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Chiefs remain in thick of muddled AFC playoff picture after beating Broncos
Copyright 2020 by Getty Images
David Eulitt/Getty
KANSAS CITY, MISSOURI - JANUARY 19: A general view of the AFC Championship signage before the AFC Championship Game between the Kansas City Chiefs and the Tennessee Titans at Arrowhead Stadium on January 19, 2020 in Kansas City, Missouri.
By: Tod Palmer
KANSAS CITY, Mo. — If the playoffs started next week, the Kansas City Chiefs would be the No. 4 seed in the AFC.
A quick peek at the AFC playoff standings shows a familiar team in position for the No. 1 seed, the New England Patriots.
Led by rookie quarterback Mac Jones, a stout running game and Bill Belichick's masterfully coached defense, the Patriots square off with the Buffalo Bills on Monday Night Football with first place in the conference standings at stake.
For now, though, all four division leaders in the AFC sit at 8-4 and the reality is that it's a wide-open race for No. 1 seed — and the only postseason bye under the NFL's expanded playoff format, which went into effect last season.
Baltimore and Tennessee, which beat Kansas City earlier in the season, also sit at 8-4.
Given the offense's recent struggles, the Chiefs clearly have less margin for error than the last two seasons, when Kansas City had a first-round bye in the playoffs and parlayed that into a Super Bowl appearance.
That puts a premium on getting to sit out the opening week of the postseason, and the Chiefs are well-positioned to control their own fate.
Twelve of the 16 teams in the AFC are .500 or better, including the rest of the AFC West, with surging Miami (6-7) still lurking in the playoff picture as well.
The Chiefs' path still includes fast-fading Las Vegas (6-6) next Sunday at Arrowhead Stadium and a Thursday trip to Los Angeles to battle the Chargers (7-5) on Dec. 16.
The Chiefs host the Steelers (6-5-1) on Dec. 26 and wrap up the season at Cincinnati (7-5) and with a rematch at Denver (6-6), so every remaining team is in the playoff hunt.
It makes for a challenge, but it's also an opportunity — a chance to improve their conference record and distance themselves from those teams in the playoff race.
"For the most part, it's just all about the guys in the room trying to believe in each other," safety Tyrann Mathieu said. "I still don't think we've played our best game yet, so hopefully that game is — I don't know — the Super Bowl. But we're just trying to keep going and continue to push. This is a big stretch for us. We're dealing with all AFC teams to close the season out, so it will be important for us to win all these games and put ourselves in a position where our fans can show their impact in the postseason."
Division leaders
1. New England Patriots (8-4)
Remaining schedule: Dec. 6 at Buffalo, Dec. 18 at Indianapolis, Dec. 26 vs. Buffalo, Jan. 2 vs. Jacksonville, Jan. 9 at Miami
Outlook: The Patriots are the hottest team in football. Belichick's formula — stout defense, a strong run game and mistake-free quarterback play — is tried and true. But is it too early for Mac Jones to consistently do it under pressure? We're all about to find out. Oh, and if you're wondering who to cheer for, a split would be great for Kansas City this month.
2. Tennessee Titans (8-4)
Remaining schedule: Dec. 12 vs. Jacksonville, Dec. 19 at Pittsburgh, Dec. 23 vs. San Francisco, Jan. 2 vs. Miami, Jan. 9 at Houston
Outlook: The Titans' offense has sputtered without Derrick Henry, especially with AJ Brown and Julio Jones also banged up and missing time. Tennessee has one of the easier remaining schedules, but it's hard to imagine they get through the next five weeks unscathed.
3. Baltimore Ravens (8-4)
Remaining schedule: Dec. 12 at Cleveland, Dec. 19 vs. Green Bay, Dec. 26 at Cincinnati, Jan. 2 vs. Los Angeles Rams, Jan. 9 vs. Pittsburgh
Outlook: Living on the razor's edge caught up with the Ravens against Pittsburgh on Sunday, which is perhaps a sign the late-game luck — that's always broken their way through the first three months of the season — may have run out. And that schedule is daunting.
4. Kansas City Chiefs (8-4)
Remaining schedule: Dec. 12 vs. Las Vegas, Dec. 16 at Los Angeles Chargers, Dec. 26 vs. Pittsburgh, Jan. 2 at Cincinnati, Jan. 9 at Denver
Outlook: There are no gimmes, but it's probably fair today to assume the Chiefs will be favored in every remaining game (except perhaps at the Chargers). Kansas City has to win four — and maybe all five — remaining games to grab the top seed. But it's certainly possible.
Wild card race
5. Buffalo Bills (7-4)
Remaining schedule: Dec. 6 vs. New England, Dec. 12 at Tampa Bay, Dec. 19 vs. Carolina, Dec. 26 at New England, Jan. 2 vs. Atlanta, Jan. 9 vs. New York Jets
Outlook: If the Bills can sweep the Patriots and dethrone the Buccaneers to close out December, they'll deserve the top seed and justifiably be favored to reach the Super Bowl. But the offense's recent struggles suggest that's unlikely.
6. Los Angeles Chargers (7-5)
Remaining schedule: Dec. 12 vs. New York Giants, Dec. 16 vs. Kansas City, Dec. 26 at Houston, Jan. 2 vs. Denver, Jan. 9 at Los Angeles Rams
Outlook: No team has been more inconsistent than the Chargers in recent weeks. The AFC West comes down to that Dec. 16 meeting against the Chiefs at SoFi Stadium. If Justin Herbert and company want some respect, they'll have to take it from Patrick Mahomes and company that night.
7. Cincinnati Bengals (7-5)
Remaining schedule: Dec. 12 vs. San Francisco, Dec. 19 at Denver, Dec. 26 vs. Baltimore, Jan. 2 vs. Kansas City, Jan. 9 at Cleveland
Outlook: The Bengals seem like the best team in the AFC some weeks then remind the NFL world why the Bungles are a thing the next. It's probably too soon for them to be true contenders, but they are dangerous and could spoil Kansas City's or Baltimore's home-field advantage aspirations.
In the hunt
8. Pittsburgh Steelers (6-5-1)
Remaining schedule: Dec. 9 at Minnesota, Dec. 19 vs. Tennessee, Dec. 26 at Kansas City, Jan. 3 vs. Cleveland, Jan. 9 at Baltimore
Outlook: The offense might not even be good enough to get the Steelers into the playoffs, especially if the defense continues to struggle to stay healthy. But Mike Tomlin's teams always play hard.
9. Indianapolis Colts (7-6)
Remaining schedule: Dec. 18 vs. New England, Dec. 25 at Arizona, Jan. 2 vs. Las Vegas, Jan. 9 at Jacksonville
Outlook: Arguably the most dangerous team in the AFC right now, the Colts can't afford any more slip-ups or they may not get the chance to prove they're the best team in the playoffs after those early-season hiccups.
10. Las Vegas Raiders (6-6)
Remaining schedule: Dec. 12 at Kansas City, Dec. 18 at Cleveland, Dec. 26 vs. Denver, Jan. 2 at Indianapolis, Jan. 9 vs. Los Angeles Chargers
Outlook: The Raiders — as any team would given all the locker room has been through in 2021 — have cracked. So, once again, Las Vegas' Super Bowl will be in Kansas City this year as a brutal finishing stretch awaits.
11. Cleveland Browns (6-6)
Remaining schedule: Dec. 12 vs. Baltimore, Dec. 18 vs. Las Vegas, Dec. 25 at Green Bay, Jan. 3 at Pittsburgh, Jan. 9 vs. Cincinnati
Outlook: The Browns are too banged up to be a playoff threat, especially with that schedule, but they can help Kansas City out by beating Baltimore.
12. Denver Broncos (6-6)
Remaining schedule: Dec. 12 vs. Detroit, Dec. 19 vs. Cincinnati, Dec. 26 at Las Vegas, Jan. 2 at Los Angeles Chargers, Jan. 9 vs. Kansas City
Outlook: If the Broncos want to trip up the Bengals or Chargers, Chiefs fans won't complain. But Denver will be watching the playoffs from home.
13. Miami Dolphins (6-7)
Remaining schedule: Dec. 19 vs. New York Jets, Dec. 27 at New Orleans, Jan. 2 at Tennessee, Jan. 9 vs. New England
Outlook: Arguably the Chiefs' best friends in the playoff chase, it may be too late for the Dolphins to get into the playoffs, but wins against the Titans and Patriots would do wonders for the Chiefs' top-seed chances.


Daniel Ellsberg, the US whistleblower celebrated in Steven Spielberg's new film, The Post, was called "the most dangerous man in America" by the Nixon administration in the 70s. More than 40 years later, the man he helped inspire, Edward Snowden, was called "the terrible traitor" by Donald Trump, as he called for Snowden's execution.
