Mortara has been awarded a multi-year contract for ongoing maintenance and support of the FDA ECG Warehouse including continuous ECG studies analyzed by VERITAS^TM.

Mortara collaborated with the FDA to develop the ECG Warehouse which was initially deployed in 2005. The ECG Warehouse acts as a repository for annotated electrocardiograph (‘ECG’) studies provided to the FDA in support of new drug applications. With the ECG Warehouse, the FDA uses Mortara’s VERITAS ECG algorithms and viewing technologies to review ECG data submitted as part of new drug applications.

Since inception of the ECG Warehouse, more than 9 million resting ECGs have been analyzed with Mortara’s VERITAS algorithms, making this one of the largest cloud-based clinical data repositories in the world. The ECG Warehouse has subsequently been expanded to also include continuous 12-lead recordings, which now number nearly 800 in total. The warehouse tools include web-based upload, navigation of continuous data, arrhythmia identification and waveform morphology comparison.

Under this expanded ECG Warehouse contract, Mortara will continue to support Sponsor and ECG Central Laboratory upload of ECG studies, provide support to FDA personnel and provide on-going basic development enhancements to the ECG Warehouse including advances in the VERITAS ECG algorithms.

‘Mortara is pleased to continue its longstanding relationship with the FDA in providing the ECG Warehouse solution,’ said Dr. Justin Mortara, CEO of Mortara. ‘This award is testimony to our leadership role in ECG acquisition and algorithm technologies. We are honored to be chosen by the FDA and to play our part in the cardiac safety evaluation of new drugs.’

About Mortara
For over 30 years, Mortara Instrument, Inc. has served as a leading designer, developer, and manufacturer of diagnostic cardiology and, most recently, patient monitoring technologies. Mortara is focused on delivering world-class medical devices, as evidenced by its innovative portfolio of solutions designed to serve throughout the continuum of clinical care. The company’s comprehensive range of products spans modalities including resting ECG, cardiac stress exercise, Holter monitoring, cardiac and pulmonary rehabilitation, and ambulatory blood pressure and multi-parameter patient monitoring. Mortara’s global headquarters is located in Milwaukee, Wisconsin with direct operations in Australia, Germany, Italy, the Netherlands, and the United Kingdom. While Mortara distributes its products and technologies globally, it remains dedicated to manufacturing in the United States in order to consistently deliver the quality products for which it is known.
Mortara’s approach to innovation has a global reach that impacts both mature and emerging healthcare systems. To learn more about Mortara and its expanding product portfolio, including the Burdick and Quinton brands, visit www.mortara.com.

Hospital noise is an issue for babies born prematurely who are at high risk when it comes to external influences such as noise. Their systems are underdeveloped and they need as much sleep and rest as possible to recuperate. This is one of the reasons why the Neonatal Unit at the highly specialized Rigshospitalet hospital in Denmark, began cooperating with the noise measurement company SoundEar this year.

Not all sound is noise
Staff at the Neonatal Unit stress that there is a difference between what they call good sound’ and noise. The point being that not all sound is noise, and not all sound should be eliminated. It is important for the development of the newborns that they hear sound such as their parents and siblings talking and singing to them. It is also important that staff can communicate audibly in critical situations, and it is inevitable that some medical equipment, such as respirators, are noisy. What they do want to reduce is unnecessary sound stemming from alarms, furniture, work flow and talk.

Keeping parents in the loop
An important part of the project is to keep parents informed about why the noise meters are installed and not only focus on reducing noise, but also inform them that they should still talk to their newborns and that some medical care routines will result in a certain level of noise. One way of going about this has been to develop a flyer to hand out to new parents in the neonatal intensive care unit (NICU).

Reducing hospital noise through awareness
The aim is to bring down hospital noise levels at the NICU through installing noise meters in all rooms. Half of the noise meters are anonymous white boxes which solely measure and collect noise levels. The other half of the noise meters also have a display with an ear, that lights up green, yellow or red, indicating the current level of noise in the room.
Reduction in noise levels at the NICU is expected to be achieved through different layers of nudging:

• The noise meters with displays should help staff and families become aware of their own noise levels and change their noisy behaviour.
• The software helps staff become aware of when and where noise levels are critical and something should be done differently.
• The software sends out noise reports on a weekly basis via email to key staff members who use these reports as a basis for further discussion about noise at staff meetings.

