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Hot Tickets: Shows to See in February
Time flies when you're having fun, and we sure must have been having a lot of it because January came and went with a blink of an eye. However, February in San Francisco is an exciting time for music lovers. Not only does it signify the beginning of festival season (Noise Pop's pre-party is on 2/18 and they're pumping music nearly every night straight through 3/1), it's also the start of big artists' West Coast legs of their tour. Yay for us! Noise Pop coverage to come, but to warm you up here's this month's hot list.
Mates of State, Café du Nord, 2/1: Obviously this show sold out in minutes, these SF transplants by way of Lawrence, Kansas are veterans in the indie arena (the duo formed officially in 1997 and wed, yes, wed each other in 2001), yet they've never lost their creative charm. Get to Craigslisting to snag a peek at this cutesy couple in the most intimate of venues.
Felix Da Housecat, Yoshi's, 2/4: Chicago-bred second-wave house revolutionary captured the scene entirely by surprise with his own recordings, various aliases, and his 90's premiere label, Radikal Fear Records. Still a house and electro staple to this day, FDH still flips fans upside down with his fresh spins.
The Thermals, Thao with the Get Down Stay Down, Great American Music Hall, 2/5: Courting their best album to date, The Thermals deliver high energy intelligent punk, showing off their best skills on the live stage. Apparently they discovered the fourth chord in pop-punk, not particularly interesting except to extreme music nerds, but you will appreciate it when you hear it in person. One of our favorite loveable locals, Thao with the Get Down Stay Down, is co-headlining with their edgy folk feel. Definitely a show to get down to (no pun intended).
Nouvelle Vague, The Regency Ballroom, 2/7: Seems like the French invasion has officially begun. With Phoenix selling out the Fillmore this week, and Nouvelle Vague popping in the next, we just can't escape all these talented Frenchies (but we're sure not complaining!). Nouvelle Vague's particular claim to fame was, and still is, their beautiful covers of new wave and punk classics. As of late, they've pumped some heavy American country and bluegrass that still stay true to their bold bossa nova ways. You'll fall back in love with classics you never knew you loved in the first place.
St. Vincent, Wildbirds & Peacedrums, Great American Music Hall, 2/8: Our favorite Polyphonic Spree soloist, Annie Clark (aka St. Vincent) comes back to visit laying down her complicated compositions and high-energy multi-instrumentalist talent. You'll be blown away by her multi-tasking skills, but when she opens her mouth, you'll fall in love. Opening for her are the up-and-coming Swedish husband-and-wife drum and vocal duo of Wildbirds & Peacedrums. Their latest album The Snake has been praised by Pitchfork (among many others) for their, "application of deceptively simple techniques to create highly complex and agile pop music." They've already received an award for Swedish Jazz Act of the Year (in 2008), and we won't be surprised when they do it again this year with this presumably dark, but impressive album.
The Editors, The Warfield, 2/8: Their brand new album In This Light And On This Evening literally just hit stores a little over a week ago where it debuted at #1 on the UK charts and has been consistently in the top 10 across Europe. Now we know Europe always seems to be a little ahead of the curve when it comes to hit-makers, but here's a rare glimpse into the future. Prepare for The Editors to dominate the US in years to come. Taking on a more electro, synth-heavy and mechanical feel than their previous, The Editors constantly stay on key and manage to create a completely new sound while still maintaining their old identity.
Vivian Girls, Bottom of the Hill 2/9: NY-based all girl trio formed a large cult following from their early beginnings playing their home underground scene. After a drummer change and a second album release in late '09, they're touring just as strong as ever.
Eyedea & Abilities, Bottom of the Hill, 2/10: Blaze Battle winner (broadcast on HBO), Eyedea, performs under many monikers including Oliver Hart, where he gained fast fame with a notable reputation in the underground battle scene, then by touring with Slug (of Atmosphere) as well as other Rhymesayers label-mates. Collaborating with DJ Abilities turned out to be more of a long term love affair than they originally predicted, and the duo have since released three albums together. If you like up-beat, fresh, and intelligent conscious hip-hop, this is where you need to be.
Wild Beasts, The Independent, 2/11: Leeds-based four-piece have raced through to the top of many reputable charts and "best of" lists skating by with just their incredibly catchy and perfected indie pop. No gimmicks, no designated genre, or scene, Wild Beasts just dominate being plain and simply, themselves.
The Album Leaf, Magik Magik Orchestra, Great American Music Hall, 2/12: Classically trained pianist, Jimmy LaValle (The Album Leaf) will be accompanied by a selection from the modular orchestra of 100 classical musicians (Magik Magik Orchestra) between the ages of 18-35, all from Northern California, and based in our great City. LaValle is involved with various projects from GoGoGo Airheart, to Tristeza, the Locusts and Black Heart Procession. This will be an incredible twist on beautifully orchestrated instrumentalism.
P.O.S., Bottom of the Hill, 2/18: There must be something in the water in the Midwest, or more specifically, Minnesota, where this blow-up hip-hop artist is also from (along with the entirety of Rhymesayers and then some). Punk-influenced multi-instrumentalist and soulful lyricist P.O.S. (real name, Stefon Alexander) has taken on the mainstream as of late all while retaining his underground wit and charm. By the way, in case you're wondering, P.O.S. doesn't necessarily stand for what you think, he's cited explanations such as, but not limited to, Pissed Off Stef, Promise of Stress, Promise of Skill, Product of Society, and of course, the obvious.
John Butler Trio, Great American Music Hall, 2/20: It feels as though we're almost teasing you with this sold out super-group. John Butler finally debuts his accompanying band made up of Nicky Bomba and Byron Luiters. Most likely living up to the hype, their debut album April Uprising is said to take on a new journey for John Butler, confirmed with positive critical reviews.
Noise Pop, various venues, 2/23-3/1: Full Noise Pop previews and coverage are coming to a computer screen near you. To get you vaguely excited, highlights include: Yoko Ono Plastic Ono Band, Rogue Wave, Foreign Born, The Dodos and Magik Magik Orchestra Collaborative Performance, Zee Avi, John Vanderslice, Atlas Sound, Geographer, The Mumlers, Wallpaper, Battlehooch, The Limousines, Rainbow Arabia, Scissors For Lefty, Judgement Day, Memory Tapes, Loquat, Birds & Batteries, We Were Promised Jetpacks, Mirah, Music For Animals, !!!, Maus Haus, Sugar and Gold, Magnetic Fields, Avi Buffalo, Edward Sharpe & The Magnetic Zeros, and AB & The Sea among others...and that's just the music portion (the film debuts are just as impressive). Stay tuned.
the independent the warfield regency ballroom bottom of the hill great american yoshi's café du nord
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17 Fun Things: Celebrate women chefs, Sunday Streets on Valencia + more events this week
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REVERIST- This eclectic,indie pop band from Central Florida began as the brainchild of keyboardist and vocalist Omar Qazi, who used songwriting as a creative release while in medical school. That 'release' became a passion that would develop into the musical project called Reverist with the addition of drummer Steve Addington. The pair released their first EPDreaming Onward in 2015 and began playing to live audiences from Tampa to Boston. From a city known more for theme parks than music, Orlando's Reverist has been dishing out a healthy dose of danceable melodies and catchy choruses to audiences from the Florida Music Festival to the House of Blues and opening for national acts R.LUM.R, Japanese Breakfast, Porches and more.Fans of Walk the Moon, Coldplay and Cold War Kids will pick upon that influence here.


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#good&bad #dumptruck Hello Kids, Welcome to Good and bad cartoon series , The best channel for kids to watch the Good & bad vehicles cartoon Series .