The Guardian has brought the two together – the most famous whistleblower of the 20th century and the most famous of the 21st so far – to discuss leaks, press freedom and other issues raised in Spielberg's film.
Starring Meryl Streep and Tom Hanks, The Post deals with Ellsberg's 1971 leak of the Pentagon Papers, which revealed presidents from Truman to Nixon lying about the Vietnam war. It deals, too, with the battle of the US media, primarily the Washington Post and the New York Times, to protect press freedom.
During a two-hour internet linkup between Ellsberg in Berkeley, California, Snowden in Moscow and the Guardian in London, the whistleblowers discussed the ethics, practicalities and agonised internal debate involved in whistleblowing and how The Post has a special resonance today in Trump's America.
They are worried about Trump's assault on press freedom and express fear that journalists could be indicted for the first time in US history. And they are alarmed by the prospect of a US nuclear strike against North Korea, urging a new generation of whistleblowers to come forward from the Pentagon or White House to stop it.
Matthew Rhys as Daniel Ellsberg in The Post.
"It is madly reckless for this president to be doing what he is doing. Whether he is, in some clinical sense, crazy or not, what he is doing is crazy," says Ellsberg. His book based on his experience as a defence analyst and nuclear war planner, The Doomsday Machine, was published in December.
Back when Snowden was debating whether to leak secret NSA documents, showing the scale of government mass surveillance, he found inspiration in a 2009 documentary, The Most Dangerous Man in America: Daniel Ellsberg and the Pentagon Papers. After Snowden handed over material to journalists in 2013, Ellsberg was among the first to express support and the two became friends, with Ellsberg visiting Snowden, who is living in exile in Moscow, in 2015.
They have a shared interest in press freedom. Ellsberg cofounded the US-based, not-for-profit Freedom of the Press Foundation, which helped organise the linkup. Snowden, who also serves on the foundation's board, devotes much of his time in Moscow to developing tools that help journalists protect their communications and sources.
Ewen MacAskill: How has whistleblowing changed in the 40-plus years between your leaks? One of the striking images from The Post is of leaked documents having to be laboriously photocopied, in contrast with today.
Daniel Ellsberg: Certainly, the ability to copy and release hundreds of thousands of files or documents, as Chelsea Manning did, or millions of pages, as Ed Snowden did, was quite impossible then. I was using the cutting-edge technology of the day, Xerox, to do what I did do, which was to copy 7,000 "top secret" pages. That could not have been done before Xerox.
So, in a sense, it is easier to get the truth out now than it was in my day. It took me months of effort – copying night after night. On the other hand, unless you are an expert like Ed or Chelsea, their ability to trace who has done the leak is probably greater than it used to be. You can't do it safely. As I understand it from Ed – you tell me, Ed, if I am wrong here – you felt with your counterespionage expertise you probably could have done it anonymously, but you chose not to do so. But others would be more likely to be caught.
Edward Snowden: First of all, a small correction for the record. Dan said I gave millions of documents to journalists. The figure is thousands. The point between the period of Dan's activities and mine is the expansion of reach of a particular source who witnessed some wrongdoing. In Dan's case, what he had in his safe was the limitation of his reach. My reach was across a network rather than the confines of a safe … And what this ultimately results in is a dynamic where a particular employee can plausibly – in fact, not just plausibly but demonstrably – have more access at their fingertips than the director of an office or a unit or a group or an agency – or perhaps even the president.
EM: Another difference is Ed was able to operate solo whereas you, Dan, needed a team of volunteers.
DE: There was a kind of pickup crew, largely graduate students at Harvard, who helped find us places to stay and helped transport these papers. They were known as the Lavender Hill Mob, after the British movie in which a random bunch of petty criminals carry off a great heist. When my book, Secrets: A Memoir of Vietnam and the Pentagon Papers, came out in 2003, I wanted to tell their story, but they still did not want their names known because they thought the attorney general, John Ashcroft (who was in George W Bush's administration), might have imprisoned them. I was signing books and people were giving me little cards with the inscriptions they wanted me to write. A little card appeared: "To the Lavender Hill Mob." And there was someone I had not seen in 40 years.
EM: How do you feel about your portrayal in The Post?
DE: I am portrayed by a very handsome actor, Matthew Rhys. So my wife and I are quite satisfied with that. The movie is incredibly timely because we are dealing with a president who lies as he breathes, unapologetically. Also, a president who is contemptuous of the press. Nixon called the press the enemy. And Trump's people say it is the opposition party, which is of course the enemy. When I was watching the film's premiere, I was thinking: this is a question of freedom of the press.
EM: How about you, Ed, your portrayal by Joseph Gordon-Levitt in Oliver Stone's 2016 movie? Did it have the impact you hoped for?
ES: I loved Joseph Gordon-Levitt. One of the funny things is they have trapped me in time over the course of my existence as the way I looked when I came forward, always wearing glasses, kind of nerdy. But the funny thing is most of my life, even today, I never wore glasses. I wear glasses in professional settings not because I love the look or whatever. For all the complexities of the film, which was basically slapped together in a hurry because events were developing around the world, they got the core of it, the most important part of it, right, which is what is happening with mass surveillance and why it matters.
When we talk about the impact that it produced in the public, I see responses to this day from people who had seen this but who have not seen Citizenfour [Laura Poitras's 2014 documentary about Snowden], which is the real documentary. And they just had not understood the issue. News reports had not reached them, but cinema did. They might not be the type to watch documentaries but they are the type to watch a drama. I think that is an incredible thing.
EM: What motivated you to take the final step in becoming a whistleblower?
DE: I would not have thought of doing what I did, which I knew would risk prison for life, without the public example of young Americans going to prison to make a strong statement that the Vietnam war was wrong and they would not participate, even at the cost of their own freedom. Without them, there would have been no Pentagon Papers. Courage is contagious. I have heard you say, Ed, that The Most Dangerous Man in America was a factor in encouraging you to do what you did.
ES: That is absolutely true. While I was weighing up whether to come forward or not – and this was an agonising process because it was certainly life-changing – I watched that documentary. Dan's example, hearing the arguments from someone who has lived through this, it helps prepare someone to make that jump themselves.
I read, Dan, that you were described, maybe it was by Nixon, as self-righteous. But there is in whistleblowing a kind of righteousness that is required, even self-righteousness. Everything in your head, in society and everything we have been indoctrinated into believing is screaming: "Don't do this!" And yet there is some voice that builds over time that has to persuade a person that they do not just have the right to do this but a responsibility to do so; to make the move that will certainly burn their life to the ground. But, theoretically, the wellspring of hope that is the motivational force behind this is that it will redress some wrongdoing.
EM: Is the threat posed by Trump greater than that posed by Nixon?
DE: I believe this president will indict journalists, which has not happened yet in our country. We fought a revolution to avoid that. And we have not yet broken that first amendment, which protects press freedom, in our constitution. But this president is likely to do so. The climate has changed. And that was true under Obama, who prosecuted three times as many people for leaking as all previous presidents put together – he prosecuted nine. I think Trump will build on that precedent. He will go further and do what Obama did not do and directly indict journalists.
EM: Is the WikiLeaks founder, Julian Assange, holed up in the Ecuadorian embassy in London and fearful of extradition to the US, one of those at risk?
ES: Julian's best defence, perhaps his only enduring defence, is that he is a publisher and has never even tried, as far as we are aware, to publish something untruthful. There are lots of criticisms, many of which are legitimate, to be said about his political views or his personal expressions or the way he put things or his agenda. But ultimately the truth speaks for itself.
DE: Assange is in danger. There are those who say that Julian does not have to fear extradition if he came out of the embassy and served a brief sentence, if anything at all, for violating the rules. I think that is absurd. I think Britain would ship him over here [to the US] in a minute and we would never see or hear from him again … under Trump, he may well be the first journalist in this country to be indicted.
EM: What about whistleblowing to prevent a US attack on North Korea?
DE: I am sure there are thousands of people in the Pentagon and the White House who know an attack on North Korea would be disastrous because they have estimates and studies that show the outcome of a supposedly limited attack would be catastrophic in terms of hundreds of thousands of lives, millions of lives and what comes after.
ES: What would you say, Dan, to the next whistleblower, who is sitting in the Pentagon? They have seen the attack on North Korea planned, they have seen the consequences and it can be stopped.
DE: They have, of course, something I did not have then, which is they can go directly to the internet. And that is not something I would advise them to do. I think that, let's see, in your case you went to the Guardian, you did not put the stuff on the net directly as you could have done. I think you did the right thing … If the New York Times does not do it, if the Guardian does not do it, you have the internet to go to.
EM: Was whistleblowing worth it?
DE: I once read a statement by Ed Snowden that there are things worth dying for. And I read the same thing by Manning, who said she was ready to go to prison or even face a death sentence for what she was doing. And I read those comments and I thought: that is what I felt. That is right. It is worth it. Is it worth someone's freedom or life to avert a war with North Korea? I would say unhesitatingly: "Yes, of course." Was it worth Ed Snowden spending his life in exile to do what he did? Was it worth it for Manning, spending seven and a half years in prison? Yes, I think so. And I think they think so. And I think they are right.


