laboratory values, postoperative complications, and mortality. Handgrip strength correlated with serum albumin levels (r = 0.334, P = .004). Compared with baseline, handgrip strength increased post-VAD implantation by 18.2 ± 5.6% at 3 months (n = 29) and 45.5 ± 23.9% at 6 months (n = 27). Patients with a handgrip strength25% of body weight had an increased risk of mortality, increased postoperative complications, and lower survival after VAD implantation.Patients with advanced HF show impaired handgrip strength indicating a global myopathy. Handgrip strength25% of body weight is associated with higher postoperative complication rates and increased mortality after VAD implantation. Thus, the addition of measures of skeletal muscle function underlying the frailty phenotype to traditional risk markers might have incremental prognostic value in patients undergoing evaluation for VAD placement.

Background: Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. Methods: A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. Results: The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. Conclusions: A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

Interrogation of the tumor microenvironment (TME) is crucial to provide insight into biological activity, resistance mechanisms and implementation of rational combination immunotherapies. Semaphorin 4D (SEMA4D, CD100) has broad immunomodulatory effects in the TME. In preclinical models, antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the TME. Importantly, preclinical combinations of anti-SEMA4D with immune checkpoint inhibitors (ICIs) enhanced T cell activity and tumor regression. VX15/2503 (pepinemab), an IgG4 humanized monoclonal antibody targeting SEMA4D, is currently being evaluated in window of opportunity, integrated biomarker trials to characterize immunomodulatory effects in pancreatic (PDAC), colorectal (CRC), and head and neck squamous cell (HNSCC) carcinomas, and melanoma. At present, three biomarker trials are recruiting patients with four resectable indications to investigate novel combinations of pepinemab with ICIs; 1) PDAC and CRC with resectable liver mets (NCT03373188, n=32), 2) HNSCC (NCT03690986, n=36), and 3) metastatic melanoma (NCT03769155, n=36). Prior to surgery, patients enroll in treatment cohorts including combinations of pepinemab with nivolumab and /or with ipilimumab, single agents, or no treatment. Three to seven weeks later, patients will undergo surgery and a substantial surgical section will be collected under the guidance of a pathologist for comparison across treatment groups and with a pre-dose tissue biopsy. Blood will be collected for PK, PD, and additional correlative biomarker assessments. The primary objective is to evaluate the treatment-induced effects on the immune profile in the TME and in peripheral blood. Additional objectives include, extending the previously reported safety profile of single agent pepinemab to ICI combination therapies, as well as exploring pathologic and radiographic responses in the melanoma study. Correlative multiplex flow cytometric flow panels have been established to phenotype cells in the TME and periphery. A multiplex IHC assay utilizing a sequential probe and strip procedure has also been qualified that allows co-localization, spatial orientation, and quantitation of multiple immune markers. Analysis of immune subsets include but are not limited to activated T cells, neutrophils, Treg cells, DCs, monocytes, macrophages, and importantly myeloid-derived suppressor cells (MDSCs). Target engagement and expression of SEMA4D and its cognate receptors will also be evaluated. Seven subjects have been enrolled in these studies as of 7 Jan 2019. These trials will provide the first integrated clinical assessment of anti-SEMA4D antibody activity to reprogram the TME. Citation Format: Gregory B. Lesinski, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Conor Steuer, Nabil F. Saba, Michael Lowe, Ragini R. Kudchadkar, Brian Olson, Christina Wu. Integrated biomarker trials of VX15/2503 (pepinemab) in combination with checkpoint inhibitors in window of opportunity studies in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT016.

