Sunday, May 27, 2018
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Setbacks and success


Pat Krzeminski was so agitated before her surgery, her husband, Ed, says the family had to 'run for cover.' He gives Pat a kiss before anesthesiologists sedate her for her eighth cancer operation.

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(Last year, five women with recurring cancer allowed Blade science writer Jenni Laidman and photographer Jetta Fraser to follow them through an experimental drug trial at the Medical College of Ohio. This is the fifth and final part in a series about that trial -- called "Working on a cure: Cancer on trial". It begins a yearlong examination of cancer by The Blade. )

Pat Krzeminski doesn't know.

Around her swarms a council of blue-clad doctors. They peer into her anxiously.

At the lead is Dr. James Fanning. He's sweating under the hot lamps that make Pat's organs glisten like red jewels. “Get that heat down in here,'' he pleads to the circulating nurse. To those not huddled in the circle of light and blood, the room is chilly. But to the surgeon and assistants, it's unbearably tropical.

Dr. Fanning slices open skin, wrenches apart muscle with bear-trap metal jaws, and gently, persistently, slivers the adhering scars of seven previous cancer surgeries.

Yards of intestine are shunted aside. The bladder wall, infiltrated with tumor, is excavated and stitched closed.

Dr. Fanning's voice is intimately low as he talks to the surrounding doctors. Of the cancer crawling through Pat's bladder, he says, “This is something you don't normally see in ovarian cancer. We're keeping people alive six, seven years, and you're starting to see these weird things.''

He wields sharp knives, hot cutters, tools of shining stainless steel. Yards of white towel go into the yawning canyon of wound; rivers of pink towel come out again. A resident fills a bucket with salt water and dumps it into the opening. He does it again and again.

This is an industrial surgery. It's huge.

Finally, there is nowhere else to go. Dr. Fanning takes an electric cutting tool with a loop at the end. Gently he shaves it across the curve of tailbone. Tumor tissue comes away in parchment-thin curls, pink with blood.

Then, Dr. Fanning does what Pat so hoped he could avoid. He creates a colostomy, an intestinal opening through which her feces will flow into a bag. She's had a colostomy before. She hated its mess and smell.

And now, she has one again. She's asleep. She doesn't know yet. Before surgery began, Pat said, “I don't mind the surgery. I don't mind going to sleep. It's not knowing what I'll wake up to that I hate.''

Like that time, she says, when she awoke to a colostomy.

Cancer pioneers

Pat Krzeminski is one of a dozen people helping a Toronto company find a safe dose for what they hope is a life-saving cancer therapy.

The 50-year-old Petersburg, Mich, woman did her job well. Because of her efforts, which included allergic reactions and dozens of blood samples, Pat and her colleagues in cancer found the dose.

They were the pioneers. They tested the H11 antibody when no one knew how it would behave in humans. They kept using it when the U.S. Food and Drug Administration closed the trial to new patients due to safety concerns, and they were still using it when the federal agency reopened the trial to new patients in May.

The people who will participate in a Phase II trial that could start later this year at MCO will benefit from Pat's research. These will be breast cancer patients exclusively. They will alternate antibody treatment with chemotherapy, receiveing H11 three times a week.

Each of the Phase II patients will be healthier than Pat, Cissi Jackson, and the other Phase I participants. Each will seek a cure. But each will contribute most effectively to the health of future patients, the hundreds who could someday fill a Phase III trial.

Pat's secret

For all Pat's success in science, she failed her personal mission. She found no cure for herself. At the end of her second round of antibody therapy, her cancer was growing.

She hid the signs from herself. Maybe the constipation and abdominal discomfort didn't signify an intestinal blockage. Maybe the increased vaginal discharge had some source other than cancer.

When an exam confirmed her symptoms stemmed from a growth, she decided it was probably benign - not this time the malignant monster. Maybe for once it was just a sleepy lump, an exuberance of innocent cells, a small disobedience of biology.