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Cool Next-Generation Gaming Phones
The modern gaming phone first began to take shape with Singaporean gaming manufacturer Razer's acquisition of smartphone start-up Nextbit in 2017. Using the base chassis of the Nextbit Robin, a cloud-computing oriented, crowd funded smartphone, Razer built out a phone that would prioritise competency in gaming above all other factors. In order to achieve this, the phone launched in late 2017 with a top tier Snapdragon 835 processor, 8GB or Ram and 64GB expandable storage. It had a wide aspect 16:9 5.7" IPS display that was famous for its then unprecedentedly fast refresh rate of 120hz. This meant that gaming on the phone was seamless and much more fluid than on competitive flagship devices.
The Razer Phone also launched with a large 4000mAh battery as well as a host of peripherals, including a physical game-pad and a clip-on fan for improved cooling and performance. This combination of peripherals, high refresh rate screens as well as plenty of RAM and battery capacity set the template for all other gaming-centric phones. Razer launched the Razer Phone 2 in 2018, but has not returned with a third iteration as of yet. The sector itself is hotting up with many brands seeking to platform their own gaming phone including Xiaomi's Black Shark, the ZTE Nubia Red Magic and Asus' Rog Series of phones.
Razor Phone 2
These new devices are paving the way for increasingly ambitious game ports from more traditional hardware like home games consoles and PCs. Genshin Impact, the open-world action RPG developed by miHoYO, has been lauded for its scale and graphical quality. Some might not believe it possible that it has been ported to the likes of Android devices, and in truth if you're running sub-optimal hardware you're going to have a hard time getting the most out playing the game this way. It is an example of a game that has been very clearly optimised to play on a device such as the latest Asus ROG Phone 5 Series, which will be able to deliver you the type of buttery 60fps gaming experience you wouldn't have thought possible on such a tiny device.
Genshin Impact joins the likes of FPS Shadowgun Legends and the Dinosaur survival sim ARK: Survival Evolved in pushing the limits of mobile gaming. Simpler titles also stand to benefit on these devices, whether they take the form of classic casino experiences like online slot games or an 8-bit farming adventure like Pocket Harvest. This is due to the fact phones in this product category ship with proprietary software that enables users to remap controller layouts and add hotkey shortcuts for more comfortable sustained gaming sessions. In addition to this, their high refresh rate screens, surround sound audio and incredible battery life make them the all round best choice for gaming on mobile no matter what you want to play.
Fast forward to today and the latest devices in this sector are once again redefining the limits of current smartphone hardware. Xiaomi's Black Shark Pro 3 is pushing the limits of heat efficiency with its 4th generation liquid cooling system. It utilises a special "sandwich" structure to improve cooling surface area and efficiency, preventing the processing core from thermal throttling under stress. Asus, who have made a name for themselves in gaming-centric computer hardware under their ROG (Republic of Gamers) sub-brand, just launched the 5th version of their ROG Phone.
It ships with an overclocked Snapdragon 888, an absolutely massive 6000mAh battery and a 144hz refresh rate display. It's also the very first smartphone to launch with the option for 16GB of RAM. Pre-orders are already available for ZTE's latest gaming phone, the Nubia Red Magic Pro 6. It matches the ROG Series 5 for RAM capacity and processing speeds, but pushes the display refresh rate up to a world-first 162hz. One thing we can reliably predict about these phones is that they are here to stay and will continue to push the limits of pocket gaming.
Gaming, Mobile Phones
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Current personal or leadership goals: To be the best dad and spouse I can be while helping others with their legal and personal issues (the good and the challenges); to help guide our younger professionals in my firm and hopefully inspire them to excel in their personal and professional endeavors.
Fully engage in the process – some may have started this journey because they were "forced" to do so by their bosses or companies – you will find that after your time together, you will miss the monthly gatherings of your new friends.
Getting tazered at the CMPD Academy because no one else volunteered and I always wondered what it felt like. And I got to see the video footage afterward – didn't know my face and body could contort like that.
My professional training and experience causes me to see different viewpoints on any particular issue but from a focused business and legal lens only – there are many other types of lenses – more personal ones – out there for every situation which are a result of others' backgrounds and experiences. My LC experience taught me how to better recognize and integrate more personal lenses into the mix of what I was hearing and seeing in my interactions with others.
My church, Christ Lutheran. We are blessed with a great church family and a wonderful worship service week after week with a lot of talent – from our Pastors' messages to the music – it is like going to a symphony concert every week – and the youth program is top of its class.
I don't know if LC classes still do this, but we were required to write a letter to ourselves at the beginning of the class year. The letters were then sent to us by Elizabeth via regular mail several months after the class year has concluded. I keep that letter in my nightstand and pull it out often to remind me of the goals I set for myself way back then and to continue to strive for those which I have not yet reached. It also brings me back to that time and puts me in a frame of mind as to "what would they [my classmates] do" for anything that is weighing on me at that time.


When should families consider home care?
Over time, you might notice signs that Mom or Dad is slowing down. Maybe Mom's arthritis is making housekeeping difficult. Perhaps Dad is becoming increasingly forgetful, or he's not eating as well as he should. It's important to take these troubling signs seriously.
Family members can pitch in whenever possible, but eventually, seniors may need more care and support than relatives can provide. It can be incredibly difficult for adult children to meet the needs of aging parents in addition to raising kids and working full-time. It's common for sons and daughters in the "sandwich generation" to feel anxious, helpless or guilty, knowing that they can't offer the ongoing support a parent needs. And living far away can make the situation even more stressful.
If an aging parent is having trouble managing at home, it's important to take action, before more problems arise. Start by determining what Mom or Dad needs, perhaps with the help of other family members and your loved one's physician. Then you can explore the options for senior care in your loved one's community.
Most seniors prefer to "age in place," in their own home and neighbourhood, rather than move to an assisted-living facility or live with relatives. Home care services, such as personal care, housekeeping and companionship, can help older adults keep living independently for as long as possible. Qualified home care professionals provide much-needed support, and they also give concerned family members greater peace of mind.
Even if you can't visit Mom or Dad as often as you would like, there is much you can do to support an aging parent remotely. If other family members can help, divide up these tasks and work as a team.
• Get in touch with your loved one frequently. This will help you monitor their well-being, and they will appreciate knowing that you care. You could schedule weekly phone or Skype chats, for example.
• Offer to help Mom or Dad get their legal documents and finances in order – for example, managing their bill payments, and checking if they are eligible for home care funding through government programs or an insurance policy.
• Help your loved one access community resources they need, such as a social worker, a seniors' day program or a meal delivery service, by doing online research or making a few phone calls.
• Arrange for home care services, such as housekeeping, companionship, or transportation to medical appointments, as needed. If you're not sure what your parent needs, a home care agency can conduct an assessment and prepare an individualized care plan.
• Make a list of contact information for key people such as your loved one's physician, specialists, insurance company, friends, neighbours, etc., and give a copy to family members.
• Develop an emergency plan. Who can go to your loved one in the event of a crisis, and how will they get there?
• Investigate technology that helps seniors stay safe at home, such as a security system, motion sensors or emergency devices.
If your loved one doesn't live close and needs a little extra help, contact Bayshore Home Health. We offer a wide range of home care services to help Canadians live independently for as long as possible. Contact us at 1-877-289-3997 for details.


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Chapter 06: A Love of Teaching and Discovering that Administration Can Impact Research
James M. Bowen PhD, The University of Texas MD Anderson Cancer Center
Louis J. Marchiafava PhD
In this chapter, Dr. Bowen talks about his involvement in teaching and administrative duties at MD Anderson, his love of teaching, and his work "helping nonmedical, nonscientific people learn more about cancer." He also discusses his involvement in securing research grants for the institution.
BowenJM_01_20000327_C06
Louis J. Marchiafava, PhD, Oral History Interview, March 27, 2000
The Interview Subject's Story - Overview; Professional Path; Building/Transforming the Institution; Education; On Education; Activities Outside Institution; Leadership; On Leadership; Mentoring; On Mentoring; Formative Experiences; Evolution of Career
James M. Bowen, PhD:
But almost an accident got me first involved in M. D. Anderson's administrative activity. Through the influence of Dr. Clark and the very excellent stewardship of Dr. Felix Haas, the institution received a grant that allowed a peer committee to sub-award small research grants to investigators based on an internal peer review of the quality of their projects.
Louis J. Marchiafava, PhD:
Now, what period was this?
