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NCI launches ALCHEMIST to investigate precision medicine in early lung cancer
A second precision medicine collaboration focused on lung cancer has been launched as part of the new National Cancer Institue–supported National Clinical Trials Network. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST, will screen early-stage lung cancer patients for tumor EGFR mutations or ALK rearrangements and evaluate whether adjuvant targeted treatment can prevent recurrence and improve survival, according to a statement issued by the National Institutes of Health.
The first trial, Lung-MAP, for patients with advanced squamous cell lung cancer, launched in June. ALCHEMIST is an integration of three trials for patients with stage IB, II or IIIA non-squamous non-small cell lung cancer. A screening trial will screen 6,000-8,000 potential participants over 5-6 years to identify those with EGFR and ALK alterations.
Eligible patients will then be referred to one of two randomized, placebo-controlled ALCHEMIST treatment trials, one to evaluate erlotinib, and the other crizotinib, in the post-operative setting.
The researchers expect a total enrollment of approximately 800 patients in each of the treatment trials.
All of the NCI-supported National Clinical Trials Network groups collaborated in the development of ALCHEMIST and are participating in the component trials, the NIH statement says.
On Twitter @nikolaideslaura
A second precision medicine collaboration focused on lung cancer has been launched as part of the new National Cancer Institue–supported National Clinical Trials Network. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST, will screen early-stage lung cancer patients for tumor EGFR mutations or ALK rearrangements and evaluate whether adjuvant targeted treatment can prevent recurrence and improve survival, according to a statement issued by the National Institutes of Health.
The first trial, Lung-MAP, for patients with advanced squamous cell lung cancer, launched in June. ALCHEMIST is an integration of three trials for patients with stage IB, II or IIIA non-squamous non-small cell lung cancer. A screening trial will screen 6,000-8,000 potential participants over 5-6 years to identify those with EGFR and ALK alterations.
Eligible patients will then be referred to one of two randomized, placebo-controlled ALCHEMIST treatment trials, one to evaluate erlotinib, and the other crizotinib, in the post-operative setting.
The researchers expect a total enrollment of approximately 800 patients in each of the treatment trials.
All of the NCI-supported National Clinical Trials Network groups collaborated in the development of ALCHEMIST and are participating in the component trials, the NIH statement says.
On Twitter @nikolaideslaura
A second precision medicine collaboration focused on lung cancer has been launched as part of the new National Cancer Institue–supported National Clinical Trials Network. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST, will screen early-stage lung cancer patients for tumor EGFR mutations or ALK rearrangements and evaluate whether adjuvant targeted treatment can prevent recurrence and improve survival, according to a statement issued by the National Institutes of Health.
The first trial, Lung-MAP, for patients with advanced squamous cell lung cancer, launched in June. ALCHEMIST is an integration of three trials for patients with stage IB, II or IIIA non-squamous non-small cell lung cancer. A screening trial will screen 6,000-8,000 potential participants over 5-6 years to identify those with EGFR and ALK alterations.
Eligible patients will then be referred to one of two randomized, placebo-controlled ALCHEMIST treatment trials, one to evaluate erlotinib, and the other crizotinib, in the post-operative setting.
The researchers expect a total enrollment of approximately 800 patients in each of the treatment trials.
All of the NCI-supported National Clinical Trials Network groups collaborated in the development of ALCHEMIST and are participating in the component trials, the NIH statement says.
On Twitter @nikolaideslaura
ESMO updates practice guidelines for bladder cancer
Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.
The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).
Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.
The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.
On Twitter @nikolaideslaura
Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.
The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).
Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.
The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.
On Twitter @nikolaideslaura
Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.
The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).
Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.
The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.
On Twitter @nikolaideslaura
FROM ANNALS OF ONCOLOGY
VIDEO: ABT-199 alone and in combination shows promise against advanced CLL
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
AT THE EHA CONGRESS
Latest evidence clarifies management of prostate cancer in elderly
A review of the existing evidence to date on the management of prostate cancer in the older population was published online July 28 as part of a special issue of the Journal of Clinical Oncology devoted to geriatric oncology.
Underlying health status and age-related changes can have an effect on tolerance of hormonal therapy and chemotherapy in men with advanced disease, said Dr. Chunkit Fung of the University of Rochester (N.Y.) and his associates.
They recommend using common geriatric assessment tools to categorize men into "stages of age" to assist with decision making. They used this framework – categorizing men as fit, vulnerable, and frail – to provide an evidence-based guide to the management of older men with prostate cancer, with a focus on systemic disease. The review is available on the journal’s website here.