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Tank cartoon "Monster trucks became a tanks"
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By Allison R. Scales on	 January 5, 2022 Story books
IIn a bowling alley somewhere in post-apocalyptic rural America, a 10-year-old scholar celebrates his birthday. His mother chose this moment to tell him, via the unusual method of rendering a murder scene as icing on her cake, that her father killed his grandfather. The baker, however, got it wrong and garnished the cake with an edible version of Saturn devouring his son Goya., an image so disturbing that it leads the child to wonder about his own existence. "Saturn", a guest at the party usefully informs him, "represents Time, which, with its voracious appetite for life, devours all its creations". Later, we'll learn that bowling never existed, and some or all of these characters may very well be dead.
Welcome, if you've never been here before, to the world of Joy Williams – widely praised, unfortunately not as widely read. My dazzling vintage 2001 The Quick and the Dead paperback contains admiring quotes from Don DeLillo, Raymond Carver and Bret Easton Ellis, but in the UK it is hopelessly out of print. The Williams 2015 News Collection The Visiting Privilege was hailed by all who read it as a major literary event, but it took the tiny Tuskar Rock imprint to bring it to the UK market.
At first glance, Harrow, her first novel in over 20 years, seems unlikely to broaden its audience. That's not to say the book isn't brilliant – it is. It's just that Williams didn't make any concessions; it remains wonderfully and resolutely itself. What might be a little different, however, is the world in which her work emerges and the reality that she so boldly alchemizes in her vision.
Each sentence is shot in elegant and surprising perfection
Attempting to give an overview of this novel sounds exactly like the kind of misguided effort Williams would despise, but let me give it a try. Harrow takes place in the near indefinite future in which the global environmental situation has gone from a "point that people thought would last forever" to total catastrophe. Khristen, the not quite central character in the novel, died briefly as a baby, or so his mother adamantly believes, and may never have fully returned. After the disaster, in the middle of hallucinatory terrain which may or may not be a beyond, she finds herself at the Institute, where a cowardly collective of geriatric terrorists "in poor health but with the heart of a suicide bomber" plots missions suicides targeting vivisectionists and pesticide vendors. in the hope that it will "refresh, with insane violence, a plundered land".
The Williams method is a method of contiguity rather than linearity. Language, not narrative, is connective tissue. To read it is to be thrown in all directions: from the deep spiritual to the ridiculously bizarre. One minute we observe "unprepared souls, moments from the clarity of their death." Next we are invited to consider the condition of a very old man's penis: "She wondered if his penis was as shredded, nibbled and nicked as the rest of him or whether it was hanging down wonderfully, incredibly smooth and distant." , his oak head. "
Each sentence is shot in elegant and surprising perfection. In bowling, serious bowlers "took the rest of their poses for a vanity of time." A crashing car flies away "like a crumpled Kleenex in a cement utility pole through which it has been trepanned with sparkling efficiency." A salesperson is so talented that he "might sell a doberman a shock collar." Even seemingly flippant sentences shine with wit. Admire if you want the sung perfection of "Eddie Fucking Emerald offed by a grass in a Caddy".
Focusing on our collective complacency and denial, Williams is both ironic and ruthless, bemoaning "twelve lane highways with bicycle surcharges" and people "who think they can still save the earth by crushing modest nuts or beans for a pancake meal ". Pre-collapse environment lecture includes lecture titled The Potentiality of Landscape Emptiness: The Integrity of Half-Measures. A television channel only broadcasts minutes of silence.
"We all lead three lives," says Khristen. "The true, the false, and the one we are unaware of." This life we are not aware of is Williams' big topic. It peels away the visible and the known, revealing the death and chaos below. While walking through a bird rescue center, Khristen comes across "an old oil barrel, overflowing with amputated wings." A grove of trees is "surprisingly green and freshly pleasant, except for the bundles of meat thrown into it." What appears to be a live broadcast of a nesting bird is actually a recording, the bird having flown in a truck long ago.
Part of what makes Williams' work so unsettling is that the agency is almost irrelevant. Navigating a world that makes no sense, his characters are lost and bewildered, their actions and ideas meaningless. These are people who "suspected they were meant to be more or different but groped in the smoky light of half-realized lives." With free will in question and the boundaries between life and death or reality and illusion almost blurring, individuality itself begins to unravel. "Each person," Williams tells us, "considered themselves unique as snowflakes, but overall they were a blizzard, a veil of swirling expectation and denial."
In his remarkable Hawk essay, on a beloved dog who inexplicably attacks him, Williams writes: "The experience is fundamentally illusory. When we experience pain or emotional grief, it feels like everything that happens in life is unreal. And that's a good understanding of life. Harrow reminds us that in the aftermath of climate collapse, trauma and grief are the condition of our collective existence. As our world disintegrates, it will take with it what we consider to be reality. Addressing this in fiction will be the work, in part, of some type of modern mystic. Williams – a great virtuoso of the unreal – is one of them.
Harrow by Joy Williams is published by Tuskar Rock (£ 14.99). Sam Byers' latest novel is Come Join Our Disease (Faber). To support The Guardian and Observer, order your copy at guardianbookshop.com. Delivery charges may apply.
Recent books of the Faculty | Stories | Notre-Dame review
Discover the latest books at the Jervis public library

redpajama_set_name: RedPajamaCommonCrawl


The Motion Picture Association of America has never been a very popular organization. Film sites like this one have been calling for its dissolution for more than a decade now, but in the past few weeks their mainstream public profile has gotten even worse. It's safe to say that after their support of widely decried censorship legislation like SOPA and PIPA, for a growing number of people, they've just become public enemy #1.
Those who count on quote 'Hollywood' for support need to understand that this industry is watching very carefully who's going to stand up for them when their job is at stake. Don't ask me to write a check for you when you think your job is at risk and then don't pay any attention to me when my job is at stake.
There's some debate as to whether this meets the legal qualifications necessary to begin an investigation for bribery, but most seem to agree that it definitely meets all of the moral ones. The public wants answers. So where did they turn? To the Obama administration. And now the Obama administration has, in essence, told everyone to forget it.
Last week we told you here about a petition started on the Whitehouse website asking the Obama administration to investigate the possibility that the MPAA may be bribing politicians to get their way. The petition was filed as part of a special program created by the Whitehouse to bring transparency in government. In theory any petition started there is supposed to be answered, should it receive the requisite number of signatures. This particular petition rapidly received far more than the required number and now the Obama administration has responded. They've responded by saying they aren't going to comment.
Thank you for signing this petition. We appreciate your participation in the We the People platform on Whitehouse.gov. However, consistent with the We the People Terms of Participation and our responses to similar petitions in the past, the White House declines to comment on this petition because it requests a specific law enforcement action.
Most expected a response like this, and the truth is that the Whitehouse's "petition the government" tool is really little more than a PR excercise. They tend to pick and choose which questions they want to answer, regardless of whether or not the petition gets enough signatures to get an answer. They were bound to find a loophole somewhere.
That doesn't mean, however, that it doesn't matter. The Whitehouse is probably hoping it'll go away, but at least they had to notice it existed, and perhaps it means they'll pay more attention to whatever action we the people take next.
In the meantime, the push to boycott Hollywood is growing. At the forefront of the boycott Hollywood movement is Reddit where they've put forward the notion of staging a "Black March" in which protestors would use their purchasing power to hit the MPAA where it hurts, boycotting any and all entertainment products created under one of their signatory's banners for the entire month of March. This week even Anonymous joined the call, and as scary hacker organizations go, they have a reputation for getting things like this done.
Do you think a Hollywood boycott a good idea?