This was in the mid-1960s. We are talking 1965-1966. I had met, through some other reason, and I don't recall exactly how we had met, the head of Anesthesiology whose name was William Derrick. Dr. Derrick was a wonderful man. He became a good friend and a mentor, and he asked me if I would serve as one of the members of the Institutional Research Grant committee. This would probably have been in the mid to late 1960s. I spoke with Dr. Dmochowski about that and Dr. Dmochowski thought that this would be a good idea. It would be a contribution to the institution, and it also might give virologists some insights and data to access these funds. And so, I was appointed to the Institutional Research Grant committee. It was the first administrative role that I had outside of virology, although I was already acting as deputy head of virology simply because I was close to Dr. Dmochowski, and if he asked me to do something, I tried to get it done for him.
Before you go on beyond this period, there is one question that popped up at me. I notice that you had an association with the dental school.
Yes. That was in another persona that I worked to develop. And that was, while I was at Oregon State in graduate school, I was a teaching assistant for practically the whole time I was there, along with my research assistantship. And I love to teach. I love to be in front of the classroom. I love to be with students. I loved everything about teaching. And so, one of the aspects that I had discussed with Dr. Dmochowski in returning to M. D. Anderson was would I have opportunities to teach? And he said, yes, he would recommend me for a membership in the growing affiliation with the Graduate School of Biomedical Sciences, and he had some associations with Baylor and with the dental school where I might be able to do some teaching. And just about that time, one of the professors at the dental school developed an affiliation with the dental science program with the Air Force out of Wilford Hall in San Antonio, and they developed a curriculum to teach master's level dental pathology, and one of the things they had to have was a microbiology unit. But they had no money to pay anybody to teach microbiology, and they went looking for somebody who would do it for free. And when I got the opportunity, I went! They asked Dr. Dmochowski if he would do it and he did not have time. And so, he asked me if I would like to do it for him. And that developed an almost career-long affiliation with the pathology group at the dental school. And I taught virology and microbiology and microplasmology for a time to that group, just for the love of teaching.
Did this have to do with cancer of the oral cavity?
Well, only peripherally at the time. In order to complete a master of dental science curriculum in pathology at the dental school, they had to have a unit in general microbiology, and we taught actually very little cancer at that time. The pathologists taught their own oral screening and things of that sort. I taught straightforward virology. We talked about . . . [break in audio tape]
We were speaking of the kind of teaching we were doing at the then science institute. It was one of the many opportunities that came to all of us who were interested in teaching. We got to teach graduate students. I also taught in the Baylor/St. Luke's Medical Technology Program. It was great fun teaching the dentists. I made a few trips over to Wilford Hall to give special lectures in virology for the people over there, and there was a chance to go around among different universities and talk to people. And somewhere along the line, one of the personal loves that I developed was helping nonmedical, nonscientific people learn more about cancer, because Dr. Clark always impressed on us that a patient was an essential part of the treatment team, and that the more everyone knew about cancer, the better off we were. And, in later years, and this will come up again, in later years, I spent a lot of my spare time just talking to anybody who wanted to hear -- to rotary clubs and to professional organizations and chambers of commerce and so forth about cancer, particularly about cancer prevention. And that interest led me to one of the roles that I had at M. D. Anderson in my later career that I am the most excited and the proudest of, and we will talk about that later on. You had asked me about teaching in the dental school. That was just one of those opportunities that many of us academics sought because it gave us a chance to be in front of a classroom. But I taught very little oncology. I taught straight virology. It was very good for me because it made me be the best student in the class, because things were developing so rapidly in all the fields of biomedical sciences, and in virology in particular, that you had to really keep after it to keep up. And the best incentive to keep after what was going on in your own field was to have to talk to groups about it. And that was what we did. Returning to the Institutional Research Grant Committee, the evolution of that experience was after about one year on that committee, Dr. William Derrick asked me if I would be vice-chairman and a chair of the group when he was out of town, which I did. And ultimately, when he retired as chairman, I became chairman. And that was basically the first administrative role that I ever had at M. D. Anderson, and made an interesting discovery. This was one of those discoveries that a scientist makes that is both tantalizing and horrifying, and that was that I really enjoyed administration, and I felt like I had a natural flair for it because I like the enabling part of it. You know, I loved to be a part, for example, of awarding this institutional research grant, and then one year later, reading the progress report to see what could have been done. And, of course, scientists very quickly learned the politics of doing that and they always have some sort of language in a progress report that says without support of the Institutional Research Grant, we would not have been able to do this and such. We would not have been able to publish this work. We would not have been able to make this discovery. We would have not been able to apply for a much larger grant which we have just received. And I am thinking, wow, this is a way that basically in our spare time, we can make a particular contribution towards advancing the institution in fields that we have no personal ability in. So, I really liked that committee work. Dr. Dmochowski was very supportive in this. He expected time given back in return. But there was an oversight committee for all research in the institution. He made me the departmental representative for that group called the Research Committee, which basically was the approval mechanism for any research that got done at M. D. Anderson. There was a clinical research group and a basic science research group. And all projects when Dr. Clark was president, all projects, had to be reviewed by a peer group, a representative group called the research committee and approved or there could be no institutional facilities or resources allocated to that project.
Now, this was your first taste of administrative work, is that right?
It was my first taste of administrative work.
Well, you enjoyed it, as you have stated.
Some people viewed it as a burden, but I didn't.
That is rather unusual.
Yes, and it actually bothered me a little that I liked it! But there I was, you know. And much later in my career, I would look back on that as an important kind of turning point in my ultimate association with M. D. Anderson.
Bowen, James M. PhD and Marchiafava, Louis J. PhD, "Chapter 06: A Love of Teaching and Discovering that Administration Can Impact Research" (2000). Interview Chapters. 681.


text:
Immune-related adverse...
Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis
CCBYNC Open access
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k793 (Published 14 March 2018) Cite this as: BMJ 2018;360:k793
Shrujal Baxi, assistant attending123,
Annie Yang, data assistant2,
Renee L Gennarelli, assistant research biostatistician2,
Niloufer Khan, fellow1,
Ziwei Wang, resident4,
Lindsay Boyce, research informationist5,
Deborah Korenstein, chief attending12
1Department of Medicine, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, 2nd Floor, New York, NY, USA
2Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, NY, USA
3Department of Medicine, Weill Cornell Medicine, New York, NY, USA
4Department of Medicine, University of Cailfornia Los Angeles, Los Angeles, CA, USA
5Medical Library, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence to: D Korenstein korenstd{at}mskcc.org
Accepted 30 January 2018
Objective To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials.gov.
Study selection Eligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease.
Data extraction Three independent investigators extracted data on adverse events from ClinicalTrials.gov and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators.
Results 13 relevant studies were included; adverse event data were available on ClinicalTrials.gov for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.
Conclusions Organ specific immune-related adverse events are uncommon with anti-PD-1 drugs but the risk is increased compared with control treatments. General adverse events related to immune activation are largely similar. Adverse events consistent with musculoskeletal problems are inconsistently reported but adverse events may be common.
The development and rapid uptake of checkpoint inhibitors, a modern form of immunotherapy, has resulted in changes to the way numerous cancers are managed. In 2011, the Food and Drug Administration approved ipilumuab, an anti-cytotoxic T lymphocyte associated antigen 4 (CTLA-4). It was the first checkpoint inhibitor approved for the treatment of advanced melanoma, its only indication. Other checkpoint inhibitors directed at the programmed death 1 (PD-1) pathway are now approved for the treatment of multiple cancers. Anti-PD-1 drugs include monoclonal antibodies directed at both PD-1 (nivolumab and pembrolizumab) and the PD-1 ligand (PD-L1) (avelumab, atezolizumab, and durvalumab). As of May 2017, nivolumab and pembrolizumab were approved for the following indications: advanced melanoma, non-small cell lung cancer, Hodgkin's lymphoma, and bladder urothelial cancer. Pembolizumab was approved for additional indications: renal cell carcinoma, head and neck cancer, merkel cell carcinoma, and tumors of any organ with high microsatellite instability. Further idications for anti-PD-1 drugs alone, or in combination with immunotherapeutic and non-immunotherapeutic drugs, are under investigation in at least 135 clinical trials.1
Immunotherapy, as a drug class, boosts the body's natural defense against cancer. These drugs have adverse effects, collectively known as immune-related adverse events, that represent immune effects on normal tissue that can result from misdirected stimulation of the immune system. Anti-PD-1 drugs are overall less toxic than standard chemotherapy,2345678 but immune-related adverse events have been reported in clinical trails. Organ specific immune-related adverse events including colitis, hepatitis, pneumonitis, and hypothyroidism as well as more general adverse events related to immune activation, including fatigue, diarrhea, and rash, have been common.278 Other adverse events potentially attributable to systemic inflammation, particularly musculoskeletal problems, have also been described in patients treated with anti-PD-1 drugs and may negatively impact quality of life, although their frequency is not known.910 A better understanding of the immune-related adverse events is necessary to determine the risk benefit for prescribing anti-PD-1 drugs to an increasing number of patients.1
We performed a systematic review and meta-analysis of immune-related adverse events of anti-PD-1 and anti-PD-L1 drugs. We included organ specific and other adverse events potentially related to inflammation and gathered data from both ClinicalTrials.gov and published literature. We made serveral hypotheses. First, that rates of organ specific immune-related adverse events including colitis, hepatitis, pneumonitis, hypothyroidism, and hypophysitis would be low overall but higher with anti-PD-1 drugs than with standard treatments. Second, that rates of general adverse events related to immune activation specifically fatigue, diarrhea, and rash would be higher than organ specific immune-related adverse events but would not be increased compared with standard therapies. Third, that adverse events consistent with musculoskeletal problems would be common, but had been inconsistently documented.