Changing routines
After having the SoundEar devices hanging in the NICU for a few months, staff was asked to fill out a questionnaire about the perceived hospital noise levels, and whether the SoundEar devices seemed to have changed anything. 14 staff members, primarily nurses, answered the questionnaire and 78.6 percent reported that the SoundEar devices had made them more attentive to noise levels. The same amount reported to have changed some of their behaviour because of the SoundEar devices.
The change that most staff members reported to have made, was to unpack syringes and other types of medical equipment outside of patient rooms, because they had noticed that the ripping of plastic made an unnecessary amount of noise around the children. Others reported lowering their voices and lowering the noise level of alarms as changes they had made after the installation of the SoundEar devices.
Several staff members also reported to have seen an increase in parents’ attention to noise levels, and that they commented on noise to other visitors and siblings, thereby spreading the attention to noise.

Custom-made software
All the noise meters transfer noise measurement data wirelessly to a central computer, where it is accessible to staff through a piece of software, developed specifically for hospital use by SoundEar in cooperation with staff at the NICU.

Jointly creating a noise measurement system
An important part of the project was to create a system that would help reduce hospital noise and become part of the daily routine at hospitals. For SoundEar, this meant focusing on what staff needed and what their everyday work life looked like and adjusting to that.
In the early days of the project, SoundEar viewed the software platform as the main component of the system and something that staff should be able to interact with daily. They should monitor noise levels just as they were used to monitoring the health levels of the newborns.
To make the software as useful as possible, SoundEar conducted several interviews with staff members. Very soon, it became clear that even though nurses viewed reducing hospital noise as important, their focus was on the critical medical care for the newborns and keeping them alive and well. Their time was limited and they would not be able to prioritize time from their busy schedules to consult a piece of software that did not have immediate medical importance for the children.
Instead, they suggested that a few members of the staff should be responsible for driving the hospital noise reduction, checking the software and gathering insights for the rest of the staff to discuss at weekly meetings. Along the way, the procedure evolved into auto-generated noise reports being sent to key staff members to be discussed at staff meetings on a weekly basis.
www.soundear.dk

Liver disease is a growing problem across the world. It includes a large range of disorders, such as fatty liver disease (both alcoholic and non-alcoholic), drug-induced liver damage, primary biliary cirrhosis and hepatitis (viral and autoimmune).

Biopsy is gold standard for liver disease
Fibrosis is a relatively common consequence of chronic liver diseases, and its staging, alongside exclusion or confirmation of early compensated cirrhosis, are considered to be vital for surveillance and treatment decisions.
The gold standard for the confirmation of hepatic fibrosis is biopsy. However, biopsy of the liver has several disadvantages. First of all, it is invasive. It is also associated with rare but serious complications. Finally, it can sample only a small portion of the parenchyma (functional rather than connective tissue). This makes it vulnerable to sampling errors.

Non-invasive tests becoming norm
To overcome such constraints, a variety of non-invasive imaging and serological methodologies have been researched and developed for assessing fibrosis. Aside from staging, an ever-growing corpus of data from non-invasive liver tests is also yielding considerable insights for prognostic patient care.
Liver biopsy is now largely restricted to patients showing unexplained discordances in non-invasive testing or those where hepatologists suspect additional etiologies of the disease.
Indeed, non-invasive tests are fast becoming the norm in much of the world, outside the US, although there are several exceptions. The reasons for the lower penetration of non-invasive tests in the US are discussed later.

Ultrasound at forefront
New non-invasive methods for assessing liver fibrosis consists of ultrasound elastography, a diagnostic methodology to evaluate stiffness of tissue, magnetic resonance elastography and serologic testing.
To some of its proponents, elastography is simply a form of the centuries-old systems of diagnosing and assessing diseases via palpation, now extending beyond the scope of physical touch.
While a biopsy is invasive and carries bleeding and infection risks, elastography is seen as a way to get the data needed by clinicians to diagnose and stage liver diseases without the associated complications.

Ultrasound-based elastography is not only used as an alternative to liver biopsy for measuring fibrosis, but also to predict complications in patients with cirrhosis. Another advantage is that elastography, like other non-invasive imaging modalities, can be repeated as often as required to monitor disease progression. Due to their risks, this is simply not feasible with biopsy.

