Cells of the future: making living tissue from dead bodies.


At the Pasteur Institute in Paris, a scientist opens a standard kitchen refrigerator and pulls out a clear plastic vial filled with cherry-colored liquid. A small, soft, fleshy lump sits on the bottom. It is a piece of muscle, taken from a deceased 44-year-old Frenchman. The laboratory will use its stem cells to grow a brand new strip of living muscle in the hopes that — one day — post-mortem stem cells can provide sick or injured people with a whole new source of body parts.

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The near-miraculous properties of stem cells have intrigued medical researchers for years. With their ability to divide repeatedly and fabricate other cells, they are ideal for reconstructing or repairing tissue. Embryonic stem cells can give rise to any organ, while most adult stem cells are limited to their own origin — neural stem cells make neurons, those from the skin form skin, and so on. Adult stem cells are constantly regenerating our blood and skin, and they also mend tissue that has been damaged by injury or disease.

Now a group of French researchers from the Pasteur Institute have discovered another awe-inspiring property: stem cells can survive without oxygen. This means that even when the body is dead, the stem cells continue living, in a state of reduced metabolism.

The team was led by Dr. Fabrice Chrétien, a histologist and neuropathologist who made a curious observation about five years ago while performing autopsies. Even after a corpse’s muscle tissue had started to atrophy, he saw healthy-looking cells that resembled stem cells, with a normal nucleus and intact DNA. One day he ran a test on the corpse of a young adult, taking a muscle tissue biopsy and putting it into a container with culture. His suspicions were confirmed when the stem cells started to multiply. “Honestly, I was a little shocked,” he recalled. “Shocked because I had done a biopsy on an individual who had been dead for four days, and in the box of culture the cells proliferated, becoming more numerous every day. They were alive — and yet the person was undeniably dead. It makes you think twice about the definition of death.”

In a living person, certain stem cells spend long periods of time in a quiescent state, not doing much of anything until they are activated due to stress, disease or injury. This quiescence permits them to survive and maintain their potency even under hostile conditions, whether radiation treatment for cancer or a workout at the gym. Once the onslaught has passed, they reawaken and multiply to repair the injured body part.

What Chrétien’s team discovered is that they can resist anoxia, or total oxygen deprivation. He explained that inside all our cells we have little organs called mitochondria that convert oxygen into energy. When there is no oxygen, the mitochondria produce toxins that destroy the cells. “We were stupefied to see that when we removed oxygen from the environment, stem cells got rid of their mitochondria,” he said. “As a result, their DNA was not damaged.” The stem cells stopped breathing and went into a dormant state.

The Pasteur team has tested human muscle from the arm, leg and abdomen, as well as bone marrow from mice. They only work with adult stem cells. (Aside from the controversy of sacrificing embryos for research or medical purposes, Chrétien said that fetal cells that proliferate endlessly can lead to cancer.) They’ve procured viable stem cells from human bodies up to 17 days after death — the oldest corpses they have access to — and from mice up to 14 days post-mortem.

On a recent spring day, Chrétien’s colleague, Dr. Pierre Rocheteau, walked me around the lab in a new building on the campus of the venerable Pasteur Institute. He explained that the piece of muscle tissue I saw would be “digested” by enzymes, then put through a machine that discards everything but the dormant stem cells. These would go into a plastic box with culture (glucose, serum and the like) at 37 degrees Celsius, and after three weeks, a thin, whitish layer of muscle would cover the bottom of the box.

I peered into a microscope at a sample after two weeks in culture and saw a number of little spots, all different shapes and sizes. Each stem cell had a black dot of DNA in the center. Rocheteau said they were moving a lot, but the motion was not visible to the naked eye. Then he showed me a time-lapse video of post-mortem stem cells zipping around erratically, stretching out until they split in two, multiplying exponentially, colliding and fusing. Another video displayed the final result, a strip of gently throbbing muscle.

Pasteur Institute policy forbids journalists from seeing the lab mice, but Chrétien told me the team has performed several transplants, injecting bone marrow from a 4-day-old mouse corpse into living specimens that had been irradiated to destroy their own marrow. “It worked magnificently,” he said. “All the mice survived.” This augurs well for his belief that one day human corpses can provide an additional source of stem cells for medical purposes, such as repairing muscle withered by muscular dystrophy or transplanting bone marrow for leukemia patients. He said that corpses can also be a useful source of stem cells for molecular screening in the pharmacological industry.

Is corpse harvesting necessary?

After meeting with Chrétien, I spoke with Dr. Vijay Gorantla, an associate professor of surgery at the University of Pittsburgh, who has been studying the possibilities of using cadaveric bone marrow to improve hand and face transplants. There is an important linguistic difference here — Gorantla procures his marrow from brain-dead “cadavers” whose hearts are still beating, as opposed to “corpses” who are dead in every sense of the term. His team’s research involves retrieving vertebral bone marrow at the same time as a donated body part and injecting it into a transplant recipient. The idea is to trick the body into accepting the hand and its foreign DNA without needing a lifetime of immunosuppressive drugs.

In the course of these experiments, he, too, was struck by the resiliency of stem cells. A colleague, Dr. Albert Donnenberg, developed a protocol for sterilizing pieces of vertebral bone with bleach or hydrogen peroxide. Despite the harshness of this chemical treatment, the stem cells maintained their counts and viability. Not only that, he found he could hold the vertebral bodies on ice for up to 72 hours before extracting the stem cells, and they were still just fine. “There’s something in them that prevents them from dying or offers them this capacity to survive,” Gorantla said. He was intrigued by Chrétien’s findings, and imagined that one day, after further screening for infection, there could be a worldwide registry connecting patients with deceased bone marrow donors.

Other people I spoke with were more skeptical about the utility of corpses for bone marrow transplants. Dr. Willis Navarro, medical director of transplant services for the National Marrow Donor Program in Minneapolis, said that source is not a major issue. The chance of an American patient finding a living match who is willing and able to donate bone marrow is 66 to 93 percent, and umbilical cords from newborn babies can also be harvested for embryonic-like stem cells.

Chrétien believes this still isn’t enough. He said an adult patient generally needs more than one umbilical cord. And in many parts of the world — including the United States but not France, where it’s illegal –parents can privately bank their own offspring’s cord blood in case the child needs it later, making it unavailable to the general public.