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Jonathan Biss
Arts & Entertainment | Biographies & Memoirs
Jonathan Biss has appeared with the foremost orchestras of North America, Europe, Asia, and Australia. Widely regarded known not only for his artistry and poetic interpretations but also for his deep musical curiosity, Biss performs a diverse repertoire ranging from Mozart and Beethoven, through the Romantics to Janáček and Schoenberg as well as works by contemporary composers such as Gyorgy Kurtág and including commissions from Leon Kirchner, Lewis Spratian and Bernard Rands. Biss has a noted recording career. His recordings include an album of Schubert sonatas and two short Kurtág pieces that was named by NPR Music as one of the best albums of the year. In January 2012, Onyx Classics released the first CD in a nine-year, nine-disc recording cycle of Beethoven's complete sonatas. The second album of Beethoven sonatas will release in January 2013. Biss studied at Indiana University and at The Curtis Institute of Music, where he was appointed to the piano faculty in 2010. Jonathan Biss has just released a new Kindle Single, "Coda," about the idea of "Late Style" and what that means for Brahms, Schubert, Mozart, and, of course, Beethoven! His previous work on Amazon includes "A Pianist Under the Influence" and "Beethoven's Shadow," the first Kindle Single written by a classical musician. In Coda, Biss attempts to answer the timeless question of what causes artists to go in new directions towards the end of their lives. As in his previous writing, he examines the relation between the composers' lives and their music, but also talks about what the music means to him as a performer and a human being. Photo by Jamie Jung
Unquiet
My Life with Beethoven
By: Jonathan Biss
Narrated by: Jonathan Biss
In his vivid and profound addition to Audible's Words + Music series, Jonathan Biss, the world renowned pianist and critical Beethoven interpreter of our time, expounds on the spellbinding hold the classical figure and his work possesses over him....
Love, as always, is the answer.
Series: Words + Music
Included in Plus membership
Free with Plus trial
A Pianist Under the Influence
Narrated by: Jeff Woodman
World-famous pianist Jonathan Biss has had a special relationship with composer Robert Schumann since he was a child....
Schumann re-examined
By Rebecca on 11-16-13
Beethoven's Shadow
The American pianist Jonathan Biss is known to audiences throughout the world for his artistry, musical intelligence and deeply felt interpretations....
Without the music itself this makes no sense as an audiobook
By Peter Arnberg on 02-08-18
In Beethovens Schatten
Narrated by: Helmut Krauss
Jeder, der Beethovens Musik schon einmal live im Konzert gehört hat oder Aufnahmen seiner Werke kennt, lässt sich in dieser fast schon spirituellen...
Anna Ziegler
Kara Cooney
Marlo Mack
Michael Specter


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Cancer Therapy: Clinical
A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma
Gregory L. Beatty, Drew A. Torigian, E. Gabriela Chiorean, Babak Saboury, Alex Brothers, Abass Alavi, Andrea B. Troxel, Weijing Sun, Ursina R. Teitelbaum, Robert H. Vonderheide and Peter J. O'Dwyer
Gregory L. Beatty
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
Drew A. Torigian
E. Gabriela Chiorean
Babak Saboury
Alex Brothers
Abass Alavi
Andrea B. Troxel
Weijing Sun
Ursina R. Teitelbaum
Robert H. Vonderheide
Peter J. O'Dwyer
DOI: 10.1158/1078-0432.CCR-13-1320 Published November 2013
Purpose: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).
Experimental Design: Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m2 gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle.
Results: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[18F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; P = 0.007).
Conclusions: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted. Clin Cancer Res; 19(22); 6286–95. ©2013 AACR.
See related article by Le and Jaffee, p. 6061
This article is featured in Highlights of This Issue, p. 6059
This phase I study investigates the tolerability and clinical impact of an agonist CD40 monoclonal antibody (CP-870,893) when administered in combination with gemcitabine for the treatment of patients with chemotherapy-naive advanced pancreatic ductal adenocarcinoma (PDA). We show that combination of CP-870,893 with gemcitabine is well-tolerated and associated with preliminary evidence of efficacy. Treatment produced a systemic immune response that was marked by leukocyte trafficking, cytokine production, and cellular activation. Using novel analyses of metabolic imaging, we observed, in many patients, a cumulative decrease with each cycle of therapy in the metabolic activity of the primary pancreatic lesion. However, treatment responses of metastatic lesions were heterogeneous. These findings highlight the biologic heterogeneity of pancreatic carcinoma and indicate a role for metabolic imaging in understanding treatment responses.
Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, and is notoriously resistant to conventional forms of treatment including chemo- and radiotherapy (1, 2). This finding may be related to emerging data showing the importance of the tumor microenvironment in regulating therapeutic efficacy (3–6). In PDA, the tumor microenvironment is marked by poor vascularity, dense desmoplasia, and a leukocyte reaction dominated by macrophages (3, 7, 8). Strategies that target this desmoplastic reaction may be critical for improving therapeutic efficacy in PDA (3, 5).
Tumor-associated macrophages, among other hematopoietic and nonhematopoietic cells, can express the cell surface molecule CD40, a member of the TNF receptor superfamily (9). CD40 is a major determinant in the development of T-cell–dependent antitumor immunity through its ability to "license" antigen-presenting cells for tumor-specific T-cell priming and activation (10–15). In a preclinical model of PDA, we reported that systemic CD40 activation can also induce tumor regression that is independent of T cells, but requires macrophages that rapidly infiltrate tumor lesions, become tumoricidal, and attack the tumor microenvironment by facilitating stromal depletion (16).
CP-870,893 is a fully human and selective CD40 agonist monoclonal antibody (mAb) that, as a single agent, has shown promising clinical activity, particularly in patients with melanoma (17). Because preclinical data suggest that chemotherapy can synergize with CD40 agonists, we conducted a phase I study using CP-870,893 in combination with gemcitabine and observed major tumor regressions in some patients with advanced PDA (16). Here, we report a final analysis with biologic correlatives of treatment with CP-870,893 in combination with gemcitabine in patients with advanced PDA. The primary objective was to define safety, tolerability, maximum-tolerated dose (MTD), and recommended phase II dose (RP2D) of CP-870,893 when given in combination with gemcitabine. Secondary objectives were to evaluate clinical activity as well as pharmacodynamics and immune modulation. In addition, we conducted novel analyses of metabolic imaging, and report biologically important heterogeneity in the treatment response of primary and metastatic lesions.
Twenty-two patients with chemotherapy-naïve advanced PDA were enrolled between June 28, 2008 and March 19, 2010 at the Abramson Cancer Center, University of Pennsylvania (Philadelphia, PA) and the Indiana University Simon Cancer Center (Indianapolis, IN).
Inclusion criteria were age >18 years, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate end organ function. Exclusion criteria included previous systemic treatment for pancreatic cancer or radiotherapy within 4 weeks before randomization, autoimmune disorder, coagulopathy, major illness, and pregnancy or lactation.
Written informed consent was required. The study was approved by local Institutional Review Boards.
Study design and treatment plan
This was an open-label, phase I dose-escalation study. Primary objective was to determine safety, tolerability, MTD, and RP2D of CP-870,893 when given in combination with gemcitabine. Secondary objectives were to characterize pharmacodynamics, immune modulation, and preliminary evidence of efficacy including response rate, overall survival (OS) and progression-free survival (PFS).