Strain elastography and shear wave elastography
The best-known commercial ultrasound-based techniques for assessing fibrosis include strain elastography and shear wave elastography (SWE). SWE is a real-time two-dimensional elastography technique which enables making quantitative estimates of tissue stiffness in kilopascals (kPa) by virtue of the shear wave speed.
Technologically, even though strain elastography predates SWE, the latter is more easily reproducible than strain elastography, and has rapidly gained interest as the preferred technique. The two are quite different, and outside the hepatology area, seem to have significant complementarities.
Broadly speaking, strain imaging is a qualitative/semi-quantitative method influenced by histotype and lesion size. The use of semi-quantitative indices does not improve performance. Neither does it reduce interoperator variability.

SWE provides accuracy, comparability
Shear wave, on the other hand, is a quantitative method which provides a more accurate and easily comparable assessment of spatial distribution of tissue stiffness.
Most practitioners see SWE as quick and easy to perform, and easily repeated to monitor liver disease progression and measure the effect of a particular treatment. An ultrasound shear wave propagates like ripples of water, as it spreads across tissue. A coherent pattern indicates that a pulse has been applied properly and that there are no artifacts (e.g. from vessels) that would provide erroneous results.
SWE systems provide variable depth of measurement. A depth of 5-6 cms may make it difficult to scan the liver in a large or obese patient, but depths of up to 8 cms are available in certain SWE systems. However, results are not reproducible at such depths, across commercial SWE vendors.

Ease of use not universally accepted
Nevertheless, not everyone agrees that the procedure is easy, especially if SWE results need to be matched against reproducible serological tests. The Society of Radiologists in Ultrasound notes the considerable training required for precision. SWE begins with the positioning of a patient in a left posterior oblique position with the arm raised. Patients need to also breathe slowly, and when asked, suspend breathing, since movement of the liver can reduce accuracy in measurement.

Liver is principal application for SWE
So far, SWE has been used to evaluate and quantify liver fibrosis/cirrhosis of multiple etiologies or with complicating co-morbidities, including chronic hepatitis, liver cancer, steatohepatitis, and biliary atresia. The two-dimensional shear wave elastographic technique offers better performance for assessing liver fibrosis as compared to conventional transient elastography, according to a May 2016 study in the Chinese publication, World Journal of Gastroenterology’.

SWE and hepatitis C
SWE practitioners see it as a tool to assist in earlier detection of conditions such as hepatitis C, and both fatty liver and alcoholic liver disease. Alongside lab studies, SWE offers a means to closely monitor the impact of treatment and assess if the liver will normalize. For many hepatologists, fighting a liver condition before Stage 4 cirrhosis provides a good chance of reversibility.
SWE can also provide information on which hepatitis C patients might benefit from viral therapy. There are numerous reports of patients who would not have been suspected of severe fibrosis or cirrhosis, based on traditional ultrasound grey scaling. At best, the latter provides indicators such as anomalies in the liver contour. However, it does not show signs of cirrhosis such as surface nodularity which are immediately apparent in elastography.

Guiding biopsies
Some clinicians have sought to use SWE to guide liver biopsies and in certain cases, avoid or postpone biopsy. As part of this process, they have addressed one of the major limitations of biopsy, namely restrictions to choice of affected areas, erroneous samples, or inadequacy in sample size enough for interpretation. SWE allows multiple sampling across the liver and generating a mean value. This reduces what in the past would have been a large number of unnecessary biopsies, and minimizes the morbidity of liver biopsy.

SWE in children
SWE has shown specific advantages in pediatric patients. Cincinnati Children’s Hospital Medical Center is gathering data on normal’ stiffness values in children, and on rates of progression, given that published data is almost wholly based on adults.
The study groups cover children with liver transplants, metabolic disorders, cystic fibrosis and those on prolonged intravenous feeding (TPN). One specific area for attention is biliary atresia, a rare but life-threatening condition where the bile ducts in an infant’s liver lack normal openings. The bile builds up and causes damage to the liver.
The pediatric data collection for SWE on newborns with jaundice or cholestasis makes ten measurements. This adds just 5 minutes to a typical ultrasound exam.
Nevertheless, pediatric SWE also has its limitations. According to Dr. Sara O’Hara, who heads the Ultrasound Department at Cincinnati Children’s Hospital, SWE can give variable results in areas such as children with non alcoholic steatohepatitis (NASH) and fatty liver disease.