In any case, much research remains to be done regarding sterility before any human receives injections of post-mortem cells. The slightest risk of infection from bacteria in a corpse would prove fatal for a leukemia patient with a destroyed immune system. Chrétien estimates it will take at least five more years of study before corpses can be viable sources. “And you shouldn’t really wait 17 days post-mortem. We did that to prove it could be done, but it’s but not ideal. I think within 48 hours after death you can have a good quantity of very effective stem cells without any problems of sterility.”

Maintaining cells’ “stem-ness”

In the meantime, his team’s discovery also offers better ways to isolate and store stem cells. Storage can be problematic because as soon as stem cells are dissociated from tissue they start to proliferate like mad, eventually exhausting their capacity to multiply, or their “stem-ness.” But when they are deprived of oxygen and kept at 4 degrees Celsius, they hibernate for up to a month. This dormancy is reversible: the cells awaken and resume their normal activity after being put in culture or transplanted into a living body.

Currently, Chrétien’s team is studying the possible repercussions of their discovery on cancer treatments that consist of cutting off a tumor’s blood supply and starving it of oxygen. He said it would be catastrophic if cancer stem cells didn’t die with the rest of the tumor but instead went to sleep, only to wake up later and make new tumors. “We don’t want an upsurge of metastasis in a few years,” he explained. Though the research is in its early stages, he has found that cancer stem cells are in fact sensitive to oxygen deprivation in vitro. However, he cannot say if that is the case inside an actual person.

Indeed, it seems that not all of the body’s stem cells react the same way to different aggressors. Researchers at the McKnight Brain Institute in Gainesville, Fla., led a collaboration with investigators at the Kennedy Space Center, looking at the effects of cosmic rays on the brain. Surprisingly, they found that quiescent stem cells in the brain are extremely sensitive to cosmic radiation — a simulated mission to Mars showed up to 65 percent of them at risk of dying. According to Dr. Dennis Steindler, who directed the McKnight Brain Institute (and the study), this result contradicts the assumption that cancer tumors return after chemotherapy or radiotherapy because quiescence protects their stem cells.

Steindler said that understanding the metabolic requirements of different kinds of stem cells and how they behave under stress will provide scientists with valuable insight “extremely relevant to cancer research.” This knowledge can shine a light on other diseases, too. As Chrétien noted, “We are starting to see that the quantity of oxygen varies widely in different tissues of the body, and it’s not just chance — it plays a very particular role in cell fate.”

Stem cell research heralds a revolution in medical care. Cellular therapy can turn doctors into engineers of the human body, reconstructing tissue or building new organs without surgery. The fact that some stem cells have superhuman qualities makes the range of possibilities even larger. It is true that stem cells play a small role in practical medicine today. But, Chrétien predicted, “they will be enormously important tomorrow.”

Source: Smart Planet

 

 

Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis.


Abstract

Objective To determine whether antibiotic prophylaxis at the time of removal of a urinary catheter reduces the risk of subsequent symptomatic urinary tract infection.

Design Systematic review and meta-analysis of studies published before November 2012 identified through PubMed, Embase, Scopus, and the Cochrane Library; conference abstracts for 2006-12 were also reviewed.

Inclusion criteria Studies were included if they examined antibiotic prophylaxis administered to prevent symptomatic urinary tract infection after removal of a short term (≤14 days) urinary catheter.

Results Seven controlled studies had symptomatic urinary tract infection after catheter removal as an endpoint; six were randomized controlled trials (five published; one in abstract form) and one was a non-randomized controlled intervention study. Five of these seven studies were in surgical patients. Studies were heterogeneous in the type and duration of antimicrobial prophylaxis and the period of observation. Overall, antibiotic prophylaxis was associated with benefit to the patient, with an absolute reduction in risk of urinary tract infection of 5.8% between intervention and control groups. The risk ratio was 0.45 (95% confidence interval 0.28 to 0.72). The number needed to treat to prevent one urinary tract infection was 17 (12 to 30).

Conclusions Patients admitted to hospital who undergo short term urinary catheterization might benefit from antimicrobial prophylaxis when the catheter is removed as they experience fewer subsequent urinary tract infections. Potential disadvantages of more widespread antimicrobial prophylaxis (side effects and cost of antibiotics, development of antimicrobial resistance) might be mitigated by the identification of which patients are most likely to benefit from this approach.

Discussion

In our meta-analysis of pooled data from seven studies (six of which were randomized), there were significantly fewer symptomatic urinary tract infections in patients receiving prophylaxis during removal of a urinary catheter than in those not receiving prophylaxis. Our finding in favor of antibiotic prophylaxis, however, must be tempered by possible publication bias toward positive studies, the limitations of the included studies, and practical considerations about encouraging more widespread antibiotic use.

Indwelling urinary catheters pose several risks to patients, including urethral trauma, discomfort, and urinary tract infection.31 In an era of increasingly constrained fiscal resources and evolving antibiotic resistance, evidence based antimicrobial prescribing is essential to promote antimicrobial stewardship.32 Unfortunately, there is no consensus on whether clinicians should prescribe antibiotic prophylaxis to patients when an indwelling urinary catheter is removed.

Conclusions

This meta-analysis of available data indicates an overall benefit of antibiotic prophylaxis at the time of removal of a urinary catheter to prevent subsequent urinary tract infections. The number needed to treat indicates that 17 patients would need to receive prophylaxis to prevent one symptomatic urinary tract infection. We know little, however, about the potential negative consequences of implementing antibiotic prophylaxis in this setting in a wider frame or indeed which types of patients would be most likely to benefit. Increasing antimicrobial resistance, healthcare costs for antibiotics, and the potential for side effects of antibiotic administration are disadvantages that merit careful review. From a public health standpoint, we should be careful not to encourage antibiotic use when it might not be necessary. The healthcare provider of a catheterized patient, however, might consider antibiotic prophylaxis before catheter removal, after taking individual risk factors into account. Future studies should better characterize who is at risk of developing symptomatic urinary tract infection after catheter removal (whether bacteriuric or not) and then examine antibiotic prophylaxis in those at greatest risk.

What is already known on this topic

  • Catheterization of the urinary tract is associated with an increased risk of bacteriuria and symptomatic urinary tract infection
  • Antibiotic administration at the time of removal of a urinary catheter might effectively reduce urinary tract infections, but guidelines for catheter associated infections note insufficient evidence to support this practice
  • Antibiotic prophylaxis at the time of urinary catheter removal in general surgery, prostatectomy, and medical patients effectively reduced the incidence of symptomatic urinary tract infections with a number needed to treat of 17
  • The effect size of antibiotic prophylaxis in this meta-analysis was stable to sensitivity analyses with exclusion of non-randomized trials and two studies in non-surgical patients

What this study adds.

