Just In... Meeting News
Key news updates and reports from the latest meetings in oncology and hematology.
Thursday, April 7, 2016
By Mark L. Fuerst
BOSTON—New research in cancer immunology shows the promise of using T lymphocytes, the warriors of the immune system, to combat cancer in patients with metastatic disease.
Cell transfer therapy, the administration of autologous lymphocytes, to cancer patients has many advantages, said Steven A. Rosenberg, MD, PhD, Chief of Surgery at the National Cancer Institute (NCI), at the Society of Surgical Oncology Annual Cancer Symposium.
These advantages include administration of high numbers of highly selected cells with high avidity for tumor antigens; the cells can be activated outside the body to exhibit anti-tumor effects; and researchers can identify exact cell subpopulations and the functions required for cancer regression.
"Most importantly, we can manipulate the host prior to cell transfer to provide an altered environment for transferred cells," Rosenberg said, adding that "because the immune agents are taken from the body, we can eliminate negative influences so the cells we give are more effective."
Adoptive Cell Therapy
NCI researchers recently completed accrual of a trial looking at adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes with two lymphodepleting regimens. Patients were randomized to non-myeloablative chemotherapy with cyclophosphamide and fludarabine that eliminated all circulating infiltrating lymphocytes for eight days or the chemotherapy plus total body irradiation for more complete lymphodepletion.
Response rates in the 101 metastatic melanoma patients, many of them refractory to other treatments, ranged from 45-60 percent. Complete responses (CR) were achieved by 24 percent in each group, with 23 of the 24 CRs in both groups now ongoing from 14 to 53 months. "The therapy extended survival out to 3 or 4 years in metastatic melanoma patients," Rosenberg said.
Some 194 consecutive patients have received the lymphodepletion therapy. After a median follow-up of five years, 44 patients achieved CR, with only two recurrences; 42 of the CR patients are ongoing for 14 to 137 months. "This is likely a curative regimen for about one-quarter of patients who develop metastatic melanoma," Rosenberg said. "This is another example of the power of immune lymphocytes in the treatment of cancer patients."
There was no relationship between the bulk of disease or sites of disease and the likelihood of CR. Lymphocytes eliminate cancer at multiple sites, and it happens fast—the tumor may disappear before the patient leaves the hospital, some within 12 days, he said.
Only two patients received more than one treatment. "The lymphocytes administered are living cells and can manifest ongoing reactivity," he said, pointing out that most chemotherapies are excreted within minutes to hours after administration.
The researchers have seen regression in brain metastases, he noted.
TILs appear to recognize something unique to tumors. Now researchers are investigating whether mutations can be used as targets for immunotherapy. They are mining the cancer exome to identify immunogenic cancer mutations. Only rare mutations have the likelihood of being immunogenic, Rosenberg said.
"We have developed a blueprint for the generation of mutation reactive T cells from an individual patient with a common cancer. From the tumor, we do whole exome sequencing to identify mutations. Then we sequence and synthesize tandem minigenes that contain all mutations," he said.
Mutated antigens are recognized by T cells from melanoma patients. "In 25 patients with metastatic melanoma, the majority of them with complete durable regressions, we have used this technique to identify 64 different somatic mutations. All mutations were unique to that patient. There was no duplication of any antigens recognized in complete regressors from one patient to another," Rosenberg said.
Virtually none of the intracellular proteins are shared. "This is probably why cancer vaccines have not worked. No shared antigens are recognized by the immune system," he said.
Rosenberg said "ACT can mediate complete, durable, likely curative regressions of metastatic melanoma based on the recognition of immunogenic cancer mutations. Recognition of random somatic mutations is the final common pathway explaining cancer regression from most immunotherapies for solid cancers."
He noted that "IL-2, anti-CTLA4, anti-PD-1, anti-CD40, and TIL each unleash immune reactions against unique mutations in each individual patient."
The next step is to utilize this tandem minigene approach to treat common epithelial cancers. "In 22 consecutive patients with epithelial cancer, we found 57 different somatic mutations recognized by autonomous TILs," he said. The cancers included cholangiocarcinoma, and cancers of the colon, rectum, pancreas, esophagus, lung, breast, and cervix.