Breast applications benefit from SWE-plus-strain elastography
In adults, aside from the liver, SWE is seen as a useful technique for evaluation of breast lesions and prostate imaging. In both cases, the technique seems to provide best results in combination with another elastography mode.
For instance, a literature review published in the Journal of Ultrasound’ in 2012 reported that SWE and strain elastography complement each other and overcome mutual limitations in the evaluation of breast lesions.
Clearly, when both types of elastography provide similar results, there is a greater degree of confidence – especially in terms of a near-total elimination of false negatives, which sharply cuts the need for breast biopsies which later prove unnecessary.
There are however some limitations which have been reported in measuring shear wave velocity in the stiffest of breast lesions. Here, rather than propagating through the tumour, the shear wave tends to bounce back. Nevertheless, ongoing improvements in SWE, which have been further reducing examination time and enhancing field of view, means that at some point it could be a tool for breast cancer screening.

Prostate applications benefit from SWE-plus-MR elastography
The use of SWE in prostate cancer, too, shows similar potential for benefits as with breast screening. The first factor is a reduction in biopsies, which prove to have been unnecessary post facto. Studies are under way which seek to correlate stiffness with abnormalities (as well as aggressiveness of tumours) and to assist urologists determine when patients with low-grade prostate cancer must start treatment.
As with SWE and strain elastography in the breast, best results in terms of the prostate are obtained by complementing SWE with another imaging modality – magnetic resonance (MR) elastography. Some findings reveal SWE significantly superior in detecting prostate cancer in the peripheral zone – which is where most tumours occur. However, MR seems to show greater promise in the anterior gland and transitional zone.
Again, as with the breast, the fusion of two modalities permits multiple sampling and tackles a major limitation of prostate biopsy, namely inconvenience and risk, as well as limited choice of affected areas. A few experimental procedures have also targeted fusing MR and SWE images to help guide biopsies.

Using SWE in other organs
SWE has also demonstrated considerable (if still early-stage) promise for evaluating thyroid nodules, indeterminate lymph nodes and uterine fibroids. Another area for investigating SWE include kidney transplants, in order to to avoid excessive biopsies. However, limitations to shear wave captured depth remains a technology challenge for manufacturers to address.

US remains laggard in ultrasound elastography
While most of the world’s regions (Europe, Asia and Latin America) are seeing growth in the use of ultrasound elastography (both SWE and strain), in the US neither is eligible for reimbursement, even in the largest application area – the liver. This is unlike transient elastography, although critics allege it is a blind methodology which neither directly measure fibrosis and often over-estimates it.
Currently, studies in both the US and other parts of the world are seeking to establish the clinical and economic benefits of SWE and strain elastography, including unnecessary invasive biopsies with their associated costs and complications. Eventually, the results of ongoing trials are expected to produce the data which will make ultrasound elastography eligible for reimbursement.
The most self-evident advantage of ultrasound elastography is its non-invasive nature. Unlike a biopsy, it is clearly more feasible to use SWE to screen for patients at greatest risk of chronic liver disease and in need of referral or treatment.

Breast tomosynthesis exams, Hologic calls the exams 3D MAMMOGRAPHY^TM, have shown to be an advance over digital mammography, with higher cancer detection rates and fewer patient recalls for additional testing.

The new Affirm prone system, which was installed for the first time in Europe earlier last year, is widely considered one of the most significant advance in biopsy technology since the first prone biopsy system was introduced more than 20 years ago. It uses the same proven detector technology as the Hologic Selenia Dimensions breast tomosynthesis system, a top selling breast cancer screening and diagnostic system in the U.S. and in many other countries around the world. With a significantly larger field of view than the MultiCare Platinum system, along with its translucent paddles, the new prone system is designed to deliver exceptional 2D and 3D^TM images and better target lesions found during 3D MAMMOGRAPHY^TM exams, as well as other screening modalities. In addition, the Affirm prone system allows full 360degree Celsius access to the breast to accommodate most lesion locations. Users can go from a standard to lateral needle approach in seconds to accelerate procedures and ensure reaching targeted lesions.