 

Source: BMJ

 

 

e wind: �x �� �� -border-alt:none windowtext 0in; padding:0in’>12 1314 16 Although other studies have examined the links between acute kidney injury and mortality and end stage renal disease in people admitted to hospital with myocardial infarction treated with either invasive or medical management,18 33 these studies have not compared renal outcomes on the basis of treatment strategies.

 

Our findings show that acute kidney injury is a relatively common complication in people with non-ST elevation acute coronary syndrome and chronic kidney disease and increases substantially with lower baseline estimated glomerular filtration rate. However, the difference in the incidence of acute kidney injury between people who receive early invasive management and similar patients treated conservatively is relatively small. Importantly, despite the modestly higher risk of acute kidney injury associated with early invasive management at all levels of estimated glomerular filtration rate, our findings suggest that this strategy is not associated with higher risks of more clinically relevant renal outcomes (including acute dialysis or progression to end stage renal disease), which occurred much less often at all levels of baseline estimated glomerular filtration rate, regardless of treatment strategy. Since early invasive management seemed to be consistently associated with a long term survival advantage at all levels of baseline estimated glomerular filtration rate, these findings (interpreted in light of their consistency with results from randomised trials showing that early invasive management improves long term survival in high risk patients3 4) suggest that restricting or delaying access to invasive coronary procedures may not avoid most cases of clinically relevant acute kidney injury and could deny high risk individuals (including those with pre-existing chronic kidney disease) important benefits.

There are several potential mechanisms for the higher risk of acute kidney injury associated with early invasive management. People who received early invasive management were more likely to receive coronary angiography, percutaneous coronary intervention, coronary artery bypass grafting surgery, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, placing them at risk of acute kidney injury from contrast exposure, perioperative ischaemia, and haemodynamic effects. Furthermore, patients who received invasive management had a longer hospital stay and more measurements of creatinine during follow-up, which may have increased the probability that acute kidney injury would be ascertained. However, the magnitude of the increased risk associated with invasive management strategies was small, suggesting that patients’ characteristics such as age, comorbidity, pre-existing chronic kidney disease, drug use (including diuretics and inhibitors of the renin angiotensin system), and haemodynamic instability are more important contributors to the risk of acute kidney injury in patients with acute coronary syndrome than whether or not they are managed invasively or medically.

The better survival associated with early invasive management of non-ST elevation acute coronary syndrome in this cohort are in keeping with the clinical benefits of angiography and revascularisation reported in clinical trials, including subgroups with pre-existing chronic kidney disease.2 3 4 Although episodes of acute kidney injury have been linked to an increased risk of end stage renal disease,18 19 34 we did not observe a higher risk of end stage renal disease in people with otherwise similar characteristics who received early angiography despite the higher risk of acute kidney injury, even among strata with lower baseline estimated glomerular filtration rate. Radiocontrast associated acute kidney injury is typically manifested by a small change in serum creatinine levels, rarely leads to acute dialysis, and is usually reversible.10 Our findings suggest that the majority of such additional episodes of acute kidney injury associated with invasive procedures may confer relatively low risks of progression to end stage renal disease, although further studies are needed to help predict those at risk of progressive chronic kidney disease after acute kidney injury.

Conclusion

In conclusion, early invasive management of non-ST elevation acute coronary syndrome is associated with a small increase in the risk of acute kidney injury compared with a conservative management approach but is not associated with higher risks of in-hospital acute kidney injury requiring dialysis or long term risk of end stage renal disease. Given the improvement in cardiovascular outcomes and long term survival observed with early invasive management, these results suggest that invasive treatments should not be withheld solely because of concern they might increase the risk of kidney injury.

What is already known on this topic

  • Acute kidney injury after invasive coronary procedures is associated with adverse outcomes, including end stage renal disease and death
  • Fear of precipitating contrast induced acute kidney injury possibly contributes to underuse of invasive treatments for acute coronary syndrome in people at high risk of kidney disease
  • Comparisons of renal outcomes between people treated with invasive versus conservative management are lacking
  • People who received early invasive management for non-ST segment elevation acute coronary syndrome were modestly more likely to develop acute kidney injury
  • After early invasive management the risks of requiring dialysis and long term risk of end stage renal disease were similar, and patients had better long term survival than those treated conservatively
  • These findings were consistent across varying levels of baseline kidney function, suggesting similar relative risks and benefits of early invasive management in people with and without pre-existing kidney disease

What this study adds

 

Source: BMJ

 

Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study.


Abstract

Objective To assess the association between 5α-reductase inhibitor (5-ARI) use in men with lower urinary tract symptoms and prostate cancer risk.

Design Nationwide, population based case-control study for men diagnosed with prostate cancer in 2007-09 within the Prostate Cancer data Base Sweden 2.0.

Setting The National Prostate Cancer Register, National Patient Register, census, and Prescribed Drug Register in Sweden, from which we obtained data on 5-ARI use before date of prostate cancer diagnosis.

Participants 26 735 cases and 133 671 matched controls; five controls per case were randomly selected from matched men in the background population. 7815 men (1499 cases and 6316 controls) had been exposed to 5-ARI. 412 men had been exposed to 5-ARI before the diagnosis of a cancer with Gleason score 8-10.

Main outcome measures Risk of prostate cancer calculated as odds ratios and 95% confidence intervals by conditional logistic regression analyses.

Results Risk of prostate cancer overall decreased with an increasing duration of exposure; men on 5-ARI treatment for more than three years had an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89; P<0.001 for trend). The same pattern was seen for cancers with Gleason scores 2-6 and score 7 (both P<0.001 for trend). By contrast, the risk of tumours with Gleason scores 8-10 did not decrease with increasing exposure time to 5-ARI (for 0-1 year of exposure, odds ratio 0.96 (95% confidence interval 0.83 to 1.11); for 1-2 years, 1.07 (0.88 to 1.31); for 2-3 years, 0.96 (0.72 to 1.27); for >3 years, 1.23 (0.90 to 1.68); P=0.46 for trend).