Patients received 1,000 mg/m2 gemcitabine on days 1, 8, and 15 of each 28-day cycle (Fig. 1). On the basis of preclinical data showing synergy when CD40 agonists are delivered 48 hours after gemcitabine, CP-870,893 was administered once during each treatment cycle on day 3 (18, 19). To determine the MTD of CP-870,893, two dose cohorts (0.1 and 0.2 mg/kg) of at least three patients were enrolled on the basis of single-agent safety data (17, 20). To further evaluate safety and efficacy, an expansion cohort of at least 12 patients was planned. Safety assessments included incidence of treatment-related adverse events, according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 3.0, and incidence of patients experiencing dose modifications and/or premature discontinuation of study drug. Dose-limiting toxicity (DLT) was defined during cycle 1 of treatment as treatment-related nonhematologic grade 3 to 4 adverse events despite optimal supportive care; grade 3 or 4 neutropenia or grade 3 febrile neutropenia; grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding; grade 4 lymphopenia if complicated by infection, or any other grade 3 hematologic adverse event. MTD was estimated as the highest dose level at which fewer than 2 of 6 patients experienced DLT. Patients continued treatment until disease progression or unacceptable toxicity. CP-870,893 was supplied by the Pfizer Corporation (17, 21).
Treatment schema. Gemcitabine (1,000 mg/m2) was infused on days 1, 8, and 15 of each 28-day cycle, with CP-870,893 administered once during each treatment cycle on day 3.
Pharmacodynamic studies
Serum and peripheral blood for assessment of cytokines and B lymphocyte activation were obtained at baseline and at defined times during cycle 1 after infusion of gemcitabine and CP-870,893. Serum cytokine levels of interleukin (IL)-6, IL-8, and IL-10 were determined by ELISA. Peripheral blood CD19+ B lymphocytes were evaluated by flow cytometry, and molecules of equivalent soluble fluorochrome (MESF) were calculated for HLA-DR (MHC class II) and CD86 (costimulatory molecule).
Tumor response
All patients who received at least one dose of CP-870,893 were evaluated for toxicity and efficacy. Tumor response was assessed by computed tomography (CT) or MRI at baseline and every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.
Positron emission tomography data acquisition and analysis
Metabolic activity was assessed in patients enrolled in the MTD expansion cohort by determining 2-[18F]fluoro-2-deoxy-d-glucose (FDG) uptake within tumor lesions seen on positron emission tomography/computed tomography (PET/CT) imaging at baseline, 2, 8, and then every 8 weeks while on treatment. FDG-PET/CT was conducted after patients had fasted for ≥6 hours and plasma glucose levels were determined to be less than 200 mg/dL. Approximately, 15 mCi of FDG were administered intravenously, and images were acquired approximately 60 minutes later from skull base to mid-thighs. Analysis was conducted using the ROVER software package (ABX, GmbH), providing a semiautomated approach to delineate FDG-avid lesions and to estimate metabolically active volume (MAV) and mean standardized uptake value (SUVmean) for individual lesions from PET datasets as previously described (22). For each tumor lesion, mean metabolic volumetric product (MVPmean) was determined by multiplying metabolism by volume (i.e., MVPmean = SUVmean × MAV). Total MVPmean, a quantitative measure of global disease burden, was determined by summing MVPmean of all lesions. Total hepatic lesion MVPmean, a measure of hepatic disease burden, was determined by summing MVPmean of hepatic lesions only. Image assessment also included measuring the maximum SUV (SUVmax) for each of five target lesions and determining the sum of SUVmax for all lesions.
Statistical analyses were conducted using Stata 10.0 for Windows (StataCorp). PFS was defined as time from start of study treatment to disease progression or patient death, whichever occurred first. OS was defined as time from start of study treatment to patient's death. PFS and OS were analyzed using Kaplan–Meier methods. The Spearman rank test was used to estimate correlations between changes in biomarkers relative to baseline and OS. For analysis of change from baseline of pharmacodynamic end points, a repeated measures ANOVA was conducted. All analyses were conducted as per protocol on patients receiving at least one dose of CP-870,893.
Twenty-two patients with advanced chemotherapy-naïve PDA were enrolled (Table 1). Ninety percent (n = 20) of patients had metastatic disease. One patient in the MTD expansion cohort received a single dose of gemcitabine and withdrew from study before receiving CP-870,893 due to acute cholangitis related to tumor progression. The remaining patients (n = 21) received gemcitabine (1,000 mg/m2) administered on days 1, 8, and 15 with infusion of CP-870,893 at either 0.1 or 0.2 mg/kg on day 3 of a 28-day cycle (Fig. 1).
Baseline patient demographics and clinical characteristics
Safety results, DLTs, and MTD
None of the 3 patients in cohort 1 (0.1 mg/kg) or 6 patients in cohort 2 (0.2 mg/kg) experienced DLT. Among 12 evaluable patients in the expansion cohort (0.2 mg/kg), 1 patient experienced DLT due to grade 4 cerebrovascular accident on day 3 of cycle 1 after receiving CP-870,893, and was withdrawn from study. As this adverse event occurred within several hours after receiving the first dose of CP-870,893, it was considered possibly related to treatment. Clinical evaluation of the patient showed paroxysmal atrial fibrillation on telemetry, and MRI brain imaging revealed evidence of bilateral frontal and parietal region gray–white matter junction lesions consistent with both acute and chronic embolic infarcts. Together, these findings suggested a chronic pathologic process that may have been provoked by treatment. MTD and RP2D for CP-870,893, when combined with 1,000 mg/m2 gemcitabine in patients with PDA, were estimated at 0.2 mg/kg per clinical protocol.
Adverse events are summarized in Table 2. Cytokine release syndrome (CRS) was the most common adverse event; it occurred within minutes to several hours after CP-870,893 infusion, and most commonly manifested as chills and rigors. Rigors were managed with meperidine and routinely resolved within 1 hour. Prophylactic use of ibuprofen (400 mg) before CP-870,893 infusion was provided to lower CRS grade and incidence. One patient treated in cohort 1 experienced a grade 3 CRS after CP-870,893 infusion during cycle 9. Symptoms resolved with diuretic therapy, and the patient continued on study without dose modification. However, after 10 cycles of therapy in the absence of disease progression, the patient was diagnosed with glomerulonephritis related to gemcitabine and was withdrawn from the study. A second patient developed grade 3 gastrointestinal bleed related to pancreatic tumor invasion of the stomach on day 24 of cycle 1, and was eventually withdrawn from study due to development of deep vein thrombosis during hospitalization.
Summary of the most commonly reported adverse events by grade
Treatment exposure
The median number of cycles administered was 4 (range, 1–12). Gemcitabine dose was reduced by 25% for thrombocytopenia or neutropenia, and was required in 55% of patients with a median of one dose reduction (range, 0-5) per patient. No dose reductions in CP-870,893 were required. Discontinuation of therapy was due to progressive disease (n = 14; 66%), unacceptable toxicity without progressive disease (n = 1; 5%), patient discretion (n = 4; 19%), or adverse event (n = 2; 10%).
Immune modulation
Rapid decreases in absolute monocyte count (AMC) and absolute lymphocyte count (ALC) were observed in peripheral blood 1 day after gemcitabine administration (Supplementary Fig. S1A). Further decreases in AMC and ALC were observed after CP-870,893 infusion, with a nadir on day 4. Both AMC and ALC recovered by day 8 to near baseline levels. Decreases in ALC were associated with a rapid decline in absolute levels of CD19+ B lymphocytes seen within 2 hours of CP-870,893 infusion (Supplementary Fig. S1B). Cellular recovery of peripheral blood CD19+ B lymphocytes to near baseline levels was seen by day 8. A rapid increase in B-cell expression of costimulatory molecules CD86 and HLA-DR was also observed within 24 to 48 hours of CP-870,893 treatment, a pattern similar to findings previously reported for CP-870,893 when used as a single agent (17). In addition, inflammatory cytokines IL-6, -8, and -10 transiently increased in serum of patients within 24 hours after CP-870,893, but not gemcitabine, treatment (Supplementary Fig. S1C). These findings are consistent with preclinical data showing that CD40 agonists induce immune activation and trafficking of leukocytes to lymphoid organs (16). No relationship was found between peak cytokine levels and development or grade of CRS.