On Twitter @nikolaideslaura
A review of the existing evidence to date on the management of prostate cancer in the older population was published online July 28 as part of a special issue of the Journal of Clinical Oncology devoted to geriatric oncology.
Underlying health status and age-related changes can have an effect on tolerance of hormonal therapy and chemotherapy in men with advanced disease, said Dr. Chunkit Fung of the University of Rochester (N.Y.) and his associates.
They recommend using common geriatric assessment tools to categorize men into "stages of age" to assist with decision making. They used this framework – categorizing men as fit, vulnerable, and frail – to provide an evidence-based guide to the management of older men with prostate cancer, with a focus on systemic disease. The review is available on the journal’s website here.
On Twitter @nikolaideslaura
A review of the existing evidence to date on the management of prostate cancer in the older population was published online July 28 as part of a special issue of the Journal of Clinical Oncology devoted to geriatric oncology.
Underlying health status and age-related changes can have an effect on tolerance of hormonal therapy and chemotherapy in men with advanced disease, said Dr. Chunkit Fung of the University of Rochester (N.Y.) and his associates.
They recommend using common geriatric assessment tools to categorize men into "stages of age" to assist with decision making. They used this framework – categorizing men as fit, vulnerable, and frail – to provide an evidence-based guide to the management of older men with prostate cancer, with a focus on systemic disease. The review is available on the journal’s website here.
On Twitter @nikolaideslaura
FROM THE JOURNAL OF CLINICAL ONCOLOGY
TCGA investigators propose four subtypes of gastric cancer
Gastric cancer can be classified into four subtypes based on the molecular characterization of 295 primary adenocarcinomas, report investigators with The Cancer Genome Atlas (TCGA) Research Network online July 23 in Nature.
With the goal of developing classifiers that can ultimately guide patient therapy, the investigators propose four major genomic subtypes of gastric cancer: Epstein-Barr virus–infected tumors, microsatellite unstable tumors, genomically stable tumors, and chromosomally unstable tumors. Identification of these subtypes provides a road map for patient stratification and trials of targeted therapies, the network of investigators said.
The full report, Comprehensive Molecular Characterization of Gastric Adenocarcinoma, is available through open access at nature.com (doi: 10.1038/nature13480).
On Twitter @nikolaideslaura
Gastric cancer can be classified into four subtypes based on the molecular characterization of 295 primary adenocarcinomas, report investigators with The Cancer Genome Atlas (TCGA) Research Network online July 23 in Nature.
With the goal of developing classifiers that can ultimately guide patient therapy, the investigators propose four major genomic subtypes of gastric cancer: Epstein-Barr virus–infected tumors, microsatellite unstable tumors, genomically stable tumors, and chromosomally unstable tumors. Identification of these subtypes provides a road map for patient stratification and trials of targeted therapies, the network of investigators said.
The full report, Comprehensive Molecular Characterization of Gastric Adenocarcinoma, is available through open access at nature.com (doi: 10.1038/nature13480).
On Twitter @nikolaideslaura
Gastric cancer can be classified into four subtypes based on the molecular characterization of 295 primary adenocarcinomas, report investigators with The Cancer Genome Atlas (TCGA) Research Network online July 23 in Nature.
With the goal of developing classifiers that can ultimately guide patient therapy, the investigators propose four major genomic subtypes of gastric cancer: Epstein-Barr virus–infected tumors, microsatellite unstable tumors, genomically stable tumors, and chromosomally unstable tumors. Identification of these subtypes provides a road map for patient stratification and trials of targeted therapies, the network of investigators said.
The full report, Comprehensive Molecular Characterization of Gastric Adenocarcinoma, is available through open access at nature.com (doi: 10.1038/nature13480).
On Twitter @nikolaideslaura
FROM NATURE
Lung-MAP trial launched, matching patients to treatments based on tumor profiles
A phase II/III trial using genomic profiling to match patients with investigational treatments began recruiting patients with advanced squamous cell lung cancer on June 16, 2014.
The Lung-MAP (Lung Cancer Master Protocol) trial is a public-private collaboration among the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, Foundation Medicine, and five pharmaceutical companies (Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics R&D arm, MedImmune).
"Lung-MAP represents the first of several planned large, genomically driven treatment trials that will be conducted by NCI’s newly formed National Clinical Trials Network (NCTN)," Dr. Jeffrey S. Abrams, associate director of NCI’s Cancer Therapy Evaluation Program, said in a press release announcing the trial launch. "The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it now can offer an ideal platform for bringing the benefits of more precise molecular diagnostics to cancer patients in communities large and small, " he said.