We conducted a literature search to identify randomized clinical trials comparing one anti-programmed cell death 1 (anti-PD-1) or anti-PD-1 ligand (anti-PD-L1) drug to a control drug in patients with cancer. We evaluated the rates of organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems and calculated the risks compared with control treatments. We performed the study in adherence with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines.11
Data sources and searches
We electronically searched five databases (Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus) from the inception of all searched databases in August 2016 and updated the search in March 2017. For PubMed, Embase, and Cochrane, we used both controlled vocabulary and text words for synonymous terminology within titles and abstracts in the development of search strategies. Web of Science and Scopus were searched using only text word searching of titles and abstracts. The search strategy contained two concepts that were linked together with the AND operator:1 nivolumab, pembrolizumab, ipilimumab, avelumab, tremelimumab, atezolizumab, durvalumab, checkpoint inhibitors; and phase II clinical trials, phase III clinical trials, randomized controlled trials.2Box 1 shows the complete list of search terms. We combined the search results in a bibliographic management tool (EndNote) and used the Bramer method to eliminate duplicates.12
PubMed search terms
("nivolumab"[Supplementary Concept] OR "Nivolumab"[tiab] AND "Opdivo"[tiab] OR "MDX-1106"[tiab] OR "ONO-4538"[tiab] OR "BMS-936558"[tiab] OR "NIVO"[tiab] OR "pembrolizumab"[Supplementary Concept] OR "pembrolizumab" [tiab] OR "lambrolizumab"[tiab] OR "keytruda"[tiab] OR "MK-3475"[tiab] OR "SCH 900475"[tiab] OR "avelumab"[Supplementary Concept] OR "Avelumab"[tiab] OR "MSB0010718C"[tiab] OR "MPDL3280A"[Supplementary Concept] OR "MPDL3280A" [tiab] OR "atezolizumab" [tiab] OR "Tecentriq"[tiab] OR "RG7446"[tiab] OR "RO5541267"[tiab] OR "Durvalumab"[tiab] OR "MEDI4736"[tiab] OR "MEDI-4736"[tiab] OR checkpoint inhibitor*[tiab] OR "PD-1"[tiab] OR "PD-L1"[tiab]) AND (Clinical Trial, Phase III[ptyp] OR "phase 3 clinical trial"[tiab] OR "phase III clinical trial"[tiab] OR "phase 3 trial"[tiab] OR "phase III trial"[tiab] OR "phase 3 clinical study"[tiab] OR "phase III clinical study"[tiab] OR "phase 3 study"[tiab] OR "phase III study"[tiab] OR "phase 3 randomized trial"[tiab] OR "phase III randomized trial"[tiab] OR Clinical Trial, Phase II[ptyp] OR "phase 2 clinical trial"[tiab] OR "phase II clinical trial"[tiab] OR "phase 2 trial"[tiab] OR "phase II trial"[tiab] OR "phase 2 clinical study"[tiab] OR "phase II clinical study"[tiab] OR "phase 2 randomized trial"[tiab] OR "phase II randomized trial"[tiab] OR "phase 2 study"[tiab] OR "phase II study"[tiab] OR "phase 2/3 clinical trial"[tiab] OR "phase II/ III clinical trial"[tiab] OR "phase 2/3 trial"[tiab] OR "phase II/III trial"[tiab] OR "phase 2/3 clinical study"[tiab] OR "phase II/ III clinical study"[tiab] OR "phase 2/3 study"[tiab] OR "phase II/III study"[tiab] OR "phase 2/3 randomized trial"[tiab] OR "phase II/III randomized trial"[tiab] OR Randomized Controlled Trial[ptyp] OR "randomized controlled trial"[tiab] OR "RCT"[tiab])
RETURN TO TEXT
We included studies that examined a cancer and reported results of a randomized study of an anti-PD-1 or anti-PD-L1 monoclonal antibody. We excluded reviews, commentaries, studies published only in abstract form, quality of life studies, cost effectiveness analyses, and those in which the effect of the drug could not be ascertained, such as when the control was a different dose of the same drug or another checkpoint inhibitor. The study selection was performed in two stages. Two authors (SB and ZW) screened all titles and abstracts for full text review. Three authors (SB, DK, and ZW) reviewed and discussed the full text articles. Disagreements were resolved by concensus. All included studies represented unique trials.
Data from each study was extracted by two of three authors (SB, DK, and NK). Disagreements were resolved by concensus involving all three. We extracted patient characterisitics (sex, performance status, and age), the sizes of intervention and control groups, median treatment time, and median follow-up from each study. Two of three authors (DK, AY, and SB) independently assessed the quality of all articles included in the review using the Cochrane Risk of Bias Tool and used a weighted Cohen's kappa coefficient (κ) to measure agreement.13 To optimize relevance to immune-related adverse events we evaluated the risk of bias with regard to adverse event outcomes, not the efficacy outcomes the individual studies were primarily designed to assess. Differences were resolved by consensus.
Our primary outcome was the incidence of commonly described organ specific immune-related adverse events (colitis, hepatitis, pnemonitis, hypophysitis or hypopituitarism, and hypothyroidism) and general adverse events related to immune activation (fatigue, diarrhea, and rash). Our secondary outcome was the incidence of adverse events consistent with musculoskeletal problems (arthritis, arthralgia, back pain, musculoskeletal pain, and myalgia). We first searched for adverse event data on ClinicalTrials.gov on 28 March 2017. For studies for which full adverse event information was not on ClinicalTrials.gov, we used information from the publication and directly contacted study authors or pharmaceutical sponsors for additional information. We recorded data on adverse events reported as either serious or other on ClinicalTrials.gov. For data extracted from published reports, we used the Common Terminology of Clinical Adverse Events (CTCAE) categorization to identify grades 3-5 as serious and CTCAE grades 1-2 as other. For studies with information available from both sources, we prioritized data from ClinicalTrials.gov over adverse event data from the publications, because it was more complete. If the study did not report a specific adverse event, we assumed that the event did not occur. Data from different dosing arms within the same study were extracted and reported separately.
Data synthesis and analysis
We calculated overall event rates by dividing the total number of patients across trials with a given adverse event by the total number at risk. We examined the number of events for each immune-related adverse event of interest to determine whether meta-analysis was feasible. For each included study, we calculated odds ratios and 95% confidence intervals for event rates in the intervention arm compared with control based on the reported number of events and sample size. We used the I2 index and the Cochran Q statistic to examine heterogeneity across trials for each outcome. If significant heterogeneity was not present (P>0.1), pooled odds ratio and 95% confidence interval were estimated with a fixed effects model using the inverse variance method. A random effects model using the inverse variance method was used to calculate pooled odds ratio and 95% confidence interval if significant heterogeneity was present (P≤0.1). Studies were weighted based on the inverse of the variance of the effect estimate. If a study included more than one intervention arm (eg, Herbst and Ribas reported 2 mg/kg and 10 mg/kg arms for pembrolizaumab),1415 we separately compared each intervention arm with the control arm. We conducted subgroup analyses to examine studies by control group treatment (chemotherapy v targeted treatment). We used funnel plots to asses publication bias. All statistical analyses were conducted using Review Manager 5.3 (Copenhagen, Denmark).
No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community. It was not evaluated whether the studies included in the review had any patient involvement.
Figure 1 shows that our search identified 2486 records; 18 underwent full text review and 13 were included for quantitiative synthesis and meta-analysis.14151617181920212223242526 Included articles were published (online) between November 2014 and February 2017. Funnel plots showed no evidence of publication bias (web appendix 1).