Pat has a gift for weaving blue-sky predictions with nervous eruptions. She works to convince herself of her most optimistic pictures. She tries them out on friends.

“I am a nervous wreck,'' she confesses before surgery. She wonders at the size of the tumor.

“When it's blocking the end of your butt, it feels like a grapefruit,'' she says.

She keeps joking. Those around her feel her armor click into place, the wall go up, the impenetrable barrier of gags and anxiety.

After the surgery, she confesses. Although she could not hide her fretting, she was not about to express her fear. She could not let anyone in on her crying, on the days she collapsed when no one was home. That was not to share. She held it close, as though it were the real cancer, yet capable of infecting others, hers alone to deal with, to shield her family from, to hide from friends. No one saw the baffled despair she wrestled.

She was taking a bullet for us.

When cells won't die

If it were not lives at stake, if it were not families torn apart, if it were not all this pain, cancer could be a thing of beauty, a fascinating life form.

Its powers are amazing. Nothing else so illustrates the clout of genes, the muscle of evolution, the quest for genetic survival. Cancer defies laws all must obey. It invents escapes none imagined - including escaping the necessity of death.

Cancer starts as genetic mistakes accumulate, giving one cell an advantage over all others. Growth signals silent since the womb switch on. Brakes to inappropriate growth vanish. Mechanisms that repair genes go awry. The result is vigorous cancer.

The final tricks of the cancer genome provide it with eternal life.

Normal cells are disciplined. Armed with a sort of genetic cyanide, a cell will commit suicide if it perceives itself a danger to future generations. During each division, cells pause and inspect the newly created genome for errors. If errors are minor or infrequent, it repairs them. If errors are beyond fixing, the cell issues a death signal.

This suicide is not a regular kind of death; a dying that follows external events like trauma. In those accidental deaths, the cells fall apart; the contents scatter like plastic bags in the breeze. There is inflammation.

In programmed suicide, often called “apoptosis,” death is orderly. The cells break into packets of predetermined size. The cell does not disintegrate so much as repackage itself, wrapping bits of cell stuff into small membrane-enveloped parcels. Finally, the neighboring cells eat the tidy debris. There's no inflammation, no disturbance of surrounding tissue. It's as though the cell never lived.

A gene known as p53 is the star of the apoptosis story. P53 inspects gene replication, repairs mistakes, and gives the signal to die if mistakes are too numerous.

The presence of p53 is important in the treatment of cancer, since many chemotherapies and radiation treatments rely on an ability to damage DNA.

“If you zap a cell with radiation and fragment its DNA, or treat it with a standard chemotherapeutic drug, the way a cell would typically respond is to die,'' said Dr. William Maltese, chairman of MCO's biochemistry department.

It turns out, in more than half of all cancers, the apoptosis gene is deleted or damaged.

“So if you try to treat them with a chemotherapeutic agent, they resist it because the p53 gene you need to trigger the death cascade is missing,'' Dr. Maltese says.

The question before researchers is how to make cells suicidal again.

P53-mediated suicide is not the only cyanide tablet in the cell's medicine cabinet. Dr. Maltese studies another death method, a process called “autophagy'': self-eating.

In autophagy, the cell digests itself. Normally, this process serves starving cells. In order to get the amino acids it needs to survive, a famished cell begins digesting its own proteins by trapping them in little digestive compartments.

As the compartments grow, they capture all sorts of things inside, including tiny organelles crucial to cell life. In some cancers, dying cells fill with these digestive compartments and literally eat themselves to death.

While the implications of p53-directed cell death are well known in cancer, the role of autophagy is not as well understood. Research in this area made important progress a little more than a year ago when a protein called beclin was uncovered. Beclin appears to play a role in signaling a cell to eat itself.

Dr. Maltese's lab is one of only a handful in the world studying beclin and how it works.

“One thing we do know, is in a lot of breast cancers, (beclin) is deleted, and they don't respond (to treatment). But if you artificially put beclin into those same cancer cells, they will die by this autophagic process.''