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC). Prior work from our laboratory has defined a role for stroma-derived cytokines such as IL-6 as a significant barrier restraining immunity against PDAC. Our group is pursuing novel approaches to target pathways in the tumor microenvironment (TME), in an effort to improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90), is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC has not been explored in detail. We hypothesize that targeting Hsp90 can modulate the TME, through its ability to target inflammatory signaling and cytokine production by PSC and enhance the efficacy of immunotherapy. Treatment of immortalized and primary patient PSC with the Hsp90 inhibitor XL888 led to decreased IL-6 at the transcript and protein level in vitro. XL888 directly limited PSC growth, and reduced expression of alpha-SMA, Jak/STAT and MAPK signaling intermediates as determined via immunoblot. Combined therapy with XL888 and anti-PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors, as compared to treatment with either agent alone. The treatment was well-tolerated, with no difference in body weight observed in either model. Laboratory studies are assessing immune and stromal biomarkers to define the impact on PSC, cytokines and T-cell biomarkers in the TME. Finally, we have completed the dose escalation phase of a Phase Ib/II clinical trial of XL888 (Hsp90i) and pembrolizumab (anti-PD-1) at our institution. Expansion cohorts of patients with metastatic pancreatic cancer (n=16) or colorectal cancer (n=16) are now accruing, with paired biopsy and peripheral blood samples to address the impact of Hsp90 inhibition on anti-PD-1 mediated T cell proliferation, cytokine production, and PSC-derived cytokine signatures. Citation Format: Mohammad Zaidi, Yuchen Zhang, Michael B. Ware, Matthew R. Farren, Hannah Komar, Brian Olson, Ganji P. Nagaraju, Mehmet Akce, Olatunji Alese, Shishir Maithel, Juan Sarmiento, Walid Shaib, Christina Wu, Bassel El-Rayes, Gregory B. Lesinski. Heat shock protein 90 inhibitors alter pancreatic stellate cell cytokine production and enhances the efficacy of immune checkpoint blockade in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4074.

Anti-semaphorin 4D (SEMA4D, CD100) blocking antibody promotes immune infiltration, reduces immunosuppressive myeloid cells, and enhances T cell activity and tumor growth inhibition in combination with various immunotherapies in preclinical animal models. Clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab (VX15/2503), humanized anti-SEMA4D antibody, are currently underway in several cancer indications. SEMA4D exerts multi-faceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promote immunosuppressive activity of myeloid-derived cells. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and reduced both expression of chemokines that recruit MDSC and the ability of MDSC to suppress T cell activity. Antibody blockade simultaneously restored the ability of dendritic cells and cytotoxic T cells to infiltrate the TME, increasing ratio of Teffector to Tregulatory cells, in syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies, including antibodies to PD1, CTLA-4, and LAG3, epigenetic modulators, and additional novel immunomodulatory combinations in murine breast, colon, head and neck, and melanoma tumor models. New data will describe development and application of methods to assess immune phenotype and biomarkers in translational and clinical studies. These include flow cytometry and whole slide scans of multiplex IHC panels to examine MDSC, M1/M2 macrophage, monocytes, activated DC, B cells, exhausted, activated and stem-like populations of T cells in clinical samples. Expression of SEMA4D and its receptor PlexinB1 were also evaluated in spatial context and cellular co-localization. In summary, SEMA4D represents a novel target to regulate immune infiltration and mesenchymal suppression, sources of resistance to current immunotherapies. Pepinemab treatment was well tolerated in a Phase I oncology trial (NCT01313065) and is currently being evaluated as single agent or in ICI combinations in: (i) a Phase 1b/2a combination trial of pepinemab with avelumab in ICI naïve or ICI refractory NSCLC (CLASSICAL-Lung) (NCT03268057); (ii) a phase 1 combination trial of pepinemab with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1 (NCT03425461); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal, pancreatic (NCT03373188) and head and neck (NCT03690986) cancers treated with pepinemab in combination with nivolumab or ipilimumab; and (iv) a Phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Clinical trials will evaluate safety, tolerability, efficacy, and biological endpoints, including immunophenotyping tumors and blood. Citation Format: Elizabeth E. Evans, Terrence L. Fisher, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Desa Rae Pastore, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Clint Allen, Paul E. Clavijo, Gregory Lesinski, Christina Wu, Conor Steuer, Nabil F. Saba, Brian Olson, Siwen Hu-Lieskovan, Antoni Ribas, Emily G. Greengard, Ernest S. Smith, Maurice Zauderer. Altered myeloid and lymphoid composition of tumor microenvironment following anti-SEMA4D and immune checkpoint combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1545.