Doctors in Spain report handling complex biopsies that they were only able to see with breast tomosynthesis imaging with the new system
As Doctor Tejerina, a radiologist with the Centro de Patologia de la Mama, Tejerina Foundation, in Madrid, Spain, reports, feedback from the first wave of patients is very positive. ‘We have been suffering to handle complex biopsies of subtle lesions like faint calcifications or distortions that we were only able to see on 3D images,’ Dr. Tejerina says. ‘Older breast biopsy systems are restricted to 2D imaging with a narrow window for targeting the lesions. Often they require multiple X-ray exposures to find and position the suspect tumour for the biopsy needle. With tomosynthesis imaging on the new Affirm prone system, there is a much wider field of view. So the biopsy device can be positioned anywhere in a 360-degree circle, and areas of suspicion seen only with 3D imaging can be easily biopsied.’
Dr. Tejerina also notes that with the previous Hologic biopsy table, the tube head of the biopsy device had to be positioned manually. ‘The new system does this for us automatically, which saves time,’ he says. ‘The software really streamlines our workflow, so the procedure goes faster.’ And he adds, the Affirm Prone table, with its translucent paddles and wider detector, ‘helps us see lesions in the first scout and significantly reduce the number of images needed to get to the lesion.’
The Centro de Patologia de la Mama, Tejerina Foundation has been leading the way in women’s breast health for over 40 years. In 1997, the Centre was first centerein Spain to install a stereotactic guided prone biopsy table. In 2010 the Centre installed a Hologic Selenia Dimensions breast tomosynthesis system, the first site in Spain to use the innovative technology. In 2010 the Centre was also the first site in Spain to combine the Hologic Affirm^TM upright biopsy system with the Hologic tomosynthesis system. The Centre was also one of the first sites in the world to offer prone biopsies on the new Affirm system from Hologic.

Doctors in the Netherlands say Affirm system is fast and comfortable for patients
Dr. Henebiens, a radiologist at Spaarne Gasthuis Hospital in Hoofddorp-the first Affirm prone user in the Netherlands-commented on how fast doctors can do a procedure on the Affirm system and how comfortable the new system is for patients.
‘We make fewer exposures on the new Affirm prone system, compared to the older MultiCare Platinum table,’ she notes. ‘And because the table uses 3D^TM technology, we use fewer steps getting to the target and getting biopsies.’
Dr. Henebiens also likes how easy it was to get up to speed on the table. ‘The learning curve for the new table was very fast. Training was scheduled for two days, but in one day, the staff knew how to use it.’
The Spaarne Gasthuis Hospital staff had completed over 60 procedures on the table in their first 7 months of use.

Doctors in Italy report faster and lower patient dose biopsies with the new system
Doctor Gianfranco Scaperrotta, Chief of the Breast Imaging and Interventional Radiology at Fondazione IRCCS Istituto Nazionale dei Tumori (INT) in Milano, Italy was an early adopter of the Affirm prone system.
‘The Affirm prone system is a quick, effective and easy to use system,’ he says. ‘The image quality is high, comparable to the Hologic Selenia Dimensions digital mammography system. Workflow is quick thanks to a dedicated workstation and the system’s fully integrated C-arm and automated tube-head. Procedures are faster and safer with the new system thanks to the programmed needle parameters and automated calculations such as the display of safety margins and relative distance in real time.’
After 73 procedures on the new system, INT has seen a 20percent reduction in the time needed for performing a biopsy (patient time under compression) and approximately a 50percent drop in the mean glandular patient dose when they compare the new system to the older Hologic system.
The Fondazione IRCCS Istituto Nazionale dei Tumori is the largest oncology site in Lombardia, the most populous region in Italy. The research and cancer treatment site draws patients from throughout Italy.
In sum, doctors at the first three European Affirm prone install sites reported that the new system offers significant benefits to the patient, the doctor and the technologist.
So what’s next from Hologic in 2D and 3D^TM Breast Biopsy after The Affirm^TM Prone system? Hologic will show at ECR an all-integrated breast biopsy system that combines tissue acquisition, real-time imagining, and tissue handling. The new system is designed to work in synergy with imaging guidance systems like the Affirm^TM Prone table and provide actionable real-time information in the procedure room and improve biopsy workflow.