Conclusions Men treated with 5-ARI for lower urinary tract symptoms had a decreased risk of cancer with Gleason scores 2-7, and showed no evidence of an increased risk of cancer with Gleason scores 8-10 after up to four years’ treatment.

Introduction

Chemoprevention by use of 5α-reductase inhibitors (5-ARI) to decrease risk of prostate cancer has been investigated in two large randomised clinical trials. Both these trials showed a decreased risk of prostate cancer overall in men on 5-ARI—finasteride in the Prostate Cancer Prevention trial (PCPT) and dutasteride in Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.1 2 These 5-ARIs inhibit the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate, and thereby decrease androgen receptor activity.3 There was a 23-25% reduction in risk of prostate cancer at biopsy for men receiving 5-ARI, compared with men receiving placebo, in both trials. However, in both trials, there was also an increased risk of cancer with Gleason scores 8-10. Based on these findings, The US Food and Drug Administration (FDA) issued a safety announcement in 2011, stating that “5 alpha reductase inhibitors may increase the risk of a more serious form of prostate cancer.”4

The reason for the observed increase in risk in these trials has not been conclusively elucidated, with different explanations for these associations put forward.5 6 7 8 910 11 One theory is that the increase is real and that 5-ARI promotes prostate cancer with Gleason scores 8-10, possibly mediated through lower concentrations of 3β-Adiol and resulting in a decreased stimulation of the oestrogen β receptor.12 Another theory is that the association is spurious and caused by detection bias, because 5-ARI facilitates the detection of small foci of tumours with Gleason scores 8-10.4 To what degree these Gleason 8-10 cancers are associated with progression and prostate cancer death has not been studied. However, because 5-ARIs are widely used in men with lower urinary tract symptoms due to benign prostatic hyperplasia, there is a need to further elucidate the association between 5-ARI use and high grade prostate cancer.

The aim of this study was to investigate the association between the use of 5-ARI for treating lower urinary tract symptoms due to prostatic enlargement in a clinical setting and prostate cancer risk, in particular cancer with Gleason scores 8-10.

Source: BMJ

Renal outcomes associated with invasive versus conservative management of acute coronary syndrome: propensity matched cohort study.


Abstract

Objectives To examine the association of early invasive management of acute coronary syndrome with adverse renal outcomes and survival, and to determine whether the risks or benefits of early invasive management differ in people with pre-existing chronic kidney disease.

Design Propensity score matched cohort study.

Setting Acute care hospitals in Alberta, Canada, 2004-09.

Participants 10 516 adults with non-ST elevation acute coronary syndrome.

Interventions Participants were stratified by baseline estimated glomerular filtration rate and matched 1:1 on their propensity score for early invasive management (coronary catheterisation within two days of hospital admission).

Main outcome measures Risks of acute kidney injury, kidney injury requiring dialysis, progression to end stage renal disease, and all cause mortality were compared between those who received early invasive treatment versus conservative treatment.

Results Of 10 516 included participants, 4276 (40.7%) received early invasive management. After using propensity score methods to assemble a matched cohort of conservative management participants with characteristics similar to those who received early invasive management (n=6768), early invasive management was associated with an increased risk of acute kidney injury (10.3% v 8.7%, risk ratio 1.18, 95% confidence interval 1.03 to 1.36; P=0.019), but no difference in the risk of acute kidney injury requiring dialysis (0.4% v 0.3%, 1.20, 0.52 to 2.78; P=0.670). Over a median follow-up of 2.5 years, the risk of progression to end stage renal disease did not differ between the groups (0.3 v 0.4 events per 100 person years, hazard ratio 0.91, 95% confidence interval 0.55 to 1.49; P=0.712); however, early invasive management was associated with reduced long term mortality (2.4 v 3.4 events per 100 person years, 0.69, 0.58 to 0.82; P<0.001). These associations were consistent among people with pre-existing reduced estimated glomerular filtration rate and with alternate definitions for early invasive management.

Conclusions Compared with conservative management, early invasive management of acute coronary syndrome is associated with a small increase in risk of acute kidney injury but not dialysis or long term progression to end stage renal disease.

Discussion

In this cohort study, compared with people managed conservatively, people with otherwise similar characteristics who received early invasive management for non-ST segment elevation acute coronary syndrome were modestly more likely to develop acute kidney injury during admission to hospital. Despite this finding, early invasive management was not associated with a significant increase in short term risk of acute kidney injury requiring dialysis, or long term risk of end stage renal disease, but was associated with better long term survival. Similar findings were observed when people who received invasive procedures at any time during admission to hospital were compared with those managed medically, and when those who received coronary revascularisation were compared with those who received medical management alone. Although patients with lower estimated glomerular filtration rate at admission were less likely to receive invasive management and were at higher risk of adverse outcomes, the associations between invasive management and clinical outcomes remained consistent across varying levels of baseline estimated glomerular filtration rate. These finds suggest that the additional short term risks of acute kidney injury associated with invasive coronary procedures are fairly small and, when considered alongside other clinical outcomes, should not act as a deterrent to their use.

Data on the risk of adverse renal events from randomised trials of early invasive versus conservative treatment for acute coronary syndrome are limited, in part due to the exclusion of patients with moderate to severe renal insufficiency from trials. Among people with baseline serum creatinine concentrations <1.7 mg/dL (150 μmol/L) enrolled in the Fast Revascularization during InStability in Coronay artery disease (FRISC) trial, estimated glomerular filtration rate declined similarly in the early invasive and conservative management arms; however, the incidence of acute kidney injury, acute dialysis, and end stage renal disease was not reported.32 Several previous observational studies have shown a high incidence of acute kidney injury after coronary angiography and percutaneous coronary intervention in people with chronic kidney disease,10 11 and strong associations between acute kidney injury and death, major adverse cardiovascular events, and kidney failure requiring dialysis in this setting.12 1314 16 Although other studies have examined the links between acute kidney injury and mortality and end stage renal disease in people admitted to hospital with myocardial infarction treated with either invasive or medical management,18 33 these studies have not compared renal outcomes on the basis of treatment strategies.