Background: Colorectal cancer (CRC) is the second leading cause of cancer death among men and women in the United States, and additional treatment strategies are needed for patients with advanced disease. Prospective therapeutic studies based on tissue-detected genomic targets such as ERBB2 (HER2), BRAF V600E, gene rearrangements/fusions, and microsatellite instability (MSI) have demonstrated clinical benefit for mCRC patients. Although correlative studies and/or retrospective case series utilizing circulating cell-free DNA (cfDNA) next generation sequencing (NGS) have shown that plasma detection of these genomic targets shows promise in mCRC, prospective studies are lacking. We hypothesize that comprehensive genomic profiling of cfDNA will identify actionable targets and improve outcomes for patients with mCRC. Methods: COLOMATE (Colorectal Cancer and Liquid Biopsy Screening Protocol for Molecularly Assigned Therapy; NCT03765736) is a phase II umbrella screening protocol sponsored by the Academic and Community Cancer Research United (ACCRU) consortium. This study utilizes Guardant360™ (Guardant Health, Redwood City, CA) - a blood-based targeted NGS panel - to identify actionable genomic alterations in mCRC patients and to assess the impact of molecularly assigned therapy accordingly under its individual companion studies. Eligible mCRC patients must have progressed on, been intolerant to, or have a contraindication to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) and anti-epidermal growth factor receptor (EGFR) mAbs if RAS wild-type. Companion studies are dynamic and currently include those for patients whose tumors are either RAS/BRAF wild-type, HER2 amplified, FGFR altered, RAS mutated, or without any known actionable alteration. Additional companion studies are under active development. The primary objectives of this study are to perform blood-based genomic profiling on patients with treatment refractory mCRC to facilitate accrual to molecularly assigned therapies, and to obtain patient-matched tumor tissue and cell free DNA from peripheral blood to facilitate clinically annotated genomic analyses. Secondary correlative objectives are to explore mechanisms of acquired resistance to molecularly assigned therapy and to explore the correlation between cfDNA mutational burden (allele frequency, copy number) and clinical outcomes such as objective response rate, progression-free survival, and overall survival. Citation Format: Kristen K. Ciombor, Fang-Shu Ou, Andrew Dodge, Tyler Zemla, Christina Wu, Kimmie Ng, Katrina Pedersen, Shumei Kato, Pashtoon M. Kasi, Daniel Ahn, Rebecca Nagy, Richard Lanman, Scott Kopetz, John H. Strickler, Tanios Bekaii-Saab. COLOMATE: Colorectal cancer and liquid biopsy screening protocol for molecularly assigned therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-235.

Background: HER-2 is a transmembrane receptor that is overexpressed in multiple epithelial tumors. We have previously shown that a first generation HER-2 B-cell peptide vaccine targeting epitopes (628-647) and (316-339) was safe and relatively active. We recently developed a novel B-cell epitope specific vaccine (HER-Vaxx) consisting of epitopes derived from the extracellular domain of HER-2 that correspond to amino acid sequences 597-626 (pertuzumab binding site) and 266-296 (trastuzumab binding site). Methods: This first-in-human Phase 1b study evaluated the safety, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of HER-Vaxx. Using a 3+3 dose escalation design, 3 patients (pts) were treated at each dose level (DL). If Results: 49 patients with metastatic and/or recurrent solid tumors and a median of 4 prior lines of chemotherapy received at least one inoculation of HER-vaxx. Common related toxicities include injection site reactions (56% grade 1/2 and 5% grade 3/4). There were no DLTs. The OID/OBD was found to be DL 2 (1.5 mg of each peptide vaccine).A total of 28 patients received ≥ 3 vaccinations including 2 with a partial response and 14 with stable disease. Of those, 6 patients received at least one 6-month boost. The vaccine generated sustained humoral response eliciting HER-2 specific antibodies in the majority of responding patients. Conclusion: We demonstrate that HER-Vaxx is well tolerated and able to generate sustained anti-HER-2 immune response. Given the promise, continuous development of the vaccine is ongoing at the suggested OBD in HER-2 overexpressing tumors. Citation Format: Tanios Bekaii-Saab, Lai Wei, Robert Wesolowski, Daniel Ahn, Christina Wu, Maryam Lustberg, Amir Mortazavi, Bhuvaneswari Ramaswamy, Jay Overholser, Pravin Kaumaya. A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT017.