Study flow diagram
All studies were international multi center studies funded by the pharmaceutical industry, with intervention group sample sizes ranging from 59 to 609 patients. Seven were completed in patients with metastatic non-small cell lung cancer,14161721232426 three in melanoma,151920 and one each in renal cell carcinoma,18 bladder cell carcinoma,25 and head and neck squamous cell carcinoma.22 Patients in the intervention arm received nivolumab in six studies,161718192022 pembrolizumab in five studies,1415232425 and atezolizumab in two studies.2126 One trial evaluated the combination of pembrolizumab with chemotherapy (carboplatin and pemetrexed) compared with chemotherapy (carboplatin and pemetrexed) alone.23 In two studies evaluating pembrolizumab, two different doses (2 mg/kg and 10 mg/kg) were compared with each other, in addition to a standard control.1415 The control arm was one chemotherapy drug in six studies,141617192126 two chemotherapy drugs in one study,23 a small molecule inhibitor in one study,18 and the investigators' choice in four studies.15202225 For all studies, the primary endpoint was survival, with adverse events reported as secondary outcomes. All studies continued treatment until the disease progressed or severe adverse events occured. The median treatment time in the investigational arm was 3.9 months (range 3 to 8 months) and the median duration of follow-up across studies was 13.1 months (range 5 to 25 months). As of 27 March 2017, all studies were registered on ClinicalTrials.gov and adverse event data was available on ClinicalTrials.gov for eight studies.
Quality of included studies
Table 1 shows that there was high inter-rater agreement for risk of bias assessments (κ between 0.629 and 1.00 across domains).13 All studies but one were open label with primary outcome of overall survival. Reports of adverse event rates in these open label studies were unmasked because adverse event reporting was performed by the clinicians directly caring for patients. Further, because included studies were not designed primarily to assess adverse events, collection of adverse event information was poorly described, and we deemed all studies at high risk of bias with regard to incomplete outcome data and selective outcome reporting.
Risk of bias of randomized controlled trials
Organ specific immune-related adverse events
A total of 6676 patients were evaluated across the 13 studies with 3803 in the investigational arm (nivolumab 1534, pembrolizumab 1459, and azetolizmumab 751) and 2873 in control arms (chemotherapy including cetuximab 2476, or a biological agent 397). All studies reported organ specific immune-related adverse events of interest. Looking at any grade organ specific immune-related adverse events, among the 3803 total patients exposed to anti-PD-1 drugs 214 (5.6%) had hypothyroidism, 85 (2.2%) had pneumonitis, 25 (0.7%) had colitis, 6 (0.2%) had hepatitis, and 11 (0.3%) had hypophysitis. The most common serious immune-related adverse events was pneumonitis which occurred in 54 (1.4%) patients, while serious colitis, hypothyroidism, hepatitis, and hypophysitis occurred in 18 (0.5%), 6 (0.2%), 5 (0.1%), and 9 (0.2%) patients respectively. Table 2 shows the rates of organ specific serious immune-related adverse events by drug.
Incidence of severe organ specific immune-related adverse events by drug. Values are percentages (95% confidence intervals) unless stated otherwise
Figure 2 shows that in the meta-analysis, compared with patients treated in control arms, those treated with anti-PD-1 drugs were at higher risk for colitis (odds ratio 2.88, 95% confidence interval 1.30 to 6.37, P=0.009). Figure 3 shows that they were not at increased risk of hepatitis (3.14, 0.76 to 12.98, P=0.11), though events were rare. Figure 4 shows that pneumonitis, excluding the study in which the control treatment was everolimus, a drug known to causes pneumonitis, the risk of pneumonitis with anti-PD-1 drugs was also higher than the control (5.37, 2.73 to 10.56, P<0.001). The risk was lower with anti-PD-1 drugs compared with everolimus; the overall pooled estimate may not be meaningful. Figure 5 shows that patients treated with anti-PD-1 drugs were at a higher risk for any grade hypothyroidism (6.92, 3.25 to 14.75, P<0.001). Figure 6 shows that patients treated with anti-PD-1 drugs were at higher risk for any grade hypophysitis (3.38, 1.03 to 11.08, P=0.04).
Forest plot of colitis in patients treated with anti-PD-1 drugs versus control
Forest plot of hepatitis in patients treated with anti-PD-1 drugs versus control
Forest plot of pneumonitis in patients treated with anti-PD-1 drugs versus control
Forest plot of hypothyroidism in patients treated with anti-PD-1 drugs versus control
Forest plot of hypophysitis in patients treated with anti-PD-1 drugs versus control
General adverse events related to immune activation
All studies reported rates of fatigue and diarrhea and 12 reported rash. In the intervention arms of these studies, rates of fatigue, diarrhea, and rash were seen in 1208 (32%), 705 (19%), and 393 (10%) patients respectively. Figure 7 shows that patients treated with anti-PD-1 drugs were more likely to experience rash (odds ratio 2.34, 95% confidence interval 1.40 to 3.91, P=0.001). Figure 8 and figure 9 show that patients were less likely to report fatigue (0.84, 0.65 to 1.09, P=0.19) or diarrhea (0.78, 0.57 to 1.05, P=0.10) compared with patients in the control arms.
Forest plot of rash in patients treated with anti-PD-1 drugs versus control
Forest plot of fatigue in patients treated with anti-PD-1 drugs versus control
Forest plot of diarrhea in patients treated with anti-PD-1 drugs versus control
Adverse events consistent with musculoskeletal problems
Table 3 shows that reporting adverse events consistent with musculoskeletal problems, including arthritis, arthralgia, back pain, musculoskeletal pain, and myalgia, varied across studies. Three studies included no mention of musculoskeletal problems. On ClinicalTrials.gov, among the eight studies for which data was provided, arthralgia, back pain, musculoskeletal pain, and myalgia were reported in all studies while arthritis was reported in two. When reported, rates of musculoskeletal problems varied across studies in intervention groups, ranging from 10% to 26% for arthralgia, 6% to 22% for back pain, 6% to 14% for musculoskeletal pain, and 2% to 12% for myalgia. Single cases of arthritis were reported in two studies at a rate of below 1% in each. Across control groups, rates of musculoskeletal compaints ranged from 9% to 18% for arthralgia, 2% to 16% for back pain, 4% to 6% for musculoskeletal pain, and 4% to 16% for myalgia, when reported. Lack of reporting adverse events consistent with musculoskeletal problems precluded data pooling, so we did not perform a meta-analysis for these outcomes.
Incidence of adverse events consistent with musculoskeletal problems. Values are numbers (percentages) unless stated otherwise
We completed a systematic review of immune-related adverse events of anti-programmed cell death 1 (anti-PD-1) or anti-PD-1 ligand (PD-L1) monoclonal antibodies versus a standard treatment to further our understanding of the safety of this emerging class of drugs. We used data from 13 randomized trials that included over 3800 patients treated with checkpoint inhibitors and extracted data from ClinicalTrials.gov, when possible, to supplement the published evidence base.
Our study is notable for our inclusion of adverse event information from ClinicalTrials.gov and our focus on anti-PD-1 drugs. A recent meta-analysis evaluated the risk of immune-related adverse events in patients treated with any checkpoint inhibitor (including ipilimumab).27 Unlike the prior study, we found an increased risk of pneumonitis with anti-PD-1 drugs compared with control treatments other than everolimus, though our findings regarding risk of colitis were similar. Any differences in findings are likely owing to our access to more complete adverse event data through ClinicalTrials.gov and our inclusion of more studies of anti-PD-1 drugs. In addition, by using data from ClinicalTrials.gov we were able to evaluate adverse events consistent with musculoskeletal problems, which are likely to be important to patients.
Our findings have important implications for clinicians across multiple specialties. As use of anti-PD-1 drugs grows, non-oncology specialists will be increasingly called upon to manage the rare but clinically important organ specific immune-related adverse events and the more prevalent general adverse events related to immune activation.2829 In addition to severe adverse events such as pneumonitis and colitis, our study documents musculoskeletal problems that will require management by primary care physicians and rheumatologists.910 These problems are not surprising given that many autoimmune diseases have musculoskeletal manifestations.30 Inflammatory arthritis from checkpoint inhibitors has already been recognized in the rheumatology community; these adverse events are likely to grow in prevalence over time.1031323334 Currently, many oncology patients are treated primarily by their oncologists and may lose connections to other physicians.3536 This care model may poorly serve patients treated with checkpoint inhibitors, whose cancers may remain under control but in whom a variety of adverse events may threaten health and quality of life. Multidisciplinary clinical teams may better serve these patients' long term needs, though optimal clinical and care delivery approaches for the early detection and proper management of immune-related adverse events are evolving and will require further investigation.3738
Anti-PD-1 drugs can achieve long term tumor control through prolonged immune activation, so immune-related adverse events requiring management may persist, progress, or even emerge over time.29 Studies included in our analysis had a median follow-up time of 13.1 months (range 5-25 months), which may be inadequate for capturing the full spectrum of longer term immune-related adverse events. With a focus on acute or short term adverse events captured in clinical trials, our study may have underestimated the prevalence of late developing or persistent immune-related adverse events. Better understanding of the long term adverse events of monoclonal antibodies will be critical to efforts to optimize delivery of care. Phase IV studies are often recommended to enhance understanding of long term adverse events of new approved drugs, although they are seldom performed and are time consuming.39 Given the rapid anticipated growth in the number of patients treated with anti-PD-1 drugs, institutional cohort studies could provide more immediate insights into immune-related adverse events with an emphasis on not just short term, but also long term, adverse events. In addition, investigators should publish updated adverse event information as well as cancer outcomes as they report longer follow-up from earlier studies of checkpoint inhibitors. Only a small amount of this type of data are publicly available.