Our findings show that acute kidney injury is a relatively common complication in people with non-ST elevation acute coronary syndrome and chronic kidney disease and increases substantially with lower baseline estimated glomerular filtration rate. However, the difference in the incidence of acute kidney injury between people who receive early invasive management and similar patients treated conservatively is relatively small. Importantly, despite the modestly higher risk of acute kidney injury associated with early invasive management at all levels of estimated glomerular filtration rate, our findings suggest that this strategy is not associated with higher risks of more clinically relevant renal outcomes (including acute dialysis or progression to end stage renal disease), which occurred much less often at all levels of baseline estimated glomerular filtration rate, regardless of treatment strategy. Since early invasive management seemed to be consistently associated with a long term survival advantage at all levels of baseline estimated glomerular filtration rate, these findings (interpreted in light of their consistency with results from randomised trials showing that early invasive management improves long term survival in high risk patients3 4) suggest that restricting or delaying access to invasive coronary procedures may not avoid most cases of clinically relevant acute kidney injury and could deny high risk individuals (including those with pre-existing chronic kidney disease) important benefits.

There are several potential mechanisms for the higher risk of acute kidney injury associated with early invasive management. People who received early invasive management were more likely to receive coronary angiography, percutaneous coronary intervention, coronary artery bypass grafting surgery, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, placing them at risk of acute kidney injury from contrast exposure, perioperative ischaemia, and haemodynamic effects. Furthermore, patients who received invasive management had a longer hospital stay and more measurements of creatinine during follow-up, which may have increased the probability that acute kidney injury would be ascertained. However, the magnitude of the increased risk associated with invasive management strategies was small, suggesting that patients’ characteristics such as age, comorbidity, pre-existing chronic kidney disease, drug use (including diuretics and inhibitors of the renin angiotensin system), and haemodynamic instability are more important contributors to the risk of acute kidney injury in patients with acute coronary syndrome than whether or not they are managed invasively or medically.

The better survival associated with early invasive management of non-ST elevation acute coronary syndrome in this cohort are in keeping with the clinical benefits of angiography and revascularisation reported in clinical trials, including subgroups with pre-existing chronic kidney disease.2 3 4 Although episodes of acute kidney injury have been linked to an increased risk of end stage renal disease,18 19 34 we did not observe a higher risk of end stage renal disease in people with otherwise similar characteristics who received early angiography despite the higher risk of acute kidney injury, even among strata with lower baseline estimated glomerular filtration rate. Radiocontrast associated acute kidney injury is typically manifested by a small change in serum creatinine levels, rarely leads to acute dialysis, and is usually reversible.10 Our findings suggest that the majority of such additional episodes of acute kidney injury associated with invasive procedures may confer relatively low risks of progression to end stage renal disease, although further studies are needed to help predict those at risk of progressive chronic kidney disease after acute kidney injury.

Conclusion

In conclusion, early invasive management of non-ST elevation acute coronary syndrome is associated with a small increase in the risk of acute kidney injury compared with a conservative management approach but is not associated with higher risks of in-hospital acute kidney injury requiring dialysis or long term risk of end stage renal disease. Given the improvement in cardiovascular outcomes and long term survival observed with early invasive management, these results suggest that invasive treatments should not be withheld solely because of concern they might increase the risk of kidney injury.

What is already known on this topic

  • Acute kidney injury after invasive coronary procedures is associated with adverse outcomes, including end stage renal disease and death
  • Fear of precipitating contrast induced acute kidney injury possibly contributes to underuse of invasive treatments for acute coronary syndrome in people at high risk of kidney disease
  • Comparisons of renal outcomes between people treated with invasive versus conservative management are lacking
  • People who received early invasive management for non-ST segment elevation acute coronary syndrome were modestly more likely to develop acute kidney injury
  • After early invasive management the risks of requiring dialysis and long term risk of end stage renal disease were similar, and patients had better long term survival than those treated conservatively
  • These findings were consistent across varying levels of baseline kidney function, suggesting similar relative risks and benefits of early invasive management in people with and without pre-existing kidney disease

What this study adds

 

Source: BMJ

 

New study to give insight into public health risks of ESBL E. coli..


 

New project investigates public health risks of ESBL E.Coli to develop intervention plans to reduce infections caused by these bacteria.

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A new study by Public Health England (PHE) and funded by the Department of Health will, for the first time, establish the most significant reservoirs of a strain of antibiotic resistant bacteria known as ESBL-positive E. coli that cause human illness in the UK.

Its findings will help to develop intervention strategies in efforts to reduce the numbers of infections such as urinary tract infections or blood poisoning, caused by these bacteria.

The research is being led by PHE with key collaborators from the Animal Health and Veterinary Laboratories Agency, The University of Cardiff, The University of East Anglia, The University of Glasgow, Queen Mary University of London, and Health Protection Scotland.

The study will look at sewage, farm slurry and raw meat to determine whether there are any potential risks to human health in a number of different reservoirs of these bacteria. It will also look at stool samples from patients who have no symptoms of illness (asymptomatic carriage) to see whether the bacteria is in their gut (colonisation).

E. coli is a bacterium that lives in the guts of humans and many other animals. Colonisation of the gut by E. coli is perfectly normal and is harmless, although some other types cause diarrhoea. However, E. coli is also the commonest cause of urinary tract and bloodstream infections, which usually require antibiotic treatment.

Not all types of ESBL-positive E. coli bacteria cause human disease, and the contribution to human disease made by resistant strains from animals, meat and environmental sources is not well understood.

Resistant strains of E. coli are an increasing problem, reducing the number of antibiotics that a doctor can use for treatment. Many of the resistant strains produce enzymes called ESBLs (Extended-Spectrum Beta-Lactamases), which make them resistant to most penicillin-like antibiotics. E. coli with ESBLs can also be found in food animals, raw retail meat, sewage and river water, but whether these reservoirs pose any public health risk is poorly understood.

Professor Neil Woodford, Head of the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit at PHE, said:

The risks posed to human health by resistant E. coli from non-human reservoirs are not fully understood. This study will help to disentangle this complex interrelationship.

Treatment of infections caused by resistant E. coli can be difficult, which is why we need to understand the risks better. Having said that, we want to reassure the public that presence of these bacteria in the gut does not require antibiotic treatment and is usually temporary. Most colonized people never develop an infection caused by the resistant strain.

This study is very important because its results will help to shape future intervention strategies to reduce the spread of these antibiotic-resistant strains of bacteria and to reduce the numbers of infections that they cause.