Cells that have these genetic errors in their suicide program haven't quite found eternal life. But they're a lot closer.

A walking miracle

Cissi Jackson does not care about these details. She is too busy living.

“I can't believe it,'' she says. “I have to pinch myself. I could have been in a box, in a box underground.''

It's a few days before Pat Krzeminski's Sept. 7 surgery. Cissi is getting well. A medical supply company just stopped by her Pemberville, Ohio, home to take back their oxygen tank. Now she breathes on her own, night and day.

She's had 100 doses - five rounds - of H11, more of the experimental drug than any other patient.

Her tumors are gone. Only a dot of tumor remains on her neck. She seldom needs her pain medication. She feels like a walking miracle.

Now that all signs point upward, Cissi acknowledges she could have died. It's something she never seemed to know before.

When Cissi learned her daughter Heather wanted to marry in September, 2000, she made the four bridesmaids gowns and her daughter's wedding gown.

“I was overjoyed. My life was so full with all the things I had to do, I didn't even think of dying because I was so joyful. Even though I was probably physically, physically dying, I wasn't dying mentally or spiritually. I never let my spirit die.

“Physically, I knew something was happening, and probably the cancer was doing this, but mentally I wasn't going to let it happen. I just kept enjoying all the joys.''

It is not clear whether she will receive any more H11. The manufacturer, Viventia Biotech, is offering the drug to her free on a so-called compassionate basis, but MCO will not administer the drug to Cissi until the money is found to pay for the many costs associated with administering it.

And it is not clear whether Cissi's Medicaid will pick up the bill if the experimental care continues, says Sarah Lyons, trial coordinator for MCO's Cancer Institute. That's no small amount - about $300 per treatment.

And, despite all positive appearances, Dr. Mohamed will not declare Cissi cured.

“I'm excited, but it's still coupled with caution,'' Dr. Mohamed says. “We caught Cissi quite late in the course of the disease. I don't want you to think we have cured her. I don't think we've cured this woman. She's still Stage 4 disease.''' Stage 4 indicates a cancer that's metastasized to distant sites.

“The staging is the stage of a person at the time of diagnosis,'' Dr. Mohamed says. “This is what determines prognosis. She is Stage 4, with no evidence of disease, but she is still Stage 4 because, you know, it has to come back.

“If it comes back, we will need to think of something even more aggressive because every time it comes back, what comes back is a stronger cell.''

'I can't stand this'

Pat Krzeminski is miserable.

“I don't know what it feels like to not feel uncomfortable,'' Pat says. Her surgery was three weeks ago. Little has gone right since then.

“I just sit and I watch the kids and Ed, and I think, `Wouldn't it be nice to lay on the floor? Wouldn't it be nice to get up and go to the bathroom by myself?' How can they stand to get in the car and go to work? Then I think, `I was like that a month ago.'''

“I would love to get up in the morning and say, `Yes, I'm going to go do dishes. I'm going to go do laundry, and I'm going to go get groceries.'''

There was a hole between her bladder and rectum after surgery. Now, in addition to the colostomy, she has a catheter to drain urine from her bladder.

She contracted a pseudomonas infection. It meant daily trips to MCO for intravenous antibiotic treatment. By the end of that week of treatment, she felt worse.

“When I came home Friday night, my right kidney hurt so bad, I couldn't move. I really hurt bad. I went to the doctor on Monday and told him my kidney is just killing me. This time, they found a staphylococcus infection.''

It was a terrifying few weeks.

In her lowest moments she found herself thinking, “You know what, I'm really going to miss my kids. I don't want to leave them, but I can't stand this.

“But it doesn't last long before you're going, `Oh no. Oh no.' When you're that sick, you really want to fight for your life, and you don't want to die.

“This infection scared the hell out of me. More than anything else.''

The H11 trial wraps up in late fall. Of the 12 patients, only Cissi Jackson saw real improvement. Seven patients died from their cancer. Four saw little or no benefit and returned to standard treatments, including Pat Krzeminski.