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]

4110 Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.

e15693 Background: Resection of the primary tumor in metastatic neuroendocrine tumor (NET) is controversial. The aim of this study is to evaluate survival outcomes and identify prognostic variables of surgical resection of the primary tumor in metastatic NET patients. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Chi-square and ANOVA tests were done to identify factors associated with surgical modality. Univariate and multivariate cox proportional hazards models were used for association between patient characteristics and survival. Kaplan-Meier curves were generated and log-rank tests conducted to compare the survival difference of patient characteristics. Results: A total of 2,361 patients between 18 and 90 years of age with stage IV well/intermediate-differentiated NET were identified. The mean age was 62.1 years (SD±13), with an equal male to female ratio (50.0%). Majority of NET primaries were in the small intestine (33.0%), pancreas (26.3%), and lung (24.4%). The majority were well differentiated tumors (69.6%) and 42.5% of patients underwent surgery at the primary site. On multivariate analysis total surgical resection of the primary (HR 0.44; 0.22-0.90; p < 0.001), female sex, year of diagnosis 2010-2014, negative surgical margin, Charlson-Deyo score < 2, and age < 51 years at diagnosis were associated with better overall survival (OS). Conclusions: Resection of the primary in stage IV well/intermediate-differentiated NET was associated with improved 5-year OS compared to patients with no surgery in small intestine (60.1% vs 44.2%), lung (70.0% vs 20.2%), and pancreas tumors (59.3% vs 30.6%).

4116 Background: Despite the therapeutic promise of ICIs for patients (pts) with some advanced malignancies, they are FDA-approved for only a few GI cancer pts. In NSCLC, melanoma and urothelial carcinoma, there is emerging data that pts who experience IRAEs while on ICIs have improved outcomes compared with pts who do not. This association in GI cancer pts has not been reported. Methods: We retrospectively analyzed outcomes for metastatic GI cancer pts receiving ICIs for FDA-approved indications (later-line MSI-H tumors, 2nd line hepatocellular carcinoma (HCC), 3rd line PD-L1+ gastric (GA)/gastroesophageal junction (GEJ) adenocarcinoma), at Vanderbilt Ingram Cancer Center, Winship Cancer Institute and Stanford Cancer Institute. Our primary aim was to compare progression-free survival (PFS) and overall survival (OS) between pts who did and did not experience IRAEs. Secondary aims were comparison of these outcomes within pts who experienced IRAEs, by initial IRAE severity (Grade (G)3/G4 vs G1/G2) (CTCAE v5.0), time-to-onset (TTO) (≤ 6 weeks (w) vs > 6 w) and management (steroids vs drug cessation vs observation). PFS and OS were determined by Kaplan-Meier (KM) analysis; KM comparisons were done by the logrank test. Results: Between 1/2015-12/2018 61 GI cancer pts with HCC (28), colorectal cancer (27) and GA/GEJ cancer (6) were treated with ICIs; median age was 63 years. The majority (59) received single-agent nivolumab or pembrolizumab while minority (2) received nivolumab and ipilimumab; median time on ICIs was 5.9 months (mos). Twenty-four pts experienced initial IRAEs (6 G3/G4, 18 G1/G2); median TTO was 3.8 mos. Pts who experienced any IRAE had improvements in PFS and OS compared to those who did not (PFS: 32.4 mos (95% confidence interval (CI), 32.4-not reached (NR)) vs 4.8 mos (95% CI, 2.9-8.7), p = 0.0001; OS: 32.4 mos (95% CI, 32.4-NR) vs 8.5 mos (95% CI, 6-NR), p = 0.0036). Among pts who experienced IRAEs, PFS and OS differences between above-specified subgroups did not meet statistical significance. Conclusions: GI cancer pts who experienced IRAEs while on ICIs had marked improvements in PFS and OS compared to those who did not, suggesting the predictive potential for IRAEs as a clinical biomarker in this population.

e18231 Background: Knowledge about perioperative systemic therapy in metastatic colorectal cancer (mCRC) is limited. We aim to describe the nationwide pattern of use and survival outcomes of patients with mCRC treated with surgical resection. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate analyses was done to identify factors associated with patient outcome. Results: A total of 61,940 patients with stage IV CRC older than 18 years were identified. Mean age was 63.4 years (SD±14), with a male preponderance (54.8%). About 80% were Caucasian and 69.9% had colon cancer. Compared to medical treatment only, resection of both primary and metastatic sites (13.5%; HR 0.40; 0.37-0.44; p < 0.001), or primary site resection alone (49.2%; HR 0.52; 0.48-0.56; p < 0.001) were associated with improved overall survival (OS). Other co-variates associated with improved survival included younger age group, year of diagnosis (2009-2013), colon tumor location, and < 3 metastatic sites (Table). Five-year OS for resection of primary and metastatic site (28.2%) was higher than for primary site resection alone (14.9%) or no surgical treatment (4.7%). Conclusions: Resection of metastatic sites or primary tumor was associated with improved survival in patients with stage IV CRC.[Table: see text]