For specific information on what products are available for sale in a particular country, please contact your local Hologic representative or write to iims@hologic.com

In spring 2015, the New England Journal of Medicine’ reported the case of a patient with Stage IV metastatic melanoma – a disease considered close to untreatable. Although three growths in the skin had been surgically removed, one tumour under her left breast had grown deep into her chest wall. The 49-year old woman received a single treatment of an experimental combination of two drugs.
When she returned in three weeks for a second dose, the tumour had ‘kind of just dissolved’, according to Paul Chapman, the physician treating her at Memorial Sloan Kettering Cancer Center in the US.

Over one-fifth patients show complete response
The results were not an exception. 22percent of the 142 patients enrolled in the Memorial Sloan Kettering trial showed a complete response (with their cancer melting’ away), while 53percent had at least 80percent tumour shrinkage. However, there were downsides, too. Half the patients had side effects that were severe or life-threatening.
The drugs used in the trial were Yervoy (ipilimumab) and Opdivo (nivolumab). Approved by the Food and Drug Administration (FDA) for melanoma, the two belong to a small, new arsenal of drugs which supercharge the immune system to attack tumours. The process is known as immunotherapy, and brings together experts from several fields, ranging from oncology and immunology to cell biology and genomics.
Another well-known immunotherapy medication is Keytruda, sometimes called the Jimmy Carter drug’. Combined with surgery and radiotherapy, Keytruda has halted recurrence of melanoma in the former US president, although the disease had spread to his liver and brain.

Single drugs work too
One analysis of 4,846 advanced melanoma patients treated with Yervoy alone found 21percent still alive after three years. Patients who make it to three years ‘do not die of melanoma,’ according to James Allison of the MD Anderson Cancer Center in Houston, Texas, who is widely credited with pioneering modern immunotherapy.
Meanwhile, beyond melanoma, the combination of Yervoy and Opdivo has also shown extraordinary potential in bringing about remission in advanced stages of non-small-cell lung cancer, a leading cause of cancer-related mortality.

Leveraging the immune system
Leveraging the immune system to fight cancer, once little more than a medical dream, is becoming real. Using gene sequencing technologies to classify tumours, the immune system is now becoming primed with drugs and genetically-engineered cells.
The immune system itself consists of a biochemical network which defends the body against viruses, bacteria and other invaders. Cancer, however, finds ways to hide from the immune system, or block its ability to fight.
Immunotherapy seeks to help the immune system recognize cancer as a threat, and attack it.

The medical equivalent of atomic fission
At the moment, there are hundreds of immunotherapy clinical trials under way for almost all types of cancer, individually or combined with other treatments. Eventually, researchers hope to develop blood tests that allow for the early detection of cancer, determine which medicines can be effective and monitor the response in real time.
For some oncologists, immunotherapy is the medical equivalent of splitting the atom. John Heymach, a lung cancer specialist at MD Anderson, has described immunotherapy as a ‘complete game-changer.’ Several others concur. At an AACR press conference in 2015, Louis Weiner of Georgetown University observed: ‘We are in the middle of a revolution,’ and added that ‘I don’t think that is hyperbolic.’
The media too has leaped into the fray, latching on to the enticing concept of dissolving the tumours that physically embody one of humanity’s most intractable struggles against disease. Forbes’, for example, headlines an article: ‘Immune System Drugs Melt Tumours In New Study, Leading A Cancer Revolution.’

Checkpoint inhibitors
In practical terms, there are two contemporary approaches to immunotherapy.
The first (and more-widely used) method involves the use of drugs that block a so-called checkpoint’ mechanism used by cancers to shut down the immune system. This type of drug, known as a checkpoint inhibitor, is used to treat advanced melanoma, Hodgkins lymphoma and cancers of the lung, kidney and bladder.
The drugs work in 20-40percent of patients. In many such cases, the results are nothing short of spectacular, with prolonged remissions that persist, even after treatment is halted.

Checkpoint inhibitors harness T-cells, the white blood cells which could be described as the special force soldiers of the immune system. The T-cells can, however, run out of control and attack normal, healthy tissue, leading to autoimmune disorders like rheumatoid arthritis, Crohns disease and lupus. To avoid this, built-in brakes or checkpoints’ slow or shut down T-cells.
One type of checkpoint inhibitor stops T-cells from multiplying. Another weakens them and shortens their life span. The two drugs in the Yervoy-Opdivo study reported by the New England Journal of Medicine’ were both checkpoint inhibitors. Yervoy (ipilimumab) interferes with a molecule which switches off T-cells. Opdivo (nivolumab) prevents the death of T-cells.