Pat's race against disease is as close as it has ever been.

While she finds strength for each round of trouble as it occurs, cancer also finds strength in its continuing evolution.

Eternal life

Some time in the biography of a cancer cell, it earns a ticket to eternal life. Now, instead of being merely unable to commit suicide, the cell charges forward, multiplying endlessly.

Normally, even cells that cannot commit suicide must quit dividing after 50 splits or so. They wear out.

It's an engineering problem, says Dr. Kurt Runge, a microbiologist at the Cleveland Clinic Lerner Institute. Each time a cell divides, it misses a chunk of DNA at the ends of each chromosome. Each division chews up a little more of this frayed end of DNA, called the telomere. Telomere erosion harms nothing. Its role is to fray. But when it's gone, subsequent division would miss crucial genetic material.

“Telomere shortening activates a checkpoint to tell the cell to stop growing,'' Dr. Runge said.

Only a few types of cells don't face this fate of limited dividing power. Bacterial cells can divide infinitely, as can our lymphocytes. In these ever-dividing cells, there's a gene turned on that keeps adding onto the telomeres. That gene produces an enzyme called telomerase.

In cancer, mutations that turn on telomerase production create the necessary solution for eternal life. Once telomerase flips on, cells can divide forever.

Or until they kill the host.

If humans had the persistence of cancer, we'd chisel statues to them. Such creative determination is the stuff of heroes. Few of us measure up to the indomitable development of cells run amok.

The cruel irony is, cancer requires people of such resolution.

One of Pat Krzeminski's neighbors, a student in Ida Public Schools, was assigned to write a paper about her American hero. She chose Pat.

“She is always climbing those stairs of life,'' Laura Steele wrote. “She never sits down and rests. She's always jumping over those hurdles, and when she trips and falls, she gets back up.''

Feels so good

After weeks of treatment - first surgery, then intensive care, then two painful and life-threatening antibiotic infections - Pat Krzeminski is on her feet again by the end of October.

She puts her catheter bag in a big purse and does her own grocery shopping. Since gravity is required for proper bladder drainage, every once in awhile, she slips into a less busy grocery aisle, drops the bag to the floor, and lets her bladder empty.

She's no longer sleeping until 11 a.m.

“I'm up at 9. I see the light again,'' she says.

A few weeks ago, she was trying to talk herself into raking leaves. She spent all day planning to hang clothes on the line, not certain she had the strength for a walk into the backyard.

Then, suddenly, the energy came back. She was home by herself one day when the urge to clean overwhelmed her.

“I actually got on my hands and knees, and tucked my bag into the back of my pants, and scrubbed my floor.

“My heart was beating, and I thought, `Oh! That feels so good!

“No one was home, and a song came on the radio that I liked, and I stood up and danced. And I ran around the kitchen and down the hall two or three times.''

Now that she was moving, she couldn't stop.

“Oh, this feels so good,'' she thought. “Then I'd dance some more. Then I did some stand-up exercises. It was a good feeling. It was such a good feeling, and I thought, yes! Yes!''

“I told Ed just the other day, I would do it all again. After all I've been through, I'm still alive. I like being alive. You really have to enjoy life to suffer,'' she says.

“Besides,'' she says, her eyes wide, her smile spreading, “I will get better. You just have to think, there are miracles.''


Cissi Jackson's cancer was creeping back just before publication. Sarah Lyons, MCO Cancer Institute trial coordinator, continues to search for someone to pay for Cissi's continued treatment with H11. Cissi's husband, Dave, wonders, “Is Cissi dying because they're not going to treat her?''

In the meantime, Cissi started taking a new chemotherapy drug.

Pat Krzeminski went back on chemotheropy in December. Just before publication of this story, her cancer was back under control. She had a CA-125 of 16. Anything under 35 is considered remission. Also, for the first time in six years, she celebrated Christmas with a full head of hair.

Viventia President Anthony Schincariol said the company believes it has now identified the H11 antigen, which brings it closer to understanding how the antibody works.

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