Background: There are now six approved immune checkpoint inhibitors for several different malignancies including melanoma, head and neck cancer, lung cancer, and renal cell carcinoma. Given the increased number of available immunotherapeutic agents, more patients are presenting in clinic as candidates for sequential immunotherapy. However, the efficacy of sequential immunotherapy in a trial setting is unknown. We investigated the association between prior treatment with immune checkpoint inhibitors and clinical outcomes in patients treated with subsequent immunotherapy in a phase 1 clinical trial. Methods: We conducted a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute between 2009 and 2017. We included 49 patients with an immune checkpoint-indicated histology (melanoma, lung cancer, head and neck cancer, and bladder cancer). Patients were then analyzed based on whether they had received at least one immune checkpoint inhibitor prior to enrollment. Overall survival (OS) and progression-free survival (PFS) were calculated in months from immunotherapy initiation on trial to date of death and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard or logistic regression model. Covariates included age, presence of liver metastases, number of prior lines of systemic therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results: The median age was 67 years and most patients (78%) were men. The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). The majority (81%) of patients were RMH good risk. More than half of patients (n=27, 55%) had received at least one immune checkpoint inhibitor prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination therapy, and ten received multiple immune checkpoint inhibitors. In MVA, patients who had not received a prior immune checkpoint inhibitor had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p=0.010). These patients also trended towards longer PFS (HR: 0.86, CI: 0.39-1.87, p=0.699) and higher chance of CB (HR: 2.52, CI: 0.49-12.97, p=0.268). Immunotherapy-naïve patients had substantially longer OS (24.3 vs 10.9 months) and PFS (5.1 vs. 2.8 months) than patients who had prior immunotherapy per Kaplan-Meier estimation. Conclusion: Optimal treatment options for oncology patients who progress on immune checkpoint inhibitors are lacking. In this study, patients who received at least one prior immune checkpoint inhibitor had worse clinical outcomes on immunotherapy-based phase 1 clinical trials than immune checkpoint-naïve patients. This suggests that further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. The results from this study should be validated in a larger, prospective study. Citation Format: Mehmet Bilen, Dylan Martini, Yuan Liu, Colleen Lewis, Hannah Collins, Julie Shabto, Mehmet Akce, Haydn Kissick, Bradley Carthon, Walid Shaib, Olatunji Alese, Rathi Pillai, Conor Steuer, Christina Wu, David Lawson, Ragini Kudchadkar, Bassel El-Rayes, Viraj Master, Suresh Ramalingam, Taofeek Owonikoko, R. Donald Harvey. Sequential immunotherapy and association with clinical outcomes in advanced-stage cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B176.

560 Background: Although clinical outcomes has substantially improved over the last decade, long term survival in mCRC remains rare. Molecular profiling (MP) of CRC is routinely conducted to identify potential therapeutic targets. The aim of this project is to evaluate the impact of uncommon GAs on outcomes and characterize their distribution by age. Methods: Pts were eligible if they had mCRC (synchronous or metachronous) and underwent MP between 01/2013 and 05/2018. GAs were obtained from Foundation Medicine reports. Clinical data were collected by trained personnel by detailed chart review. Multivariable survival analyses (MA) with Cox model were conducted for survival outcomes and Fisher’s exact test was used to assess the differences among age groups (< 45, 45-60, > 60). The study was reviewed by Institutional IRB ( IRB00097021 ). Results: 161 patients with mCRC had MP, and 159 of those patients had survival data. The most commonly detected GAs were APC (133/161, 82.6%) TP53 (128/161, 79.5%). In univariate analyses mutations in BRCA 1/2, RB1, SOX9, CDK8, FLT3, and IRS2 amplification were associated with worse survival outcomes. In MA, including initial stage of disease, GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 remained statistically significant (Table). When we performed MA by age groups, mutations SOX9 in age group < 45 and BRCA1/2 in age group 45-60 were significant predictors of worse outcomes. We also compared the frequency of mutations among age groups and FAM123B was significantly more common in age group 45-60 (P = 0.038). Conclusions: Our data suggests that GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 may predict worse outcomes in mCRC. Therapeutic approaches targeting these pathways should be investigated. Differences in distribution and prognostic significance of mutations were observed based on age. [Table: see text]