Limitations with checkpoint inhibitors
Nevertheless, for the bulk of patients, checkpoint inhibitors do not show any results, or work for a while and then stop. In the Yervoy-Opdivo study, 126 of 142 patients did not see their cancer vanish entirely. One of the theories being researched to explain this setback is that other, to-be-discovered checkpoints are playing a role, and these would lead to new drugs that increase the scope of their effectiveness.
Meanwhile, harnessing an immune system in overdrive can also be very risky. As mentioned earlier, one out of two patients in the Yervoy-Opdivo study had side effects that were severe or life-threatening. In many cases, treatment for such patients needs to be discontinued.
Conversely, checkpoint inhibitors can also slow down vital glands such as the pituitary and thyroid, thus creating a lifelong need for hormone treatment. This can have an impact in other areas. For example, kidney transplant patients have suffered rejection after taking checkpoint inhibitors since the latter spurred their immune system to attack the grafted organ.
Checkpoint inhibitors can also take months to begin working, and sometimes cause inflammation that make scanner data show what may, confusingly, look like a growing tumour.

CART: personalized immunotherapy
The second approach involves highly personalized treatments known as CART, with the abbreviation arising from the use of a protein chimeric antigen receptor (CAR) to modify a T-cell, which are first removed from a patient, genetically altered to kill cancer, and then re-infused.
CARTs effectively synergize antibodies, which provide precision recognition of disease targets, with the power of T-cells. Unlike antibodies, however, the modified T-cells continue to multiply, serving as a living therapy.
In autumn 2013, researchers at Fred Hutchinson Cancer Research Center in Seattle launched a (preliminary) safety trial with a CART on a lymphoma patient, who had failed to respond to elevated doses of chemotherapy. It was the first trial of its kind to be conducted on a human. At the end of a fortnight, the patient was reported telling his physicians that the lymph nodes in his neck felt like ‘ice cubes melting.’

Beyond leukemia and lymphoma
CARTs have largely worked so far in cases of leukemia or lymphoma, albeit dramatically. However, Fred Hutchinson is also working on several other cancer types, including Merkel cell carcinoma, melanoma and several sarcoma subtypes.
Elsewhere, researchers at the University of Pennsylvania are working on a CART which targets mesothelin, a protein often encountered on the surface of tumour cells. Trials involve patients with serious ovarian cancer, epithelial mesothelioma, and pancreatic cancer.

Challenges with CART
Nevertheless, many practical challenges remain to be overcome with CARTs too. They require extensive research and refinement in the lab before patient trials. Production is also labour-intensive, requiring isolation of specific T-cells from a blood sample, followed by multiplication in an incubator and the use of a hemacytometer for counting, and then concentration in a centrifuge. Apart from fine-tuning their therapeutic effects, means to cost-effectively scale the technology will also be required to bring CARTs to market.
Like checkpoint inhibitors, CART therapy also has clinical limitations, even in its mainstay application in leukemia. 20-30percent of patients are not helped, and are likely to die.

Some way to go
In the final analysis, immunotherapy still has some way to go.
In spite of their often near-miraculous performance, immunotherapy drugs have worked in what is still a minority of patients.
Researchers are clearly aware that immunotherapy is unique, potent and extraordinary, but they cannot fully understand why – or yet control it adequately.

The risks of hype
Physicians also urge caution. Media-hype has led many patients to believe the age of chemotherapy is past. There are cases of unresponsive immunotherapy patients (or those suffering from unacceptable side effects) being switched back to chemotherapy, successfully. Though this may be due to a delayed effect of immunotherapy, it is too early to tell. Indeed, one explanation is that chemotherapy and immunotherapy may be working synergistically in such cases.

Industry too may need a reality check. Asset management companies like Piper Jaffray have forecast immunotherapy boosting the cancer treatment market to half a trillion dollars a year. This may of course face a collision with reality.
Yervoy costs over USD 120,000 ( Euro 110,000) for a four-course treatment, while Keytruda is billed at about USD 150,000 ( Euro 138,000) for a year. At current prices, the combination of Opdivo and Yervoy would result in an annual cost of USD 270,000 ( Euro 248,000). On their part, CART therapies may cost even more. How exactly these sums will be financed is indeed the trillion dollar question.