Lung-MAP is expected to enroll 10,000 patients and be completed in 2022. To be eligible, patients will have progressed after receiving exactly one front-line, platinum-containing metastatic chemotherapy regimen. Between 500 and 1,000 patients will be screened per year for more than 200 cancer-related gene alterations. Based on the tumor profiles, all patients will then be assigned to one of five initial treatment arms, testing four investigational targeted treatments and an anti-PD-L1 immunotherapy.
The trial will be conducted at more than 200 medical centers. As many as five to seven additional drugs may be evaluated over the next 5 years, the press release said. Information on enrolling patients can be found on the trial website.
A phase II/III trial using genomic profiling to match patients with investigational treatments began recruiting patients with advanced squamous cell lung cancer on June 16, 2014.
The Lung-MAP (Lung Cancer Master Protocol) trial is a public-private collaboration among the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, Foundation Medicine, and five pharmaceutical companies (Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics R&D arm, MedImmune).
"Lung-MAP represents the first of several planned large, genomically driven treatment trials that will be conducted by NCI’s newly formed National Clinical Trials Network (NCTN)," Dr. Jeffrey S. Abrams, associate director of NCI’s Cancer Therapy Evaluation Program, said in a press release announcing the trial launch. "The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it now can offer an ideal platform for bringing the benefits of more precise molecular diagnostics to cancer patients in communities large and small, " he said.
Lung-MAP is expected to enroll 10,000 patients and be completed in 2022. To be eligible, patients will have progressed after receiving exactly one front-line, platinum-containing metastatic chemotherapy regimen. Between 500 and 1,000 patients will be screened per year for more than 200 cancer-related gene alterations. Based on the tumor profiles, all patients will then be assigned to one of five initial treatment arms, testing four investigational targeted treatments and an anti-PD-L1 immunotherapy.
The trial will be conducted at more than 200 medical centers. As many as five to seven additional drugs may be evaluated over the next 5 years, the press release said. Information on enrolling patients can be found on the trial website.
A phase II/III trial using genomic profiling to match patients with investigational treatments began recruiting patients with advanced squamous cell lung cancer on June 16, 2014.
The Lung-MAP (Lung Cancer Master Protocol) trial is a public-private collaboration among the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, Foundation Medicine, and five pharmaceutical companies (Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics R&D arm, MedImmune).
"Lung-MAP represents the first of several planned large, genomically driven treatment trials that will be conducted by NCI’s newly formed National Clinical Trials Network (NCTN)," Dr. Jeffrey S. Abrams, associate director of NCI’s Cancer Therapy Evaluation Program, said in a press release announcing the trial launch. "The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it now can offer an ideal platform for bringing the benefits of more precise molecular diagnostics to cancer patients in communities large and small, " he said.
Lung-MAP is expected to enroll 10,000 patients and be completed in 2022. To be eligible, patients will have progressed after receiving exactly one front-line, platinum-containing metastatic chemotherapy regimen. Between 500 and 1,000 patients will be screened per year for more than 200 cancer-related gene alterations. Based on the tumor profiles, all patients will then be assigned to one of five initial treatment arms, testing four investigational targeted treatments and an anti-PD-L1 immunotherapy.
The trial will be conducted at more than 200 medical centers. As many as five to seven additional drugs may be evaluated over the next 5 years, the press release said. Information on enrolling patients can be found on the trial website.
Low-dose IMRT may be safe for patients with HPV-positive head and neck cancer
CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.
Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.
Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.
However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.
"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.
The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.
On Twitter @nikolaideslaura
CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.
Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.
Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.
However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.
"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.
The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.
On Twitter @nikolaideslaura
CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.
Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.
Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.
However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.
"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.
The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.
On Twitter @nikolaideslaura
AT THE ASCO ANNUAL MEETING 2014
Key clinical finding: Some patients with HPV-positive oropharyngeal cancer may be able to avoid possible long-term side effects by receiving lower-dose radiation therapy, though a randomized trial is needed.
Major finding: Two-year overall survival and progression-free survival were 93% and 80%, respectively, among patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose IMRT after clinical complete response to induction.
Data source: Phase II study of 90 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received either lower-dose IMRT or standard-dose IMRT based on their response after induction chemotherapy.
Disclosures: The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.
Whole-genome sequencing not ready for prime time
Clinicians and the public have held great hope for years that genomic analysis would transform the prevention and treatment of disease, but although costs may be plummeting, challenges persist, investigators reported March 12th in JAMA.