658 Background: Appendiceal cancers (AC) comprise around 0.5% of all gastrointestinal neoplasia. The genomic landscape of AC has not been well studied. The yield of circulating tumor DNA (ctDNA) from the plasma of patients with AC has not been reported. The aim of this study is to confirm the feasibility of NGS using ctDNA and characterize common alternations in the genomic profile of AC. Methods: The molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant 360) across multiple institutions, was evaluated. The test detects single nucleotide variants in 54 -73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 303 AC patients were evaluated; 169 female (56%). Median age was 56.8 (range: 25-83). ctDNA NGS testing was done on 372 plasma samples; 48 patients had testing performed twice, 9 three times, and 1 was tested four times. Genomic alterations were defined in 207 (55.6%) samples with a total of 288 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. TP53 associated genes were most commonly altered (n = 96, 33.3%), followed by KRAS (n = 41, 14.2%), APC (n = 19, 6.6%), EGFR (n = 15, 5.2%), BRAF (n = 13, 4.5%), NF1 (n = 13, 4.5%), MYC (n = 9, 3.1%), GNAS (n = 8, 2.7%), PI3CA (n = 7, 2.4%), MET (n = 6, 2.08%), ATM in 6 (1.6%). Other genomic alterations of low frequency, but clinically relevant: AR (n = 4, 1.39%), TERT (n = 4, 1.39%), ERBB2 (n = 4, 1.39%), SMAD4 (n = 3, 1.04%), CDK4 (n = 2, 0.69%), NRAS (n = 2, 0.69%), FGFR1 (n = 2, 0.69%), FGFR2 (n = 2, 0.69%), PTEN (n = 2, 0.69%), RB1 (n = 2, 0.69%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA were all reported once. Conclusions: Evaluation of ctDNA was feasible among individuals with AC. The frequency of genomic alterations in ctDNA testing is similar to those previously reported in tissue NGS. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in patients with AC.

Purpose: Tumor growth inhibition by anti-semaphorin 4D (SEMA4D, CD100) blocking antibody is enhanced when combined with various immunotherapies in preclinical animal models. Immune checkpoint combinations with pepinemab (VX15/2503), a humanized anti-SEMA4D antibody, are currently being evaluated in several clinical trials. Methods: Expanded mechanistic studies in syngeneic preclinical models investigated the effect of SEMA4D blockade on immune contexture within the tumor microenvironment, as a single agent and in combination with various immunotherapy agents. Antitumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine and gene expression analysis. Pepinemab (VX15/2503) is currently being evaluated as single agent or in combination with other immunotherapies in four clinical trials: (i) a phase 1b/2a combination trial of pepinemab with avelumab in NSCLC (CLASSICAL-Lung) (NCT03268057); (ii) a phase 1 combination trial of pepinemab with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1 (NCT03373188); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal and pancreatic cancers treated with pepinemab in combination with nivolumab or ipilimumab (NCT03373188); and (iv) a phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Results: SEMA4D exerts multifaceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promoting immunosuppressive activity of myeloid-derived cells. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and both reduced expression of chemokines that recruit MDSC and the ability of MDSC to suppress T-cell proliferation. Antibody blockade reduced the function of immunosuppressive myeloid and regulatory T-cells in the TME while simultaneously restoring the ability of dendritic cells and cytotoxic T-cells to migrate into the tumor in several syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies in murine colon, head and neck (HNSCC), and melanoma models. For example, anti-SEMA4D plus anti-CTLA-4 resulted in 100% survival and 90% complete tumor rejection (CR) (p Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Terrence L. Fisher, Clint Allen, Paul Clavijo, Gregory Lesiniski, Christina Wu, Siwen Hu-Lieskovan, Antoni Ribas, Emily Greengard, Ernest S. Smith, Maurice Zauderer. Reprogramming myeloid cells in TME with pepinemab, first-in-class semaphorin 4D MAb, enhances combination immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR10.