When the researchers looked at the cellular level with minute detail, every one of the patients was unique. Only one gene was found in two patients, the KRAS oncogene, one of the most common oncogenes. This highlights the uniqueness of what the immune system recognizes, he said.
To treatment epithelial cancers in this way, researchers need to identify the mutation and grow T cells from fresh tumor specimens, and then purify anti-tumor cells. "Can we obtain tumor reactive cells in peripheral blood through enrichment of tumor reactive cells in TIL based on expression of PD-1?" he asked.
They have begun to look at ways to do just that using so-called exhaustion markers expressed on the surface of lymphocytes, including PD-1, LAG-3, TIM-3, and 41BB. "The selection of PD-1-positive lymphocytes from TILs and from peripheral blood can enable direct enrichment of tumor reactive cells. Peripheral blood cells with these markers can be screened with a high throughput genomic approach. Mutation-specific cells detected in TILs are most often in this population and easy to isolate," he said.
He added: "We have a way to purify cells in the peripheral blood. Any intracellular protein can become a target of therapy. It's ironic in a sense. It's possible that the Achilles' heel of cancer will be the result of the very genes that caused the cancer in the first place. To cause cancer, genes have to mutate. We may be able to take advantage of those genes to treat the patient."
The absolute frequency of T-cell receptors might be a clue to anti-tumor activity and be an easier way to find T-cell receptors with anticancer activity. "In 12 melanomas tested, within the first four the most frequent T-cell receptors had anti-cancer activity. This might be a simple way to isolate cells with substantial anti-tumor activity without doing deep sequencing and screening," he said.
Rosenberg said "cell transfer therapy can mediate durable regressions in patients who are refractory to other treatments. T cells that recognize unique somatic mutations can be found in TILs and in the peripheral blood. Identification and targeting of mutations unique to each cancer has the potential to extend cell therapy to patients with common epithelial cancers."
This approach, although daunting, may lead to highly personalized cancer therapy. "You have to create a new drug for every patient. We have to obtain T cells, identify the unique mutation present in that cancer that is capable of binding to unique MAC molecule, and use it for therapy," Rosenberg said. "Once we have a reactive T cell, it can destroy any solid tumor."
Thursday, April 7, 2016
By Mark L. Fuerst
BOSTON—Researchers have developed a new way to visualize pancreatic cancer to determine the molecular details of the disease and evaluate therapeutic opportunities using organoids, or miniature organs in vitro.
Organoids provide an opportunity to create cellular models of human disease, which can be studied in the laboratory to better understand the causes of disease and identify possible treatments. "The vision is that a pancreatic cancer patient has a surgical resection or biopsy, organoids are prepared that are characterized to look for mutations in the patient's DNA and, in parallel, in organoids subjected to drugs active against that organoid. With molecular and therapeutic information, we can go back to the treating physician and suggest which drugs to treat the cancer," said David Tuveson, MD, PhD, Professor and Deputy Director of the Cancer Center at Cold Spring Harbor Laboratory in New York, in an interview with OT.
Tuveson, who is also a practicing oncologist, presented a lecture on "Pancreatic Models and Medicine" at the 2016 Society of Surgical Oncology Annual Cancer Symposium.
At the moment, organoids are an investigational approach. Tuveson and other researchers are attempting to determine whether this is a tractable model for pancreatic cancer patients, and whether it can be generalized to other cancers as well. Results from prospective studies now being conducted to evaluate this approach in pancreatic cancer patients "will within two years let us know whether this is a research tool or can help us take care of patients," Tuveson said.
Pancreatic cancer is becoming more common and is projected to become the second leading cause of death in the US by 2020. "We need better modalities," he said.
The disease is detected late. Most patients are detected with metastatic pancreatic cancer, which has one of the poorest five-year relative survival rates of any cancer, 2 percent. The overall five-year relative survival rate is 6 percent. If resected, only 20-25 percent of patients are alive at five years, he said.
Pancreatic cancer derives from mutations in key genes, including KRAS, tumor suppressor genes, and in some inherited mutations. "Inflammation promotes pancreatic cancer and can be caused by obesity, the microbiome, tobacco smoking, or intermittent alcohol drinking. We may be able to prevent mutations or inflammation through diet, avoiding tobacco, and limiting alcohol," Tuveson said, noting many mutations are due to DNA oxidation.