Notes to editors

  1. The amount of the funding from the Department of Health is £500,000 and the study is spread over three years. The study will cover different elements.
  2. The first piece of research will look for ESBL-positive E. coli in 20-25,000 stool samples collected in five different geographical areas (London, East Anglia, North West, Scotland and Wales), which will determine rates of harmless gut carriage.
  3. Secondly, sewage samples will be collected from various sites throughout each of the five regions and numbers of ESBL-positive E. coli will be measured in each sample.
  4. Our third study will seek ESBL-positive E. coli in samples of farm slurry and from retail raw meats collected in each geographical region.
  5. In the final part of the study, the ESBL-positive E. coli collected from the different sample types and in each region will be compared with those isolated from bloodstream infections to determine whether there are any genetic similarities between the resistant strains from sewage, animals, retail raw meat, and those isolated from human faeces and blood.
  6. E. coli are bacteria that are commonly found in the gut of both people and animals where they live harmlessly. Some other strains can cause illness, including food poisoning, urinary tract infections and bloodstream infections.
  7. ESBL enzymes were first described in the 1980s and during the 1990s were mainly seen in Klebsiella species found in hospitals mostly in intensive care units. Since early 2000s, they have become a global problem in E. coli.
  8. The cycle of antibiotic resistance is complex with interlinking elements between antibiotic use and people, livestock, pets, sewage and the environment.

 

Source: www.gov.uk

 

Menstrual regulation and the sacra rosa—escaping religious rigidity.


Countries that are strongly Muslim or Roman Catholic find abortion unacceptable, but Bangladesh, a Muslim country, has found a clever way of helping women who might be pregnant and don’t want to be.

In Bangladesh induced abortion is illegal unless a woman’s life is threatened. But a woman who has missed a period may in the next eight to ten weeks undergo menstrual regulation to ensure that she is not pregnant. Menstrual regulation has been undertaken with manual vacuum aspiration, but increasingly drugs are being used. It is very important not to do a pregnancy test: if it was known that the woman was pregnant then the procedure would be an abortion and so illegal.

In 2010 some 650 000 women had menstrual regulation performed, but there were also 640 000 induced abortions, most of them illegal. Around 570 000 of the women suffer complications, and about 1%—some 6400—die. Women undergo unsafe abortions because they are unaware of menstrual regulation, lack access to the procedure, or don’t understand the difference between menstrual regulation and unsafe abortion. Unsurprisingly poor and rural women are more likely to undergo unsafe abortion.

Menstrual regulation, which seems to me a very clever idea, has been available in Bangladesh since 1979. It’s been suggested to me that it became acceptable because of the systematic raping of women during the War of Liberation, when what was East Pakistan fought off the dominance of West Pakistan and became Bangladesh, still a Muslim country, but steeped in the richness of Bengali culture.

As far as I know, other countries that are opposed to abortion on religious grounds don’t allow menstrual regulation—but perhaps they should.

I’m impressed by the ingenuity of menstrual regulation, and I was describing it to an Italian friend, who said that it reminded him what he called the sacra rosa. The way he described it even a married couple who had had children could be allowed a divorce by the Catholic Church on the grounds that one or other or both of the couple had not been thinking of sex while conceiving the children. For my friend it was a form of corruption, and the Church would need generous payment for allowing such a divorce.

I can’t find mention of the sacra rosa online, but I have learnt about the “declaration of nullity.” The Church, it seems, can’t allow separation of a couple whom God have joined, but it can accept that there are circumstances in which true marriage never took place even though the couple went through the ceremony in a church. Non-consummation is the best known cause, and both the Church and God expect sex to occur. But it also seems that “not intending, when marrying, to remain faithful to the spouse (simulation of consent)” can mean that true marriage never took place.

This would seem to be a marvellous out for the world’s many philanderers, but it leaves me wondering why all the fuss around Henry VIII and why we need the Church of England. I know the answer: it was all about politics, power, and money.

Perhaps with more of the mental ingenuity that has given us menstrual regulation and the declaration of nullity we could avoid the considerable pain and suffering that result from ideological and religious rigidity.

Source: BMJ

 

 

Patients’ attitudes about the use of placebo treatments: telephone survey.


Abstract

Objective To examine the attitudes of US patients about the use of placebo treatments in medical care.

Design One time telephone surveys.

Setting Northern California.

Participants 853 members of Kaiser Permanente Northern California, aged 18-75, who had been seen by a primary care provider for a chronic health problem at least once in the prior six months.

Results The response rate was 53.4% (853/1598) of all members who were eligible to participate, and 73.2% (853/1165) of all who could be reached by telephone. Most respondents (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to doctors’ level of certainty about the benefits and safety of the treatment, the purpose of the treatment, and the transparency with which the treatment was described to patients. Only 21.9% of respondents judged that it was never acceptable for doctors to recommend placebo treatments. Respondents valued honesty by physicians regarding the use of placebos and believed that non-transparent use could undermine the relationship between patients and physicians.

Conclusions Most patients in this survey seemed favorable to the idea of placebo treatments and valued honesty and transparency in this context, suggesting that physicians should consider engaging with patients to discuss their values and attitudes about the appropriateness of using treatments aimed at promoting placebo responses in the context of clinical decision making.

Discussion

The opinions of US patients have been missing from debates over the use of placebo treatments in clinical practice and deliberate efforts by physicians to enhance patient care by promoting placebo responses. Our data show that patients are open to the idea of placebo treatments. Most (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to the doctor’s level of certainty about the benefits of the treatment, the purpose of the treatment (for example, to address a patient’s need to receive a treatment), and the transparency with which the treatment was described to patients. Fewer than a quarter stated that it was never acceptable for doctors to recommend placebo treatments. In addition, many respondents indicated a willingness to try placebo treatments in different scenarios. This is generally compatible with trends reported in previous patient surveys in other countries regarding willingness to try placebo treatments.16 17 18 20

Our findings also underscore the importance of honesty and trust in the prescription of placebo treatments. Respondents indicated that the use of placebo treatments could have a negative impact on the doctor-patient relationship if patients learnt that a doctor had recommended a placebo to placate patient’s expectations for treatment–especially if it did not work. Respondents said that doctors should be honest about an intervention being a placebo treatment when patients ask specific questions about the treatment, and they disagreed about whether it is acceptable for physicians to call a placebo treatment “real medicine.” Interestingly, some respondents thought that doctors should not disclose that a treatment is a placebo if it is working, suggesting some support for the non-transparent use of placebo treatments, a finding not reported in previous surveys.