435 Background: There is no consensus regarding treatment for HCC variants. Clinical outcomes of HCC variants differ from pure HCC. The aim of this study is to compare clinicopathological characteristics, treatment, and outcomes of HCC variants with pure HCC. Methods: Patients with HCC and variants with 8170/3-8175/3 and 8180/3 ICD-O-3 codes were identified from National Cancer Database between 2004 and 2013. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. The mean age was similar in all except FLHCC (37.9 vs. 60.9-64.1 years, p < 0.001). Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p < 0.001). Pure HCC (10.57%) underwent surgical resection less often than variants; FLHCC (54.8%), clear cell (34.5%), mixed HCC (29.8%), spindle cell (33.3%), pleomorphic (34.8%), and scirrhous (9.9%) (p < 0.001). Ablation was performed in 9.8% of pure HCC, and in up to 8.7% of HCC variants. More than a third of all patients received chemotherapy; pure HCC (42.3%), mixed HCC (38.5%), scirrhous (31.1%), spindle cell (36.1%), clear cell (35.5%), pleomorphic (34.8%), and FLHCC (41.3%). FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In univariate and multivariate analyses, fibrolamellar histology, female sex, diagnosis between 2009 and 2013, treatment at academic center, well/moderately differentiated histology, early stage, and chemotherapy was associated with better OS compared to pure HCC, male sex, diagnosis between 2004 and 2008, treatment at community cancer program, poorly differentiated, late stage, and no chemotherapy (p < 0.001). Conclusions: HCC variants underwent surgical resection more often than HCC. FLHCC had the best 5-year OS. Liver transplant is commonly performed in HCC variants.

Dans cet entretien, Zainal Arif Mantaha, ambassadeur de Singapour en France, revient sur la diversite de la gastronomie singapourienne. Reflet des multiples cultures qui composent la cite-Etat, la cuisine se trouve au cœur des relations diplomatiques qu’elle developpe avec la France. Des evenements ponctuels sont organises pour la promouvoir aupres du public francais. En parallele, la volonte de faire inscrire la culture hawker comme patrimoine culturel immateriel de l’humanite affirme le caractere international de la gastronomie singapourienne.

En 1907, le scoutisme est cree en Grande-Bretagne en tant que projet educatif destine a limiter les effets emollients de la vie dans une societe desormais industrialisee et urbaine. Il s’etend progressivement dans tout l’Empire. Paradoxalement, son succes au sein des societes coloniales ne tient pas a son message de regeneration des valeurs viriles et primitives. Au contraire, c’est parce que le scoutisme est percu comme revelant des codes de la societe britannique et sa modernite qu’il est adopte par les elites autochtones. Pour les uns, il s’agit d’un retour revivifiant a la nature. Pour d’autres, il s’agit d’un rite initiatique qui permet d’acceder aux valeurs de la metropole. En s’appuyant sur le cas malais, l’objet de cet article est d’analyser ces deux perceptions. Dans une perspective comparee, il s’agira de mesurer comment codes sociaux et politiques sont reinterpretes au fil de leur transmission entre la societe metropolitaine et le monde colonial.

Hypoalbuminemia has been recognized as a prognostic indicator in patients with heart failure. We aimed to investigate the association of hypoalbuminemia with postoperative mortality in patients undergoing left ventricular assist device (LVAD) implantation. We studied 272 consecutive patients undergoing LVAD implantation from 2000 to 2010 at our institution. Preoperative clinical characteristics and laboratory variables associated with mortality were analyzed. Postoperative survival of patients with preoperative hypoalbuminemia (

This article pursues a context-rich understanding of how digital media offer unique opportunities for citizens residing in mainland China to participate in civic engagement and organize their civic values. While the Chinese state authority keeps a heavy hand in any form of media, old or new, for use of overt political expressions, I provide empirical demonstration of the link between entertainment media experiences and the exchange on more serious civic topics. In doing so, I argue for a more expanded notion of civic engagement for political environments such as China and develop an empirical scheme that incorporates ordinary citizens' interactions with more leisure-oriented media texts. Such theoretical and empirical moves, as I point out, can contribute to a more thoughtful discussion of the Internet and civic engagement in China. Furthermore, this article pays particular attention to how the Internet provides a valuable channel for community formation among ordinary Chinese citizens outside the mainstr...