FDG-PET response
Ten patients in the MTD expansion cohort were evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) criteria for partial metabolic response (PMR; >25% reduction in SUVmax) detected by FDG-PET/CT (23). Eight of 10 patients completed at least two cycles of therapy, and two achieved a PMR. To further quantify metabolic responses, we determined the percentage reduction in the sum of SUVmax for up to five predefined lesions (up to two per organ) with the most intense FDG uptake (24). On average, the sum of SUVmax was reduced by 29% in target lesions after two cycles of therapy, with 6 of 8 patients achieving >25% reduction.
Because preclinical data show the capacity of CD40 agonists to target the microenvironment of primary pancreatic tumors (16), we examined metabolic responses specifically within the primary lesion. After two cycles of therapy, an average reduction of 26.9% in SUVmax was observed in pancreatic lesions, and all patients showed some reduction. To quantify this metabolic response, changes in primary tumor MVPmean were determined. A decrease in MVPmean was observed in 6 of 8 patients after two cycles of therapy, with changes seen as early as day 15 (Fig. 2A and B). Further reductions in MVPmean were also observed with subsequent cycles of therapy. However, after six cycles of therapy, 3 patients, despite achieving more than 50% reduction in MVPmean of the primary lesion, were withdrawn from study due to progressive disease of metastatic lesions. This suggested heterogeneity of the tumor response to therapy, which prompted investigation of metastatic lesions.
FDG-PET/CT imaging of (A and B) primary pancreatic tumors and (C and D) metastatic hepatic lesions. A and C, change relative to baseline in MVPmean as a measure of metabolic activity. B and D, CT, FDG-PET, and fused PET/CT images (baseline vs. end of cycle 4) showing (B), a responding primary pancreatic lesion (green arrow) and (D) a mixed response in liver with representative new or progressive lesions (red arrowheads), stable lesions (yellow arrowheads), and responding lesions (green arrows). Normal FDG excretion in kidneys and ureters is also seen.
The most common metastatic site in this study was the liver (Table 1). For this reason, we evaluated the impact of therapy on metabolic responses of hepatic lesions only. Eight of 10 patients had hepatic lesions; 6 of these patients completed at least two cycles of therapy. Four patients achieved more than 25% reduction in total hepatic lesion MVPmean; this metabolic response, however, was sometimes transient (Fig. 2C). Moreover, metabolic changes in hepatic lesions were found to be heterogeneous (Fig. 2D). For patient 10031016, a marked metabolic response was observed in both the primary and hepatic lesions (Fig. 2). After four cycles of therapy, we biopsied the responding hepatic lesion. We previously reported histologic analysis of this lesion, which showed an impressive immune infiltrate that was dominated by macrophages with an absence of viable tumor cells (16). Thus, a metabolic response correlated with a pathologic response for this patient. To understand the heterogeneity of metabolic responses observed with treatment, we quantified responses of all identifiable lesions after two cycles of therapy (Fig. 3A). This analysis revealed that metabolic responses within individual patients varied considerably from complete metabolic response (CMR) to progression, sometimes with development of new lesions. This treatment response heterogeneity was particularly pronounced in the liver (Fig. 3B). Taken together, these data show that FDG-PET/CT–based treatment responses were heterogeneous in many patients.
The response of individual lesions measured by changes in lesional MVPmean from baseline to end of cycle 2, shown for: A, each patient, and B, for each metastatic site (all patient lesions pooled) including liver, lung, lymph node (LN), and peritoneal cavity. Changes in MVPmean were classified as CMR indicating disappearance of lesion; PMR indicating ≥25% reduction in MVPmean; progressive metabolic disease (PMD) indicating >25% increase in MVPmean or new lesion; and stable metabolic disease (SMD) indicating insufficient decrease to qualify for PMR and insufficient increase to qualify for PMD.
Efficacy, pharmacodynamic and immunologic correlative results
Median PFS was 5.2 months [95% confidence interval (CI), 1.9–7.4 months]; median OS was 8.4 months (95% CI, 5.3–11.8 months); and 1-year OS was 28.6% (Fig. 4A).
Biologic correlatives for OS after treatment with CP-870,893 in combination with gemcitabine. A, median OS and PFS for patients (n = 21) receiving at least one dose of CP-870,893. Relationship between (B) percentage change in CA19-9 at end of one cycle of therapy compared with baseline (R = −0.579; P = 0.049), (C) OS and tumor response determined by RECIST 1.0 at completion of two cycles of therapy (R = −0.652; P = 0.002), and (D) percentage change in total MVPmean for all lesions, primary pancreatic lesion, and all hepatic lesions after 2 weeks of therapy compared with baseline (R = −0.929; P = 0.007). Best overall tumor response measured by RECIST 1.0 is indicated in (B), (C), and (D) using open circles (PR), gray circles (stable disease), and black circles (progressive disease).
Response rate.
Overall response rate (ORR) based on RECIST 1.0 was 19%, with 4 patients achieving a partial response (PR). Stable disease was seen in 11 patients. In addition, 1 patient withdrawn after one dose of CP-870,893 due to DLT restarted gemcitabine alone and achieved a PR off-study, as previously reported (16).
Correlative studies.
Exploratory analyses were conducted to correlate changes in immune activation, tumor biomarkers, tumor response, and metabolic response with OS. Treatment-related increases in cytokine levels (i.e., IL-6, -8, and -10) during cycle 1 were not associated with OS (Supplementary Table S1). CA19-9 levels were available for 12 patients, with 9 patients showing decreases after cycle 1 that correlated with improved OS (Fig. 4B). Response rate determined by RECIST 1.0 after cycle 2 was also associated with improved OS (Fig. 4C). In contrast, metabolic responses using EORTC criteria or by evaluating SUVmax for up to five predefined lesions did not correlate with OS (Supplementary Table S1).
Because metabolic responses to therapy were heterogeneous, we examined the association between OS and changes in metabolic activity observed within the liver and pancreas separately. Changes in total MVPmean as well as SUVmax and MVPmean of primary pancreatic lesions were not associated with OS. In contrast, a decrease in total hepatic lesion MVPmean after cycle 2 was associated with improved OS (Supplementary Table S1). Furthermore, analysis of 7 patients with hepatic lesions who underwent FDG-PET/CT after 2 weeks of therapy revealed a decrease in total hepatic lesion MVPmean at this early time point that was also strongly correlated with OS (Fig. 4D). Patients with a metabolic response in the liver at 2 weeks also achieved a PR by RECIST 1.0.
This investigation evaluated the safety and biologic impact of combining a fully human agonist CD40 mAb (CP-870,893) with gemcitabine for treatment of patients with advanced PDA. Combination treatment with CP-870,893 and full-dose gemcitabine was well-tolerated and associated with objective tumor responses (19%) in patients with advanced PDA. In addition, FDG-PET/CT imaging revealed therapy-induced metabolic responses in both primary and metastatic lesions. These responses, however, were heterogeneous, with some lesions responding and others progressing during therapy. All patients receiving CP-870,893 in combination with gemcitabine responded with immune activation (i.e., increases in serum cytokines and/or upregulation of costimulatory molecules on B lymphocytes) that was transient. However, we determined that changes in serum cytokines and peripheral lymphocyte cell populations did not correlate as biomarkers of tumor response or survival parameters. In contrast, in an exploratory analysis we found that improved OS correlated with a decrease in FDG uptake in hepatic lesions.