We found that despite high rates of adverse events consistent with muscoskeletal problems, reporting of these adverse events was inconsistent and incomplete across trials. Accessing adverse events data on ClinicalTrials.gov enabled us to include information that did not appear in publications, however, we remained constrained by the recording methods for adverse events in clinical trials. Adverse events in clinical trials are reported using Common Terminology of Clinical Adverse Events (CTCAE), which prompts investigators to note the presence or absence of a symptom or an abnormal laboratory value and grade it based upon its clinical significance. The process is highly subjective and relies on investigator recognition and identification of syndromes of interest, thus investigators may be more likely to classify patient complaints or findings as diagnoses of which they have high suspicion. In the case of anti-PD-1 drugs, investigators are aware of well described immune-related adverse events such as colitis, hepatitis, pneumonitis, or hypothyroidism and are likely to report them accurately. Investogators may be less aware of other potentially relevant adverse events such as musculoskeletal problems and may therefore inaccurately diagnose and record them. Emerging case reports and case series have described rheumatologic and musculoskeletal syndromes related to systemic inflammation that have been seen in clinical practice but not described in primary publications of trial results.91040 Similar attention has been turned to less frequent, but important adverse events impacting the neurologic, cardiac, and ocular systems.41424344 As these receive more attention, problems such as arthritis, arthralgia, and myalgia may become more accurately reported in future studies.
Weaknesses of this study
Our study has important limitations. A major challenge of this review was the overlap in CTCAE definitions which prevents understanding the true rates of specific adverse events. For example, immune-related hepatitis could be captured as hepatitis or as an abnormal laboratory value (elevated aspartate transaminase and alanine transaminase) and immune-mediated colitis could be categorized as colitis or diarrhea. This could lead to potential uncertainty regarding the quality of the data, which will need to be addressed moving forward for studies of immunologic drugs. Further, a limitation of this analysis is that we assumed that the non-reporting of adverse event data was the result of either no events or non-measurement of the outcome. If a selective non-reporting mechanism were present, such that the adverse event data was measured but not reported based on the results, then there is the possibility that we may have overestimated the drugs' safety.45 In addition, while a strength of our study is our use of ClinicalTrials.gov to collect more complete adverse event data than what was available in published trial reports, we were able to include adverse event data from ClinicalTrials.gov for only eight of 13 studies. However, it is unlikely that more publicly reported data would have substantially altered our findings. In addition, we combined all non-immunotherapy drugs into one control category, including both traditional chemotherapy and two targeted drugs, cetuximab and everolimus. We performed a subset analysis separating targeted from non-targeted control treatment. Risks of pneumonitis and rash differ for targeted treatments compared with traditional chemotherapy and odds ratios differed across control treatments, so targeted drugs are presented separately. For other outcomes there was no heterogeneity based on comparator so all studies are presented together. Finally, we pooled data from studies that used different anti-PD-1 drugs at variable doses so we may have missed differences in adverse event rates across drugs or based on dosage differences. Given the wide variation in drug and dose across studies we were unable to perform subgroup analyses to examine these factors. However, we found little heterogeneity across studies for adverse event outcomes, suggesting little difference based on the specific drug or dose.
Unanswered questions and future research
Our study provides insight into the adverse events from treatment with anti-PD-1 drugs, which have revolutionized care for patients with cancer in the last few years. We found that anti-PD-1 drugs are more likely than standard treatments to cause pneumonitis, colitis, rash, and hypothyroidism but not fatigue or diarrhea. We also found variable reporting of musculoskeletal problems, with high rates in some studies, suggesting that anti-PD-1 drugs likely do cause some bone, muscle, and joint adverse events. However, owing to the short interval of follow-up data currently available from clinical trials and a lack of clarity in the systematic capture of many adverse events, we are likely to have underestimated the true rates of adverse events. Moving forward, longer term follow-up and specific attention to a variety of immune-related adverse events may enhance our understanding. Until then, for the practicing clinician, our findings suggest the importance of monitoring all adverse events in patients treated with anti-PD-1 drugs.
We found that the risk of organ specific immune-related adverse events such as hypothyroidism, colitis, and perhaps pneumonitis are increased with anti-PD-1 drugs compared with standard treatments although overall event rates remain low. In contrast, compared with control arms, the risk of general adverse events related to immune activation, such as fatigue and diarrhea, are not increased. Further, we found that anti-PD-1 drugs seem to lead to musculoskeletal problems such as arthralgia, back pain, musculoskeletal pain, and myalgia, that can negatively impact quality of life and long term tolerability of immotherapy, though reporting of these adverse events was inconsistent.
What is already known on this topic
Drugs targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) are being used more frequently to treat cancer
Proper clinical management requires understanding associated immune-related adverse events that can include organ specific adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems
Rates of these adverse events are unclear and publications from clinical trials may inconsistently report unexpected adverse events
What this study adds
Organ specific immune-related adverse events are uncommon with anti-PD-1 drugs but that risk is increased compared with control treatments
General adverse events related to immune activation such as fatigue are largely similar
Adverse events consistent with musculoskeletal problems are inconsistently reported but may be common
Contributors: All authors had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. DK is the guarantor.
Funding: This study was supported in part by the National Institutes of Health and National Cancer Institute Cancer Center Support Grant (P30 CA008748). The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; or approval of the finished manuscript.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data are available.
Transparency: The lead author (SB) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Data supplement
Shrujal Baxi assistant attending, Annie Yang data assistant, Renee L Gennarelli assistant research biostatistician, Niloufer Khan fellow, Ziwei Wang resident, Lindsay Boyce research informationist et al
Baxi Shrujal, Yang Annie, Gennarelli Renee L, Khan Niloufer, Wang Ziwei, Boyce Lindsay et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis BMJ 2018; 360 :k793
Articles by Shrujal Baxi
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For almost a decade, I owned an U.S. export management services and inter-Asian trading company. Starting in the late 1980s, my travels took me extensively throughout Southeast Asia. I had the opportunity to meet many interesting business folk, a few of which remain good friends. One of these interesting folk was an ex-patriot living in southern Thailand . He managed a network of business interests, including a substantial jewelry manufacturing company. In one of my trading activities with him, I was offered as payment for my services 845 carats of industrial grade, cut, semi-precious, red ruby stones from the Thai Chanthaburi-Trat and Burmese Magok gem fields. One potential difficulty with accepting this intriguing and untraditional currency was how to transport my payment back to the US . Thailand was in the middle of my itinerary and I was not looking forward to explaining to customs officers at my pending stops in Cambodia , the Philippines , Taiwan , and Korea how I came upon 845 carats of deep red rubies. My friend then sweetened the offer by including the rubies in his next shipment of jewelry to the US, delivering them to my front door.
A few weeks after my return to the US , a Brink's armored truck drove up to my house. My friend had the rubies picked up in Thailand and transported to my house in one seamless transaction, including international customs clearing. Just like they do at the banks, two Brink's guards, in their full security gear, walked up my front steps, rang the door bell, and delivered my rubies. It was the buzz of the neighborhood for some time thereafter.
This was my first personal encounter with the Brink's Company (BCO $35). Founded as an armored trucking firm in 1859 by Mr. Perry Brink, BCO has been transforming itself over the past few years. During the heyday of building mega-businesses, Brink's Company expanded into other security related fields, and merged into a natural resources firm with assets in coal, timber, natural gas and gold. Following the mid-90s fad of issuing tracking stock for different operating units, Brink's Co. became part of a three class stock offering of the Pittston Brink's Group. However, the coal business developed long-term medical liability issues that nearly sank the company in the late 1990s. From 2000 to 2003, management reworked the company, selling all natural resource assets, settling long-term liability issues, and focusing its attention on the commercial and personal protection business. After a few years of restructuring, it seems management has rediscovered its growth platforms – security and international markets.
Today, BCO is a fascinating mix of businesses operating in three groups: Brink's Int'l, Brink's Home Security, and BAX Global. Revenues in 2004 totaled $4.7 billion, an increase of 18 percent over 2003. Operating profit in 2004 totaled $282 million. Standard and Poor's is anticipating companywide revenue growth this year to be in the 6 to 8 percent range. Earnings per share (from continuing operations) should rise from $1.82 in 2004 to around $2.11 in 2005 and between $2.20 and $2.30 in 2006. Long-term, Wall Street analysts are expecting a moderate 15 percent earnings growth.