"We are developing accurate model systems to enable basic observations to establish dependencies and discover new therapeutics and diagnostics. We are learning more about disease onset and progression and finding new cancer vulnerabilities," he said.
Researchers are looking for therapeutics to kill the cancer, including more effective new drug combinations and novel therapies with increased efficacy, as well as biomarkers to detect pancreatic cancer earlier.
Previously, in vitro and mouse models have defined the early steps in cancer initiation. The new model adapts a system of culturing primary tissue to develop pancreatic ductal organoids. Researchers derive and culture organoids by growing a tumor or the normal duct from a human or mouse rapidly in three dimensions. "We are modeling disease progression relative to the normal pancreatic tissue in 3D culture," Tuveson said.
"We are learning from organoids to develop better therapeutics and diagnostics for a personalized approach," he continued. Organoids are used for precision medicine for biomarker discovery, therapeutic testing, to identify resistance mechanisms, characterize genetic lesions, study interactions between cell types, and predict treatment response.
After deep sequencing of tumors and organoids from tumors, "we have found more mutations in organoids than in the primary tumor," he said, adding that organoids may miss a few mutations and may be unstable. In pancreatic cancer, the stroma masks the ability to see mutations. Organoids may be a new way to unmask mutations.
Tuveson is leading the Actionable Loci in Pancreatic Cancer Specimens (ALPS) trial, which is being assessed by regulatory bodies. The trial, which plans to open this spring, will follow 50 patients with pancreatic cancer who had surgery and 50 patients with newly diagnosed metastatic pancreatic cancer, taking 300 specimens from each group.
"The idea is to develop organoids to identify drugs and demonstrate we can generate organoids in a timely fashion. The goal is to define molecular abnormalities in pancreatic cancer and to correlate this with specific therapeutic sensitivities that exist for that version of the cancer," he said. "If we make organoids on day one, will we have an answer for a physician in six months."
Tuveson likens this process to a microbiologist identifying the bacteria present in an infection, and then recommending the best drug to kill the bacteria.
He noted that seven drugs are FDA-approved for the treatment of pancreatic cancer. "We always look at them first, and then all other FDA-approved cancer drugs, as well as investigational drugs that may be promising," he said.
A spin off of the ALPS trial could help find better drugs. "Once we show that organoids can be generated, the next trial is to use organoids to direct patient management. We would have multiple arms open, similar to trials for lung cancer patients who are separated into groups based on the molecular characteristics of their tumors. Not just what the pancreatic tumor looks like, but how the tumor responds in the lab, trying to move it to be more like microbiologists," Tuveson said.
Organoids also can be used to find diagnostic biomarkers, both universal and personal. "Universal biomarkers will be useful for early detection of cancer, and personal biomarkers for longitudinal studies. We can identify multiple mutations in a patient's genome and look for epitopes on the surface of organoids," Tuveson said.
In the future, researchers may assemble a large collection of organoids in all variants of pancreatic cancer. "This bank of organoids will be used for therapeutic investigations for optimal strategies that can be provided to new patients on demand. We will still need individual organoids for personal diagnostics and to follow patients in the future, when we expect we will have better drugs and patients will become resistant to drugs for different reasons," Tuveson said.
He foresees a registry of cross species of organoids to reveal biomarkers of early pancreatic ductal adenocarcinoma. "We could develop a blood test for pancreatic cancer using a protein-based assay," he said.
Organoids "may be a new way to get tissue from patients as we care for them. The tissue may be a crystal ball into their disease. We can peer into the molecular causes of the cancer, look for therapeutic methods to treatment it, and develop diagnostics for their specific cancer," Tuveson said.
"It's a method that makes sense," he continued. "It's something that we could scale up and speed up. The idea is to do it rapidly, efficiently, and economically. This may be a new way to look at cancer in patients. I anticipate it has a good shot at playing a role of how we take care of pancreatic cancer patients in the future."
Thursday, April 7, 2016
By Mark L. Fuerst
BOSTON—Cancer will become the first serious battlefield of precision medicine, according to one of the leaders in the revolution to bring genomics into clinical practice.
"Clinical genomics will become an integral part of an oncologist's clinical practice. It will open up tremendous possibilities for physicians and their patients. Within two years, the field will make this available to practicing physicians, not just academic institutions, and will permeate every single clinical practice," said Jose Baselga, MD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, in an interview.