Strategies that target the stromal microenvironment may improve outcomes for patients with PDA. Preclinical studies have suggested that the mechanism of action of CP-870,893 when used in PDA is dependent on peripheral blood monocytes which are induced to rapidly leave circulation, infiltrate tumor lesions, and orchestrate degradation of the stromal microenvironment (16). Consistent with this, we observed a rapid decrease in monocyte levels in patients after CP-870,893 infusion; however, because gemcitabine also produced a decrease in peripheral blood monocytes, we speculate that the full antitumor activity of an agonist CD40 antibody in patients may have been hindered in the current study by myelosuppression from repeated administration of gemcitabine. In this regard, because agonist CD40 antibodies can rapidly deplete the stroma that is a critical barrier to drug delivery, we propose that chemotherapy administration after, rather than before, the infusion of CD40 agonists would represent a novel approach to enhance efficacy while eliminating potential deleterious effects of chemotherapy on CP-870,893 activity. Moreover, this treatment schedule would permit the use of functional imaging approaches such as FDG-PET/CT conducted 1 day after administration of CP-870,893 to investigate the impact of delivering an agonist CD40 antibody on the biology of primary and metastatic tumor lesions. To understand the impact of therapy on tumor-associated stroma, tissue biopsies could also be conducted before and after delivery of CP-870,893 or, alternatively, CP-870,893 could be administered to patients with resectable PDA in the neoadjuvant setting before surgical resection. It is expected that these study approaches would provide further insight into the biologic impact of CP-870,893 on PDA tumor biology.
In this phase I study, we administered CP-870,893 2 days after gemcitabine chemotherapy based on preclinical data showing the effectiveness of this treatment schedule in producing robust T–cell dependent antitumor immunity (18). Treatment with CP-870,893 was administered monthly to allow sufficient time for resolution of immune activation and to coincide with the schedule of gemcitabine chemotherapy. In addition, this timeframe was selected on the basis of previous investigation showing deleterious effects on T cells when CP-870,893 was administered more frequently (i.e., weekly dosing) to patients with advanced cancer (20). However, in our studies of this treatment schedule, we have found that antitumor T-cell immunity is not induced when a CD40 agonist is administered 2 days after gemcitabine chemotherapy in a clinically relevant mouse model of PDA (16). This discrepancy between our findings and previously reported work may be related to immune suppression imposed by PDA, which may inhibit the development of productive antitumor T-cell immunity. Consistent with our preclinical findings, tumor biopsies from patients with PDA treated in this phase I study revealed an absence of tumor-infiltrating lymphocytes and an abundance of macrophages, which we have previously reported are required for the antitumor effects observed with CD40 agonists (16). Although lymphocytes do not seem to be involved in antitumor immunity induced with CD40 agonists in PDA, we speculate that chronic immune activation reported with weekly dosing of CP-870,893 could be detrimental as inflammation can also be a key driver of tumorigenesis. Nonetheless, shorter dosing intervals that allow for sufficient time for resolution of immune activation (e.g., every 3 weeks) could be explored in subsequent clinical studies. Moreover, future combinations of CP-870,893 with chemotherapy should include more efficacious chemotherapeutic regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel (5, 25).
To understand the impact of therapy on tumor biology, we incorporated FDG-PET/CT imaging into this study. FDG-PET/CT has been used to assess responses to chemotherapies and targeted therapies in various solid malignancies including PDA (5, 26, 27). However, its use in predicting responsiveness to immunotherapy in solid malignancies has not been well explored. SUVmax is the most common semiquantitative approach applied to PET image analysis; however, SUVmax only reflects a small fraction of the metabolic activity in any given lesion. For this reason, we calculated MVPmean of individual lesions as an overall measure of metabolic activity (22) and showed the ability of FDG-PET/CT, obtained as early as 2 weeks after therapy, to detect metabolic responses in primary and metastatic lesions. In our investigation for imaging biomarkers, we found a lack of statistically significant associations between OS and changes in many FDG-PET imaging correlatives, including EORTC criteria. This finding may reflect the small sample size of this study. However, consistent with the heterogeneity in metabolic responses that we observed between primary and metastatic lesions, we found that changes in hepatic lesion MVPmean determined by FDG-PET/CT strongly correlated with OS. Although decreases in primary lesion MVPmean were not statistically significant, a trend toward improved OS was observed and may have been appreciated with a larger sample size.
Metabolic responses were commonly seen within primary lesions with each cycle of therapy. However, the metabolic response of hepatic lesions was heterogeneous with some lesions showing no response to therapy, even in patients where other lesions responded with complete loss of metabolic activity. This disparity in response observed between primary and metastatic lesions can be observed by FDG-PET imaging in some patients receiving standard chemotherapy alone (28–30). Here, we have used FDG-PET/CT imaging to show and quantify heterogeneity in metabolic responses observed with therapy in PDA. Although the role of CP-870,893 in contributing to response heterogeneity seen between primary and metastatic lesions cannot be determined from our analyses, the disparate responses observed suggest differences in tumor biology such that metastasis biology may be a unique and major site of resistance for both chemotherapy- and immunotherapy-based approaches.
Although the results from this phase I study are encouraging, our sample size was small and, thus, we are unable to determine the clinical benefit achieved with the addition of CP-870,893 to gemcitabine chemotherapy. As a result, further investigation with randomized clinical studies will be necessary to determine a role for CP-870,893 in the treatment of PDA. Nonetheless, our study suggests the value of incorporating early FDG-PET/CT imaging to evaluate benefit from therapeutic approaches in PDA and for understanding heterogeneity in treatment responses.
R.H. Vonderheide has other commercial research support and P. O'Dwyer has commercial research grant from Pfizer. No potential conflicts of interest were disclosed by the other authors.
Conception and design: G.L. Beatty, D.A. Torigian, B. Saboury, A. Alavi, W. Sun, R.H. Vonderheide, P. O'Dwyer
Development of methodology: G.L. Beatty, D.A. Torigian, B. Saboury, A. Alavi, W. Sun, R.H. Vonderheide
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): G.L. Beatty, D.A. Torigian, E.G. Chiorean, B. Saboury, A. Brothers, A. Alavi, W. Sun, U.R. Teitelbaum, R.H. Vonderheide, P. O'Dwyer
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G.L. Beatty, D.A. Torigian, B. Saboury, A. Brothers, A. Alavi, W. Sun, R.H. Vonderheide, P. O'Dwyer
Writing, review, and/or revision of the manuscript: G.L. Beatty, D.A. Torigian, E.G. Chiorean, B. Saboury, A. Brothers, A. Alavi, W. Sun, U.R. Teitelbaum, R.H. Vonderheide, P. O'Dwyer
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): G.L. Beatty, E.G. Chiorean, B. Saboury, A. Alavi, R.H. Vonderheide, P. O'Dwyer
Study supervision: G.L. Beatty, E.G. Chiorean, B. Saboury, A. Alavi, P. O'Dwyer
The clinical trial described in this work was financially supported by the Pfizer Corporation. Additional support was provided in part by an American Society Clinical Oncology Young Investigator Award (to G.L. Beatty) and by grants no. K08 CA138907-02 (to G.L. Beatty) and R01 CA169123 (to R.H. Vonderheide) from the NIH.
The authors thank Maryann Redlinger, Amy Kramer, and all of the nurses and data managers from the Abramson Cancer Center for their outstanding and dedicated patient care and for careful data collection.
Prior presentation: Preliminary findings have been reported in Science 2011;331:1612–6 and at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4–8, 2010, Chicago, IL.
This article presents original results of a phase I study of CP-870,893 with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.
Revision received July 30, 2013.
Accepted August 17, 2013.
American Cancer Society: Cancer facts and figures 2012. Atlanta, GA: American Cancer Society; 2012.
Hidalgo M
. Pancreatic cancer. N Engl J Med 2010;362:1605–17.