Although clinical practice guidelines recommend against the use of placebo treatments to mollify patients,10 most participants in this survey judged their use to be acceptable to address patients’ need to feel like they received some treatment. Patients did, however, specify limits on how far physicians should go to placate patients, with over 90% judging it inappropriate for doctors to prescribe antibiotics for a cold, even when patients ask for it. Yet recent surveys suggest that a small proportion of physicians would indeed prescribe antibiotics to some patients in this situation, and that they had done so at least once within the past year.4 21 Taken together, these findings hint at a disconnect between clinical practice guidelines, patients’ opinions, and physicians’ practices that should be further explored.

Although our data indicate a general acceptance of placebo treatments by patients, responses to different questions about the effectiveness of such treatments varied. While most thought when asked directly that placebo treatments are only effective when patients do not know they are receiving them, the responses to the more nuanced scenarios indicated a general acceptance of transparently prescribed “open” placebo treatments—both a belief that they are effective (62%) and a willingness to take them (61-65%). This discrepancy prompts questions about how well patients understand the concept of placebo treatments in general and whether providing additional detail in the scenarios adds to their understanding such that their answers to the corresponding questions are more accurate.

The study sample was representative of the population of Northern California but may not be representative of US patients in general. Our sample was more highly educated (≥44% college graduates) than the general population, had health insurance coverage through Kaiser Permanente Northern California, and had seen a physician within the past six months for a chronic medical condition. Although we constructed our definition of placebo treatments based on feedback from focus groups and pretest interviews, respondents may none the less have variable or limited understandings of the concepts of the placebo effect and placebo treatments. This is perhaps not surprising, given the variable understandings of these concepts among the placebo research community.5In view of the widespread variability in definitions and conceptions of placebo in the literature, we endeavored to employ a pragmatic definition of the placebo effect in our questionnaire that would be useful in the context of a patient survey. While there may be some vagueness and ambiguity in the concept of placebo treatments, the pattern of survey responses and our experience in exploring placebo treatments with focus groups indicate that patients are able to understand the difference between treatments that work on the basis of their inherent pharmacologic properties and those that may produce benefit primarily by means of positive expectations. We observed some variability in answers to analogous questions that were asked in different ways (for example, directly versus in contextualized scenarios), and it is difficult to know which formulation of the questions is likely to reflect attitudes more accurately. Furthermore, the survey captures patients’ opinions about a series of plausible hypothetical scenarios rather than actual behaviors and experiences.

Researchers of one study have argued that models of shared decision making need to include conversations between physicians and patients about the role of the placebo effect in clinical care,22 and clinical practice guidelines leave the door open for the use of placebo treatments when presented to patients transparently.10 Researchers of another study further suggest that attitudinal data can help develop and foster the use of effective and non-deceptive placebo treatment techniques.20 That many patients in this survey seem favorable to the idea of placebo treatments suggests that physicians should consider engaging with patients to discuss their values and attitudes concerning the appropriateness of using placebos in the context of clinical decision making. Such conversations could allow physicians to determine which patients might be open to the use of placebo treatments and could help physicians tailor their description of placebo treatments according to patients’ preferences and level of understanding. Further research is needed to determine how physicians can optimally promote placebo responses in clinical practice and to guide the appropriate use of placebo treatments.

What is already known on this topic

  • The use of placebo treatments by physicians in clinical practice has been documented in recent surveys
  • Attitudinal surveys in other countries suggest that patients are open to the use of placebo treatments in specific circumstances
  • This study provides data on US patients’ attitudes about the use of placebo treatments in clinical practice
  • These data suggest that many patients are favorable to the idea of placebo treatments

What this study adds

 

Source: BMJ

 

Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies.


Abstract

Objectives To investigate the association between intake of fish and n-3 polyunsaturated fatty acids (n-3 PUFA) and the risk of breast cancer and to evaluate the potential dose-response relation.

Design Meta-analysis and systematic review of prospective cohort studies.

Data sources PubMed and Embase up to December 2012 and references of retrieved relevant articles.

Eligibility criteria for selecting studies Prospective cohort studies with relative risk and 95% confidence intervals for breast cancer according to fish intake, n-3 PUFA intake, or tissue biomarkers.

Results Twenty six publications, including 20 905 cases of breast cancer and 883 585 participants from 21 independent prospective cohort studies were eligible. Eleven articles (13 323 breast cancer events and 687 770 participants) investigated fish intake, 17 articles investigated marine n-3 PUFA (16 178 breast cancer events and 527 392 participants), and 12 articles investigated alpha linolenic acid (14 284 breast cancer events and 405 592 participants). Marine n-3 PUFA was associated with 14% reduction of risk of breast cancer (relative risk for highest v lowest category 0.86 (95% confidence interval 0.78 to 0.94), I2=54), and the relative risk remained similar whether marine n-3 PUFA was measured as dietary intake (0.85, 0.76 to 0.96, I2=67%) or as tissue biomarkers (0.86, 0.71 to 1.03, I2=8%). Subgroup analyses also indicated that the inverse association between marine n-3 PUFA and risk was more evident in studies that did not adjust for body mass index (BMI) (0.74, 0.64 to 0.86, I2=0) than in studies that did adjust for BMI (0.90, 0.80 to 1.01, I2=63.2%). Dose-response analysis indicated that risk of breast cancer was reduced by 5% per 0.1g/day (0.95, 0.90 to 1.00, I2=52%) or 0.1% energy/day (0.95, 0.90 to 1.00, I2=79%) increment of dietary marine n-3 PUFA intake. No significant association was observed for fish intake or exposure to alpha linolenic acid.

Conclusions Higher consumption of dietary marine n-3 PUFA is associated with a lower risk of breast cancer. The associations of fish and alpha linolenic acid intake with risk warrant further investigation of prospective cohort studies. These findings could have public health implications with regard to prevention of breast cancer through dietary and lifestyle interventions.

Discussion

In this meta-analysis dietary intake of marine n-3 polyunsaturated fatty acids (PUFA), but not alpha linolenic acid (ALA), was associated with a lower risk of breast cancer. Fish consumption was not associated with risk. Dose-response analyses indicated a 5% lower risk of breast cancer per 0.1g/day or 0.1% energy/day increment of dietary marine n-3 PUFA, but no significant trend for ALA or fish intake. To the best of our knowledge, this is the first time meta-analysis has systematically and quantitatively evaluated the association between intake of fish and n-3 PUFA and risk of breast cancer.

Source: BMJ

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.


BACKGROUND

Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.