Baselga presented a talk on "Bringing Precision Cancer Medicine Forward" at the 2016 Society of Surgical Oncology Annual Cancer Symposium.
The big revolution will be in so-called "liquid biopsies" using circulating tumor DNA (ctDNA), he said. "It won't take that long to bring this vision of precision medicine forward. The technology is already here and the cost of tumor sequencing is going down. We could see genomic tests for less $1,000," Baselga said, adding that the costs will need to be reimbursed.
The ability of ctDNA analysis to reveal new mutations allows monitoring of clonal heterogeneity without the need for multiple tumor biopsies. The promise of ctDNA monitoring is to allow clinicians to detect resistant mechanisms early, and then to tailor treatments. It may also have important applications to stratify treatment after surgery or radical radiotherapy and may play a role in patient screening.
"It's not feasible to biopsy every metastatic site to sequence tumors. We also need to improve the way we assess response. Using CT or MRI takes months. That is too long. Now it's possible to look at the presence of DNA or nucleic acids in the blood and get results within days. This will clearly change medicine," Baselga said.
Researchers at MSKCC have launched a comprehensive effort to study ctDNA in a Liquid Biopsy Task Force. They have collected 2,400 samples from 964 patients with breast cancer (metastatic, neoadjuvant, early) and lung cancer (metastatic and early). They are using a 504 gene pan-cancer panel to detect ctDNA and attempting to utilize this as a surrogate for multiple repeated biopsies to predict response to therapy or recurrence.
"We are starting to use this as a marker to detect early disease. We can detect stage 1 breast cancer just by taking a look at the blood," Baselga said. "In the blood, we can see everything present in tumor in a less-invasive fashion. Going forward, we are beginning to monitor ctDNA as part of routine clinical research. We are using liquid biopsy in every targeted therapy trial. We have the possibility to select patients not based on tumor biopsy, but on the presence of ctDNA in the blood."
Tumor DNA is now being checked in the blood with the hopes of capturing the presence of DNA mutations. "The principle is we can get good representation across the whole ecosystem of a particular tumor. At resistance, we can look at what's going on as well," he said.
Unlike serial biopsies that capture different mutations at different sites, "liquid biopsies detect everything," Baselga said.
Another application is to monitor response to therapy. "Early on, by day 4 to 6, we can know if the tumor is responding. If it is not shrinking within one week, we know that the treatment is not working and we need to do something else," he said.
In his talk, he mentioned an anecdote about a breast cancer patient who had an estrogen receptor clone that was noted on ctDNA testing. An antiestrogen was added to her therapy, and she has responded for more than 300 days.
At the moment, the limiting step in using ctDNA analysis is not in sequencing tumors, but in sharing information with clinicians.
"We need to provide knowledge that will enable physicians and patients to make decisions about therapy. We realize data need to be annotated for practicing physicians so they understand what the ctDNA profile means," he said.
"We need a system that provides clinical, real-time annotations, for example, that a certain tumor is eligible for a clinical trial, or that a patient should receive a certain type of therapy."
This type of system is already taking shape in academic centers, and a number of initiatives have been launched by the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO). "The goal is to improve therapies based on genomic findings," he said.
The AACR Project Genomics, Evidence, Neoplasia, Information, Exchange) is a multi-phase, multi-year, international data-sharing project that catalyzes precision oncology through the development of a regulatory-grade registry that aggregates and links clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at multiple international institutions.
The ASCO Institute for Quality, LLC, is leading the development of CancerLinQ, a cutting-edge health information technology platform. The goal is to aggregate and analyze a massive web of real-world cancer care data to provide real-time quality feedback to providers, feed personalized insights to doctors, and uncover patterns that can improve care.
"If we sequence tumors, and especially ctDNA in the blood and monitor tumor evolution as it occurs, we will be able, for each tumor type and genomic alteration, to map out a book of rules," Baselga said. "There are only a certain number of strategies that a tumor may have to escape from selective pressure from a given therapy. If we study multiple tumor types, how they evolve and develop resistance, then we can define a book of rules so we can predict what will happen next."