The Brink's Int'l operating group offers traditional armored car services, along with bank automatic teller machines services, secure air transport of valuables, and foreign currency deposit processing. Brink's Int'l generated $1.9 billion in revenues and 51 percent of overall company operating profits. Brink's Home Security operating group supplies mainly residential security and fire alarm systems. Home Security monitored around 921,000 systems last year, representing 18 percent growth over the previous year. While generating a relatively small $330 million, or 7 percent of total revenues, the Home Security group chipped in a substantial 29 percent of total operating profits, thanks to a hefty 23 percent operating profit margin. BAX Global operating group is a multi-model, international transportation and supply chain management provider, focused on the business to business, heavy freight market. Management performance at BAX Global has been spotty over the past few years, albeit in difficult market conditionings. In 2004, BAX Global represented 52 percent of company revenues, or about $2.4 billion, but only 20 percent of operating profits.
The growth platforms for Brink's Company are the home security and the armored car groups. While the number of customers seeking home monitoring services experienced a sizzling expansion in 2004, client growth rates will probably taper off this year and next. Brink's Home Security is the second largest US residential alarm services company. Not only is new subscriber growth critical to overall performance, retaining new clients is equally important. Brink's Home Security's disconnect rate has trended downward over the past few years, demonstrating improved client satisfaction. Operating profit margins in 2004 for the Home Security group were an attractive 23 percent, compared to 7 percent for the armored car group and 2 percent for BAX Global. The residential alarm monitoring service industry is highly fragmented and enjoys less than a 30 percent overall market penetration. This should allow Brink's to gain additional clients through higher overall market penetration, increased market share, and timely acquisitions.
The transportation of cash around the globe remains a profitable service with growth potential. Banks, retailers and financial institutions are seeking to outsource more of their cash processing needs. With higher security concerns and growing demands for more convenient ATMs, financial institutions continue to expand their cash processing expenditure budgets. As a leader in the outsourcing of cash processing, Brink's Int'l should continue to enjoy steady growth in revenues and profits. While operating profit margins are not very exciting, the consistent cash flow should grab investor's attention.
Brink's Company generated almost 54 percent of total 2004 company revenues and 46 percent of total 2004 operating profit outside the Americas . In addition, international business has provided the company with increasing profitability. For example, in 2004, Brink's Int'l armored car group grew by 2 percent in revenues and 3 percent in profits in the Americas , while the same international business grew by 23 percent and 51 percent respectively.
Brink's Company is not without problems. BAX Global has been an underperforming asset for a number of years. While BAX Global represents a substantial percentage of overall revenues, the group has been unable to consistently contribute in profits. Some company followers believe non-security related BAX Global assets could be sold, further downsizing the company, and the capital reinvested in other growth platforms.
In addition, as settlement of litigation concerning medical liability issues arising from its divested coal mining businesses, Brink's Company agreed to fund a benefit's trust. Management has targeted to contribute $300 to $400 million into the trust. Known as its "Legacy Liability", Brink's Company has already contributed $132 million over the past two years, and anticipates contributing between $30 and $50 million a year over the next five years. This diversion of company operating cash flow will impair potential earnings growth going forward, but its impact will diminish over time.
I own 200 shares of Brink's, purchased in January 2004, the same time as the company was added to the MoneySaver Overlooked Stock Portfolio. The stock price is up 58 percent since its addition, for a 39 percent annualized gain. BCO appears to be in a holding pattern since last November, trading between $32 and $38, or around a forward PEG ratio of 1.00 to 1.10.
In my opinion, while not particularly undervalued at its current stock price, Brink's Company provides a unique long-term, international opportunity worthy of most investor's further investigation. Patient investors with realistic expectations should be amply rewarded as Brink's Company expands its security and international growth platforms.


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Chuze Fitness Opens First of Three "Gyms for the Rest of Us" in Westminster
Lauren Archuletta
Lauren Archuletta | September 8, 2016 | 7:47am
A new "gym for the rest of us" has moved into the metro fitness market, bringing low prices, a movie theater and an intimidation-free zone. Chuze Fitness recently opened the first of three planned Colorado locations in Westminster; all promise to break free of the typical "big-box gym concept."
For starters, Bryan Brown, general manager of the Westminster spot, says that Chuze Fitness isn't Planet Fitness. "When I think of Planet Fitness, I thought they had a really good business model, but I think we've improved, especially by way of amenities," he adds, pointing to the Westminster club's pool, jacuzzi and Chuze Cinema, the cardio-trademarked room featuring a full-theater movie experience. "But, really, it's about our atmosphere. We want everyone to just be comfortable and feel at home with us, and we've gone above and beyond when it comes to service-based attitude."
Melissa Sowell, chief administration officer and director of human resources at Chuze Fitness, echoes Brown's comments, saying that all sixteen of the Chuze Fitness locations across the country strive to be as welcoming as possible. "We truly want to know your name and assure you that there really is no judgment here," Sowell says. "We teach customer-service training to everyone, and even our Group X instructors — who may only be working an hour or two a week — have their own culture trainings so that no one is ever made to feel unwelcome."
The Chuze Fitness motto is "Less Attitude, More Fitness," Sowell notes, and guests can do the workout of their choice through three levels of membership. The basic membership grants access to the Chuze Cinema and a complimentary team-training session for $9.99 per month; the premium membership costs $19.99 a month, grants access to all amenities and adds weekend guest privileges to the team-training session; the "MORE" membership is $1 to join and $39.99 monthly, and includes everything in the lower levels, plus unlimited guest privileges and child care for up to two children.
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Though the Denver fitness market is highly competitive, Sowell says that the company's dedication to cleanliness, customer service and its price point — which Chuze has held since inception — will make it stand out. "We've been looking at the Denver market for a while, and Colorado is a great state to expand into," she explains. "The people are friendly and it's a very active demographic. Naturally, there are some competitors here, but there's a place for all of us. We just wanted to be a part of this."
Chuze Fitness at 8601 Sheridan Boulevard in Westminster boasts a 38,000-square-foot gym, more than 100 cardio machines, an indoor lap pool and hydromassage, among other amenities and classes. The California-based chain plans to open two more Colorado locations — in Thornton and Littleton — later this year. Visit chuzefitness.com for more information.
Lauren Archuletta is a contributor for Westword's arts section, covering Denver's health and wellness scene. Follow her work for tips on cheap workouts and which yoga classes include mimosas and beer.
Twitter: @laureneverytime


The emotional colour of your separation and imminent divorce changes from when it's pre, mid and post divorce and don't think it'll end up being three shades of black!
Have a little quiet time today to focus on what colour you feel it is now , what colour it has been and what colour you would eventually like it to be.
This entry was posted on January 18, 2016 by The Team.


What is the one thing you learned that you didn't expect from homeschooling?
We start our homeschooling journeys with expectations of ourselves and our children. Sometimes they are unrealistic, sometimes they are pretty accurate. What are some of the aspects of homeschooling that surprised you? Did you find you were harder or easier than you expected? What have your children taught you? What can you share with new parents regarding expectations? What do you wish you'd known from the beginning? What has been the greatest 'personal' lesson you have received through your homeschooling journey?
When I started my homeschool journey, I had the notion that I was just going to do school at home. I could tailor the lessons from the textbooks to my kids learning styles but just stick with textbooks, worksheets, and standard tests. What was I thinking??? Seriously, I have no idea why I thought that the education I received in college about teaching would really work and was the only way to do it. Teachers do what they were taught to do and the schools are failing. So why follow those failing principles at home?
As I said, I have no idea what I was thinking. I have come so far from those first days of schooling. I have learned that, at least for our family, homeschool is a way of life not just something we do. I have learned to find a learning/teaching opportunity in every situation and activity. Along with that, I have learned that textbooks are not the only way to learn. For us, the textbooks have become a supplement to what we are learning. It seems so backwards and wrong compared to my original way of thinking but I have seen great fruit from doing it this way.
I also learned about the amazing flexibility that comes with homeschooling. When I started this adventure, I thought you had to stick to the normal school schedule. I quickly discovered that you can start late in the day if need be, take days off as needed, start earlier in the year, end later in the year, or adjust to whatever our needs are at that moment. Also, what I did last month may not work this month so I can change things around so everything does work and then next month tweak things again.
Some days are hard and some days are easy. Sometimes school takes a lot of work on my part (like when I design a unit study around a 4th grader, a 3rd grader, and a 1st grader), and other times, not so much.
The most amazing thing I have learned through this endeavor is how strong a relationship you can build with your children and the relationship they build with each other when you get to spend every day with them.
I will go back and make sure, but I do believe that I only had the 2 options (allows full page, pop-up.
Weird, on my last comment my Google account wouldn't pop up and now it did.
Yep, I only have 2 options.
All parents want to give the best for their child, and, of course, to protect their offspring from the mischiefs of the world outside home. That's why some parents decide to educate their children at home, instead of letting them to school.