METHODS

In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.

RESULTS

The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.

.

CONCLUSIONS

A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM

 

 

 

 

Toward Patient-Centered Drug Development in Oncology.


As an oncologist, when I sit with patients to discuss starting a new chemotherapy regimen, their first questions are often “How will it make me feel?” and “How did patients like me feel with this treatment?” Regrettably, this information is generally missing from U.S. drug labels and from published reports of clinical trials — the two information sources most commonly available to people trying to understand the clinical effects of cancer drugs.

In 2011, 15 hematology–oncology drugs were approved by the U.S. Food and Drug Administration (FDA). In only one case — that of ruxolitinib for the management of myelofibrosis — was symptom information included in the portion of the label that manufacturers can legally use for marketing purposes. In fact, ruxolitinib was the first cancer therapeutic in more than a decade for which symptom information was included in a U.S. drug label.

Cancer-drug labels stand in sharp contrast to labels for other types of drugs, about 25% of which list the drugs’ effects on patients’ symptoms or functioning.1 That disparity is surprising, given how common symptoms and functional impairment are in patients with cancer and how toxic oncology drugs can be.

The FDA has taken several recent steps toward encouraging inclusion of the patient perspective in drug development. It issued highly influential guidance on the use of patient-reported outcomes (PROs) in drug development,2 collaborated with the Critical Path Institute and industry to form the PRO Consortium with the aim of developing robust symptom-measurement tools, and obtained support from Congress in the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA) to expand its internal expertise on the methodology of measuring PROs. (Unfortunately, allocated PDUFA funds have been withheld, which substantially impairs the FDA’s ability to implement planned patient-centered programs.)

These FDA efforts are evident in the ruxolitinib label and in the label for abiraterone acetate, approved this year for metastatic prostate cancer, which describes beneficial delays in time to the development of pain and the need for opioid use. Yet in preapproval trials in patients with cancer, symptom or functional-status evaluations that meet the FDA’s standards remain rare.

Some experts have argued that the FDA has raised the methodologic bar too high, whereas others accuse the pharmaceutical industry of paying too little attention to patients’ experiences. The bottom line is that both regulators and industry continue to prioritize survival-based end points rather than patient-experience end points in cancer-drug development.

Yet as patients live longer with cancer, they must increasingly choose among agents with varying efficacy–toxicity balances. And as approved drugs continue to yield only tiny median survival benefits (often measured in weeks), patients understandably want to know how their peers felt during and after a treatment. Moreover, payers increasingly seek information about patients’ comparative experiences with different products, because patients with worse symptoms or functional status utilize more supportive services.3

On the industry side, information about the patient experience is sometimes gathered in preapproval “pivotal” clinical trials (trials intended to provide evidence of the safety and efficacy of a product to support regulatory approval) through questionnaires focused on health-related quality of life (HRQOL). Often, this information is gathered to satisfy European regulators as well as payers, who seek a demonstration of economic value. Unfortunately, these end points are generally exploratory, and protocol-specified hypotheses and analytic or statistical plans are lacking. Data are commonly missing, and the results are rarely (or highly selectively) included in primary publications of trial results4 and are generally not intended for inclusion in U.S. oncology-drug labels.

We can, and ought to, aim higher. The examples of ruxolitinib and abiraterone, as well as experiences outside oncology, demonstrate six key steps that can move drug development toward a more patient-centered approach — one in which developers and regulators systematically consider patient perspectives in the design, conduct, and reporting of research .

In the case of ruxolitinib, the sponsor was a small company whose leadership was committed to including the patient perspective in key trial end points. When early clinical experience and published data for the target population revealed a constellation of symptoms related to the disease that were viewed as important by patients (step 1), the company began discussions with the FDA (step 2) and collaborated with academic researchers and a consulting firm to develop a patient-reported outcome measure (step 3). This measure was tested and refined through use with patients representing the target population before it was employed in a pivotal trial (step 4). The questions were loaded into a handheld device that patients used to report their own responses daily, with near perfect levels of compliance — despite their debilitating symptoms. The company had ongoing communication with and feedback from the FDA throughout this process.

Ruxolitinib demonstrates the particular value that PROs provide for understanding clinical benefits when studies are not designed to detect overall survival advantages and instead rely on end points such as tumor response, progression-free survival, or noninferiority. Although overall, ruxolitinib represents a success story, measurement of fatigue and HRQOL decrements — which are prevalent and widely viewed as important to patients — were not included as key end points because the FDA had methodologic concerns about them; these omissions resulted in a label containing an incomplete picture of the patient experience (steps 2 and 6 might have prevented this).

In the case of abiraterone, the company took a risk in its pivotal trial by expending statistical power to measure the time to opioid use among men with minimal baseline symptoms, when little was known about this end point in prostate cancer (step 4). It would also have been useful to include information about symptoms other than pain that are of interest to men with this disease; according to qualitative research conducted before the pivotal trial and formal patient-engagement activities, these would include symptoms such as tiredness or sleep disturbance (steps 1 and 5). Although a broad HRQOL tool was administered with positive results, there was no protocol-specified analysis plan for it, and it did not meet the FDA’s current methodologic threshold (steps 2 and 6).

For these key steps to be taken routinely, a fundamental shift in cultural orientation among drug developers and regulatory reviewers is imperative. Specifically, the patient experience of treatment with a given drug must be regarded as essential information about the properties of the product, without which our understanding of its risk–benefit profile is incomplete. This requirement applies equally to studies with end points based on survival (such as abiraterone) and those focused on tumor response (such as ruxolitinib).

Methodologic challenges exist but should not continue to be cited as insurmountable. They have been shown to be addressable in many trials,1 and multiple documents offering guidance on methods are available.2,5 Examples include minimizing and analyzing missing data, identifying meaningful score changes for questionnaires, and analyzing PRO data in nonblinded trials. Additional research is warranted both to advance measurement science in these areas and to develop measures in the public domain that meet regulatory standards.

But the principal barrier remains a failure to prioritize the identification and confrontation of these challenges up front. Moreover, when PRO measurement is left until the postmarketing phase, it is often too late to adequately measure outcomes in a comparative trial, which leaves the true effect of a product on the patient experience uncertain. Ideally, moving forward, whenever representatives of a pharmaceutical company and a regulatory agency sit down to discuss a product-development program, they will ask the same question my patients ask of me: “How does this product make people feel?”

Source: NEJM