Real-time monitoring of clonal composition of tumors may become possible. In a study published in Nature last year (2015;518:240-4). Baselga and colleagues found that metastatic breast cancer patients who progress on PI3K inhibitors develop specific mutations in that pathway. "If we could follow the emergence of clones of resistance, we could react must faster and better with appropriate combination therapy. If we begin to detect resistance early on, then we could intervene to wipe out a developing clone."
"For the first time, we may be ahead of the game instead of reacting," Baselga continued. "We can use cancer drugs that address the underlying mechanism of resistance instead of waiting for months, as we do now."
Thursday, April 7, 2016
By Ed Susman
SAN FRANCISCO—An at-home system that monitors how well cancer patients undergoing radiation therapy are doing may help keep patients with head and neck cancer from life-threatening bouts of dehydration, suggest researchers at the University of Texas MD Anderson Cancer Center (Abstract 152).
The so-called CYCORE program, funded in an ongoing, National Cancer Institute study, uses remote-sensor technology to collect data on cancer survivors when they are away from the clinic setting, explained Susan Peterson, PhD, Professor of Behavioral Science, Cancer Prevention, and Population Sciences at MD Anderson Cancer Center, and Adjunct Professor of Health Promotion and Behavioral Sciences at the University of Texas Health Science Center at Houston School of Public Health.
"This project is specifically related to head and neck cancer who are undergoing radiation treatment," Peterson told Oncology Times. "They are at increased risk during radiation treatment for becoming dehydrated because of their treatment.
"Radiation-induced mucositis makes it very difficult to eat, to drink, to swallow, and the onset of dehydration can occur very rapidly—even within a day's time," she said at her poster presentation. "People can come in the morning for their treatment and then they can decline very quickly, which results in emergency room visits, hospitalization, increased costs, and possibly interruption in treatment."
Up to 80% of patients receiving radiation therapy for head and neck cancer experience mucositis, she said, which occurs along with other symptoms that impact eating and drinking, such as difficulty swallowing, pain, taste alterations, nausea, and appetite loss. In 2015, there were expected to be 45,780 new cases and 8,650 deaths from head and neck cancers. Up to one-third of head and neck cancer patients may be hospitalized due to dehydration during radiation therapy, she said.
As of the end of 2015, the researchers assigned 79 patients with head and neck cancer who are undergoing radiation to the intervention through the CYCORE system and 80 similar patients to usual care. The patients were gleaned from 801 patients, most of whom failed to meet entry criteria.
"We are about halfway through with recruitment," Peterson said. "We have really great recruitment—about 90% of the patients being treated—and we have 90% retention. The patients love it. Even the patients on the control arm like it. The ones on the CYCORE intervention say 'we feel we are being extra cared for' or 'this is an extra tool I can use to keep me from being sick.'"
The primary objective of the study is to reduce hospitalization and emergency room visits relative to usual care and to determine if the system reduces concomitant health care-related costs.
"Hopefully at this time next year, we will be able to show some results," Peterson reported. Early identification and mitigation of dehydration risk during radiation therapy can help avoid treatment interruptions, improve quality of life, and reduce complications and health care costs.
Peterson said the study is being developed in conjunction with colleagues at the University of California at San Diego and the University of Alabama at Birmingham Comprehensive Cancer Center.
The patients use the sensing devices at home and on the go, Peterson said. The sensors collect blood pressure, pulse and weight data. Data is sent to a 2net hub, which gathers data from sensors and then sends it on to CYCORE. Data from patient-reported outcomes on tablets or smartphones are also sent to CYCORE.
"Our clinicians log in to our system every day to take a look at the patients who are being monitored.
The patients, through a mobile app, will also answer questions related to symptoms of dehydration," Peterson said. "When these symptoms look worrisome in regard to pain or vomiting, the system also flags the condition so that the clinician's attention will be drawn to it. The clinician then evaluates the finding, will call the patient or have them come in for intravenous fluids, or talk to them about their medications."
Patients were eligible for the study if they had received a head and neck cancer diagnosis, specifically: oropharyngeal, hypopharyngeal, nasopharyngeal, laryngeal, salivary gland, thyroid, oral cavity, or unknown primary head and neck cancer with cervical metastasis. They also were required to be undergoing bilateral radiation therapy with curative intent. They were not eligible if they had prior dysphagia, radiation therapy for head and neck cancer, or enrollment in a trial with toxicity endpoint.