Olive KP,
Jacobetz MA,
Davidson CJ,
Gopinathan A,
McIntyre D,
Honess D,
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457–61.
Provenzano PP,
Cuevas C,
Chang AE,
Goel VK,
Von Hoff DD,
Hingorani SR
. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418–29.
Ramanathan RK,
Borad MJ,
Laheru DA,
Smith LS,
Wood TE,
Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548–54.
Chan DS,
Neesse A,
Bapiro TE,
Cook N,
Frese KK,
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62:112–20.
Clark CE,
Hingorani SR,
Mick R,
Combs C,
Tuveson DA,
Vonderheide RH
. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518–27.
Kurahara H,
Shinchi H,
Mataki Y,
Kuwahata T,
Maeda K,
Sakoda M,
Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011;167:e211–9.
Elgueta R,
Benson MJ,
de Vries VC,
Wasiuk A,
Noelle RJ
. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 2009;229:152–72.
Schoenberger SP,
Toes RE,
van der Voort EI,
Offringa R,
Melief CJ
. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998;393:480–3.
Bennett SR,
Carbone FR,
Karamalis F,
Flavell RA,
Miller JF,
Heath WR
. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998;393:478–80.
Ridge JP,
Di Rosa F,
Matzinger P
. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 1998;393:474–8.
French RR,
Chan HT,
Tutt AL,
Glennie MJ
. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 1999;5:548–53.
den Boer AT,
van der Voort El,
Schumacher TN,
Melief CJ,
CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 1999;5:774–9.
Sotomayor EM,
Borrello I,
Tubb E,
Rattis FM,
Bien H,
Lu Z,
Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 1999;5:780–7.
Beatty GL,
Chiorean EG,
Fishman MP,
Saboury B,
Teitelbaum UR,
Sun W,
CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011;331:1612–6.
Vonderheide RH,
Flaherty KT,
Khalil M,
Stumacher MS,
Bajor DL,
Hutnick NA,
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007;25:876–83.
Nowak AK,
Robinson BW,
Lake RA
. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 2003;63:4490–6.
Lake RA,
Robinson BW
. Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 2005;5:397–405.
Ruter J,
Antonia SJ,
Burris HA,
Huhn RD,
. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther 2010;10:983–93.
Gladue RP,
Paradis T,
Cole SH,
Donovan C,
Nelson R,
Alpert R,
The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice. Cancer Immunol Immunother 2011;60:1009–17.
Torigian DA,
Lopez RF,
Alapati S,
Bodapati G,
Hofheinz F,
van den Hoff J,
Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT. Hell J Nucl Med 2011;14:8–14.
Young H,
Baum R,
Cremerius U,
Herholz K,
Hoekstra O,
Lammertsma AA,
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999;35:1773–82.
Wahl RL,
Jacene H,
Kasamon Y,
Lodge MA
. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med 2009;50(Suppl 1):122S–50S.
Conroy T,
Desseigne F,
Ychou M,
Bouche O,
Guimbaud R,
Becouarn Y,
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–25.
Benz MR,
Herrmann K,
Walter F,
Garon EB,
Reckamp KL,
Figlin R,
(18)F-FDG PET/CT for monitoring treatment responses to the epidermal growth factor receptor inhibitor erlotinib. J Nucl Med 2011;52:1684–9.
Lordick F,
Ott K,
Krause BJ,
Weber WA,
Becker K,
Stein HJ,
PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007;8:797–805.
Kuwatani M,
Kawakami H,
Eto K,
Haba S,
Shiga T,
Tamaki N,
Modalities for evaluating chemotherapeutic efficacy and survival time in patients with advanced pancreatic cancer: comparison between FDG-PET, CT, and serum tumor markers. Intern Med (Tokyo, Japan) 2009;48:867–75.
Maisey NR,
Webb A,
Flux GD,
Padhani A,
Cunningham DC,
Ott RJ,
FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study. Br J Cancer 2000;83:287–93.
Klimant E,
Markman M,
Albu DM
. Clinically meaningful responses to sequential gemcitabine-based chemotherapy regimens in a patient with metastatic pancreatic cancer. Case Rep Oncol 2013;6:72–7.
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Games Greg Reviews
September 9, 2020 September 17, 2020 Greg HicksComment(1)
I don't think I'd have the temerity or patience for being a police officer. The constant refrain from saying what you really think to someone mouthing off at you, the faff and hassle of deploying certain bits of kit, not to mention the ensuing paperwork afterwards.
That, and the whole "being shot at" business. Admittedly more of an American practice, what with their Second Amendment-twisting shenanigans that allows everyone and their mums to be packing heat, the whole notion terrifies me.
Which is why I stick to video games. Being shot in one of those doesn't offer the same limited mortality as it does in real life, thankfully. Although after a few days with Police Stories, I've replaced the fear of being shot with the sheer annoyance of constantly being shot in this game.
While it may look like Devolver's violent, top-down caper from the other side of the law, Mighty Morgan's crime-fighting owes more of its gameplay to the Police Quest and SWAT games from Sierra. But like Hotline Miami, in terms of persevering, is it worth sticking through or would it better just to retire from the force? Grab your badge and your gun, we're going on… review patrol, or something.
You Have The Right To Not Shoot At Me, Preferably
If Hotline Miami were the yin, with its emphasis on fast-paced violence and combo mechanic, then Police Stories is the yang with its more methodical approach to each level. Which, I suppose is quite thematic, as you're a member of the law.
As such, you're given a briefing to each mission before you're allowed to kit out officers Rimes and Jones with various bits of tactical gear. As you progress you unlock more, like a borescope camera and taser, but to start with you've got lockpicks, flashbangs and medical kits. These are not to be taken for granted, as I found out, as Police Stories will punish for playing fast and loose with the rule of policing.
After a brief mission intro, you start in the relative safety of a driveway, loading bay, or something with a door in the way. The left thumbstick has you move, whilst the right pulls double duty as aiming/camera control. Again, much like Hotline Miami, but we leave those similarities at the door once it's opened. Much like in real life, you can't see through other doors or around corners, so progression becomes a tense yet rewarding process.
When you do spot a hostile target, you have several options to think of in a heartbeat: You can yell at them to surrender, you can sprint up and slap them to drop their weapon, or risk firing some warning shots in the hope that that'll make their grip weaker. Or, as a supposed last resort, you can neutralise them with bullets. I say supposed, because more often than not I could never get the warning shot system to work, and had to put them down before I ate a buckshot sandwich.
It's You And Me, Partner
The parallel to SWAT and Police Quest wasn't an idle one, though. There is an element of tactical intrusion that you are not required but heavily implied that you make use of in Police Stories.
You could, if you're feeling brave, tackle every locked door and room full of hostiles yourself. You may do alright, might take a slug to the shoulder or even worse, have a civilian shot in the crossfire, both of which negatively affect your end-level score (more on that later). But there's a reason why the load-out screen lets you kit out the pair of you, not just the lead.
You can have your buddy, Jones, pick a locked door whilst you cover his back. Or, if you're wanting to breach and clear, you can use the Command Wheel (mapped to L2 in the PS4 version) to bring up the flashbang option. This lets Jones stack up against said door, whilst you stand back, chuck a flashbang in and allows you both to storm in and subdue anyone caught in the concussive blast. Later gadgets let you scout ahead through keyholes to get some idea of who's in their, adding a massive element of pre-planning to busting doors and heads.
It's not just for room clearance that your buddy comes in handy, as you can select areas of the map for him to scout ahead or cover your six. However, this can have mixed results: On some occasions, he'll be a [police] force to be reckoned with. Others, he'll get shot more than Peter Weller did in Robocop. Again, this will have a negative effect on your score, so keep an eye on him.