Etanercept blocks tumor necrosis factor α (TNF-α), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer.Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-free survival at 6 months. Blood specimens were analyzed for TNF-α, IL-1β, IL-6, interferon-γ, IL-10, and NF-κβ activation. The trial is registered with ClinicalTrials.gov, number NCT00201838.Thirty-eight patients participated in this study. In the gemcitabine-etanercept cohort, grade 3/4 drug-related toxicities included leucopenia (3) and neutropenia (6). There were 3 (12%) patients with partial response and 8 (32%) patients with stable disease. The rate of progression-free survival at 6 months was 28% [n = 7; 95% confidence interval (CI), 20%-36%]. Median time to progression was 2.23 months (95% CI, 1.86-4.36 months) and median overall survival was 5.43 months (95% CI, 3.30-10.23 months). Clinical benefit rate was 33% of the evaluable patients. A correlation was seen between IL-10 levels and clinical benefit.Etanercept added to gemcitabine is safe but did not show significant enhancement of gemcitabine in patients with advanced pancreatic cancer.

Colorectal cancer is the third commonest cancer and second commonest cancer killer in the USA. With a median age at diagnosis of 72 years, it largely affects the elderly population. However, there is a lack of objective data with which to answer clinically relevant questions regarding adjuvant therapy in the geriatric patient population because mainly younger patients are enrolled in clinical trials. Elderly patients are undertreated in the adjuvant setting owing to multiple factors, including physician decision and patient preference. Older patients have different tumor biology, physiologic factors, and social situations to consider in comparison with younger patients. Thus, geriatric patients require more thorough assessment of their functional status and existing medical conditions as they are at risk of increased toxicities from chemotherapy and their ongoing treatment requires vigilance. Elderly patients do benefit from adjuvant chemotherapy, although subgroup analyses show that many do not derive incremental benefit from the addition of oxaliplatin to 5-fluorouracil therapy.

Background Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. Methods Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. Results A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. Conclusions Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Objectives This study evaluated the Model for End-Stage Liver Disease (MELD) score and its modified versions, which are established measures of liver dysfunction, as a tool to assess heart transplantation (HTx) urgency in ambulatory patients with heart failure. Background Liver abnormalities have a prognostic impact on the outcome of patients with advanced heart failure. Methods We retrospectively evaluated 343 patients undergoing HTx evaluation between 2005 and 2009. The prognostic effectiveness of MELD and 2 modifications (MELDNa [includes serum sodium levels] and MELD-XI [does not include international normalized ratio]) for endpoint events, defined as death/HTx/ventricular assist device requirement, was evaluated in our cohort and in subgroups of patients on and off oral anticoagulation. Results The MELD and MELDNa scores were excellent predictors for 1-year endpoint events (areas under the curve: 0.71 and 0.73, respectively). High scores (>12) were strongly associated with poor survival at 1 year (MELD 69.3% vs. 90.4% [p < 0.0001]; MELDNa 70.4% vs. 96.9% [p < 0.0001]). Increased scores were associated with increased risk for HTx (hazard ratio: 1.10 [95% confidence interval: 1.06 to 1.14]; p < 0.0001 for both scores), which was independent of other known risk factors (MELD p ¼ 0.0055; MELDNa p ¼ 0.0083). Anticoagulant use was associated with poor survival at 1 year (73.7% vs. 86.4%; p ¼ 0.0118), and the statistical significance of MELD/MELDNa was higher in patients not receiving oral anticoagulation therapy. MELD-XI was a fair but limited predictor of the endpoint events in patients receiving oral anticoagulation therapy. Conclusions Assessment of liver dysfunction according to the MELD scoring system provides additional risk information in ambulatory patients with heart failure. (J Am Coll Cardiol 2013;61:2253–61) a 2013 by the American College of Cardiology Foundation

Colorectal cancer is the third most common cancer in the Western population and has a 5-year overall survival of 5–10% when metastatic. Approximately 30% of the patients with metastatic colorectal cancer have limited disease apparently isolated to the liver and, if this can be resected, the 5-year overall survival is improved to 30–60%. Therefore, it is important to identify patients who have both resectable disease and those with initially unresectable tumors who can potentially be downsized with chemotherapy to allow resection. First-line doublet chemotherapy regimens lead to response rates of 50–60%, triplet chemotherapy regimens may result in a response rate of up to 70%, and biological agents may add to responses or induce morphologic changes that facilitate disease resection. Surgical advances in recent years have also increased resectability rates and have challenged prior rules of resectability. Local therapies including ablation and radiation, often performed in conjunction with resection, may further aid in control of disease. The aim of this article is to focus on the role of neoadjuvant therapy in the treatment of colorectal liver metastases.

Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance.Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS).When genes with an incidence 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached.In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.