In commenting on the study, Dennis H Kraus, MD, Director of the Center for Head & Neck Oncology within the New York Head & Neck Institute at Northwell Health Cancer Institute at Lenox Hill Hospital, told OT. "The problem of dehydration among people with head and neck cancer undergoing radiation is a very real problem."
The system outlined in the MD Anderson study is an innovative proposal and it may allow for early detection of patients who have become dehydrated. It really is a cool idea. I think the system has real potential for changing outcomes and avoiding hospitalizations and acute complications," Kraus said.
Thursday, April 7, 2016
By Ed Susman
SAN FRANCISCO—Younger cancer patients and those who may consider themselves financially secure appear to be the type of person who needs focused intervention in the form of cancer survivorship care plans, researchers suggested at the inaugural ASCO Cancer Survivorship Symposium. [Abstract 8]
"This is a phase of life issue," said Elizabeth Kvale, MD, Director of the Supportive Care and Survivorship Program and Associate Professor of Medicine at the University of Alabama at Birmingham.
"When you are a younger person, you have competing life priorities and cancer survivorship doesn't fit in very well," she told OT in discussing her poster presentation. "For some, it doesn't fit in at all as to where you thought you were going to be in your life trajectory."
After analyzing responses from a cohort of breast cancer survivors, Kvale and colleagues reported that baseline characteristics including younger age, lower perceived finance adequacy, higher medical comorbidity, burden of depression, and anxious/preoccupation coping were significantly associated with greater self-reported health change (P < 0.05).
Additionally, higher levels of cancer symptom severity, fatigue, lower social functioning, and mental health status at baseline were significantly correlated with greater improvement on depressive symptoms (P < 0.05). Race, education, health literacy level, and cancer stage were not associated with improved outcomes, Kvale said.
What those findings indicate is that, "while survivorship care planning is an important step to improving care for cancer survivors, it is likely that some cancer survivors need a robust intervention to support self-management of survivorship issues," the researchers reported.
The POSTCARE intervention (Patient-Owned Survivorship Transition Care for Activated, EmpoweREd Survivors) demonstrates a positive impact on quality of life, depression, and self-efficacy, Kvale said.
"Our preliminary findings suggest that patients with younger age and higher perceived financial, emotional, and cancer symptom burdens may benefit from a focused survivorship care plan intervention to a greater extent than patients without these characteristics," she said. "There have been a lot of survivorship care plans that don't show a difference, but this is a different way of doing it. The focus is on the process rather than the plan. The survivor gets to prioritize.
"Appropriate targeting of survivorship care planning interventions to patient need is essential, but little evidence exists to support systematic triaging according to survivor needs," she said. Therefore, the researchers sought to examine how patient characteristics predict response to POSTCARE.
In the parent study, researchers enrolled 79 recent breast cancer survivors. They randomized 40 women to receive the POSTCARE intervention and 39 women were assigned to usual care. Kvale said 75 participants completed post-intervention assessments at 3-month follow-up.
POSTCARE is a single coaching encounter utilizing motivational interviewing techniques to engage patients in the development of a patient-owned survivorship care plan that incorporates health goals and strategies related to surveillance, symptom management, and health behavior, Kvale explained. The survivorship coaching intervention was delivered by masters-level mental health professionals who completed motivational interviewing trainings.
The steps involved in the intervention include:
- rapport building and survivorship narration elicitation;
- a review of the treatment summary;
- identification of personalized health goals along with strategies to achieve those goals;
- identification of a health care team and a primary care provider;
- identification of red flags;
- review of medication and exploration of hormonal therapy adherence; and
- review of care transition self-management checklist and completion of the survivorship care plan.
The researchers conducted their data analyses using SPSS (Version 22) and SAS (Version 9.4) programs. Descriptive analyses were performed to assess demographic and treatment characteristics. Linear regression and mixed effect models were conducted to examine the effect of POSTCARE intervention on care coordination, health-related quality of life, and depression. Bivariate correlations were conducted to examine patient characteristics associated with response to the intervention.
Kvale said further work in creating beneficial survivorship care plans should build on errors to define targeting strategies to identify cancer survivors who will benefit from robust survivorship transition support.