Fortunately, if you have the means to do so, Police Stories can be played in local co-op. So while the element of tactic still applies, at least you can hope that someone playing next to you will have a better grip on things. I don't, so I had to micro-manage the AI not getting shot.
Just Call Me Officer Cliche, And This Is My Partner, Officer Stereotype
I'd like to tell you the story is as deep as Brad Pitt and Morgan Freeman's quoted above masterpiece, but I can't. It's not diabolically written, nor is it necessarily terrible in terms of how it all plays out either.
It's just a "standard cop drama" that unfurls about as well as you expect it would. I wouldn't call that a negative, though, as it's been entertaining throughout the several missions I've finished already. I'd love to tell you how it plays out (or at least try, without spoilers) but proceeding is much harder than anticipated. Turns out, guns may not kill people, but crack-shot smackheads do.
Police Stories starts pretty innocuously, with John Rimes returning to town and catching up with Jones over coffee in the late nineties. These two former partners aren't long reunited before they get a call out to a suspected drug den… which turns out to be a small piece in a much, much larger scene of events, all told as part of a framing device to an investigative journalist.
We're talking suspected bomb plots, string-pullers and all that jazz. As I say, it's not terribly original but it is engaging enough that you want to play through the game to see what happens. Whilst some games are a case of slogging through despite the story, or the other way around, Police Stories achieves the joy of both and is fun to play. Well, fun being subjective, as the game throws up some "That was bullshit!" moments from time to time. There's only so far skill can carry you when an unseen gunman shoots you across the room.
I Wanted To Call This "Swatline Miami"… But They're Not in Miami
I actually love Police Stories. I was sold on what I initially thought was, "Hotline Miami with the 5-0", but was pleasantly surprised when this turned out to be a bit deeper than Devolver's hit.
The tactical implementation throws back to classics like Commandos and Cannon Fodder (and recent offerings like Desperados), yet there are also interspersed moments of adrenaline-filled room clearing too. Securing targets, nabbing evidence and the occasional bomb-defusing mini-game thrown in for good measure make a great little indie to play.
The one thing that hampers it is the level progression system. You get a score as you progress through a level, and have to hit a certain amount to unlock the next one. I would have rather you just unlock the next level by completion alone, then go back and hit better scores a la Hitman Absolution, instead of having to smash a decent score on your first time through. It can derail your flow if you're a couple hundred points off, but it's not a deal breaker. It just means you have to fall in with how policing works and not shoot unarmed civilians… [insert current American climate joke here].
Fortunately, the quick restart nature and randomised enemy/hostage placement each time keeps you on your toes, enough to drive you do it properly and hit that higher score and better grade each time you conduct a raid. It treads that fine line of taking itself somewhat seriously, yet lets you occasional loose to have some high octane carnage. If you can convince someone else to join you, then that will double the fun.
Whilst it initially looks like carnage, Police Stories offers a level of tactic and forethought to the top-down shooter genre. Get past that initial steepness and there's a wealth of fun to be had in the methodical approach.
Police Stories is available now on PlayStation 4 (reviewed on PS4 Pro), Xbox One, Nintendo Switch, Mac and PC.
Developer: Mighty Morgan
Publisher: HypeTrain Digital
Disclaimer: In order to complete this review we were provided with a promotional copy of the game. For our full review policy, please go here.
Tagged HypeTrain Digital, Mighty Morgan, Police Stories
Greg Hicks
All round nerd. Has a bad habit of buying remastered games. Find me on Twitter/Instagram on @GregatonBomb. Sometimes I'm funny. Join my shenanigans over at twitch.tv/gregatonbomb
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THE CULT Is 'Long Overdue' To Release New Music
THE CULT frontman Ian Astbury has told LA Weekly in a new interview that the band is "long overdue" to release new music. "We do have some stuff we've been working on, but it's yet to see the light of day," he said. Astbury also cited David Bowie, Bob Dylan, Neil Young and Iggy Pop as some of his inspirations — artists who were never content to rest on the glories of their pasts, instead striving to create something new and exciting.
"You can't get up and put on the same clothes you wore when you were 24 and try to recreate the mindset," he explained. "To me at least, probably more so with individual artists than bands, they've produced some of their best work in their later years. Iggy Pop is one of the artists Billy [Duffy, guitar] and I bonded over. We opened for him in '87 and he appears on 'Sonic Temple', guest vocals on 'New York City'."
In a separate interview with Global News, Astbury was asked how the songwriting process has changed since he and Billy first met and started DEATH CULT over 35 years ago. He responded: "Well, when we first met, we were living in his flat in Brixton; I'd sleep on the couch. [Laughs] So yeah, you could say it's very different. We spent a lot of time together and we were immersed in each other every day. We were always exchanging ideas but now we have very separate lives. We both have different lifestyles so when we do come together, we bring whatever it is that we've been musing on outside of that. Then we come into an intensive writing period. It's a different way of writing as opposed to like a gradual thing when we were younger because as you get older, your life takes over. But we've been managed to maintain a relationship over 10 studio albums and three decades so it's still there; there's still a chemistry that works.
THE CULT's last collection of new material, "Hidden City", was released in February 2016 via Cooking Vinyl. The follow-up to 2012's "Choice Of Weapon" was written by Astbury and Duffy and was produced by Bob Rock, who has previously worked with METALLICA and MÖTLEY CRÜE.
Last month, THE CULT kicked off a North American tour in celebration of the 30th anniversary of its "Sonic Temple" album.
Tags: the cult
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On behalf of Todd L. Sallee, Attorney at Law posted in Drug Charges on Thursday, January 19, 2017.
Many Indiana jail inmates are released from their cells on special assignment work details outside prison walls. Such duties are typically closely supervised by prison guards, although there have been incidents when inmates have tried to escape or have gotten into other types of trouble along the way. Recently, five people, four of whom are currently serving time, had new drug charges filed against them for their alleged roles in an illegal drug scheme.
A 24-year-old woman is said to have sold Suboxone strips to one of the men while he was outside the prison on a work detail. This is a controlled substance often used to treat people suffering from opioid addictions. It is considered a highly dangerous drug that can cause respiratory distress and/or death when taken in high doses.
The man who reportedly purchased the drugs allegedly put them underneath lunch trays inside the prison. Eventually, the drugs reached the kitchen where another inmate now charged in the supposed scheme was working. Two others were also involved, one of whom apparently got one of his family members to pay $20 for a strip of Suboxone.
Drug charges against the five range from conspiracy to commit drug trafficking with an inmate to conspiracy to deal a controlled substance. An experienced Indiana defense attorney is well aware of how to help an inmate navigate the criminal justice system. It would be a logical choice to request a meeting with an attorney if one's situation in prison is exacerbated by additional charges. Anyone not currently in jail is also able to seek consultation with a defense lawyer to discuss various options and possible outcomes of a particular situation.


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Q: How to dynamically render images with different ext? I have a table in mysql that has a column called articleID. When a new article is created and uploaded, an image is added to the server with the filename of the articleID.
My only problem is that when trying to display the images, some of the images are png, some are jpeg/jpg and so the img source extension changes. Is there any way to make it so that the extensions are dynamic too?
My PHP code:
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redpajama_set_name: RedPajamaStackExchange


This is a beautiful Romona Keveza couture gown from her Spring 2003 collection. Worn once. Very structured and creates a beautiful silhouette, the ruffles on the train are stunning. There are some dark marks on the underside where it touched the floor, they are not noticeable when you're wearing it and may even come out with a good dry cleaning. Slight dirt spots as pictured in the close up of the ruffles. Any questions, please ask!
It was altered to fit my 5'5 frame with 2 inch heels. Ribbons were also added for a bustle so you can dance!
Once you send a message, Molly can invite you to purchase the dress.