Sequencing the genome of individuals has become much less expensive, but translating those results into clinically useful information is labor intensive, and fraught with inconsistencies and uncertainties, reported Dr. Frederick E. Dewey of the Stanford (Calif.) Center for Inherited Cardiovascular Disease and his associates (JAMA 2014;311:1035-44).
Three academic primary care physicians and two academic medical geneticists separately reviewed whole-genome sequencing (WGS) results from 12 adult participants, and each proposed clinical follow-up based on the findings. The DNA from whole-blood samples obtained from five men and seven women without any known inherited disease risk was sequenced by commonly used platforms (all 12 at Illumina, with confirmatory sequencing performed for 9 of the participants by Complete Genomics). Two of the primary care physicians had no previous experience with genomic medicine or genetics training, the investigators reported.
Up to one-fifth of gene variants known to be associated with disease risk were not covered at a minimum threshold for discovery, meaning there could be significant gaps in predicting individual risk. For those genetic variants that met the threshold, concordance between the two sequencing platforms was high for common variants (99%), but was substantially lower for genetic variants that were candidates for inherited disease risk (median, 33%; range, 10%-75%), Dr. Dewey and his associates said.
For each participant, the WGS identified between 90 and 127 novel or rare genetic variations, and between 12 and 20 commonly reported variations, all candidates for curation with respect to personal risk and carrier status for inherited disease. The geneticists’ review of the evidence for pathogenicity for each variant required a median time of 54 minutes (range, 5-223 minutes). Based on this finding, investigators estimated the median cost for sequencing and variant interpretation for each participant was $14,815.
Review of the medical genomics report by the three primary care physicians prompted consideration of a median one to three initial follow-up referrals and diagnostic tests per participant. The agreement between physicians about suitability for follow-up of findings was fair, the investigators reported.
In the end, 1 of the 12 participants went on to take action as a result of the findings. A BRCA1 mutation was found in a woman with no family history of breast or ovarian cancer, and she subsequently underwent prophylactic bilateral salpingo-oophorectomy.
Overall, the results illustrate several challenges to clinical adoption of whole-genome sequencing, the authors suggested. Although the analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. The finding of only one-third of insertion/deletion genetic variants in inherited disease genes confirmed by the second sequencing platform suggests that variants likely to be pathogenic are more often inconsistently identified, Dr. Dewey and his associates said.
"In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings," they wrote.
The research was supported by grants from the National Institutes of Health, the Breetwor Family Foundation, and the LeDucq Foundation. Dr. Dewey reported being a stockholder and member of the scientific advisory board of Personalis, a privately held genome interpretation company, and receiving royalties for patented technology related to genome sequencing. Some of his associates were scientific advisers for companies involved in genomics or received royalties for patented technologies related to genome sequencing.
On Twitter @nikolaideslaura
Clinicians and the public have held great hope for years that genomic analysis would transform the prevention and treatment of disease, but although costs may be plummeting, challenges persist, investigators reported March 12th in JAMA.
Sequencing the genome of individuals has become much less expensive, but translating those results into clinically useful information is labor intensive, and fraught with inconsistencies and uncertainties, reported Dr. Frederick E. Dewey of the Stanford (Calif.) Center for Inherited Cardiovascular Disease and his associates (JAMA 2014;311:1035-44).
Three academic primary care physicians and two academic medical geneticists separately reviewed whole-genome sequencing (WGS) results from 12 adult participants, and each proposed clinical follow-up based on the findings. The DNA from whole-blood samples obtained from five men and seven women without any known inherited disease risk was sequenced by commonly used platforms (all 12 at Illumina, with confirmatory sequencing performed for 9 of the participants by Complete Genomics). Two of the primary care physicians had no previous experience with genomic medicine or genetics training, the investigators reported.
Up to one-fifth of gene variants known to be associated with disease risk were not covered at a minimum threshold for discovery, meaning there could be significant gaps in predicting individual risk. For those genetic variants that met the threshold, concordance between the two sequencing platforms was high for common variants (99%), but was substantially lower for genetic variants that were candidates for inherited disease risk (median, 33%; range, 10%-75%), Dr. Dewey and his associates said.
For each participant, the WGS identified between 90 and 127 novel or rare genetic variations, and between 12 and 20 commonly reported variations, all candidates for curation with respect to personal risk and carrier status for inherited disease. The geneticists’ review of the evidence for pathogenicity for each variant required a median time of 54 minutes (range, 5-223 minutes). Based on this finding, investigators estimated the median cost for sequencing and variant interpretation for each participant was $14,815.
Review of the medical genomics report by the three primary care physicians prompted consideration of a median one to three initial follow-up referrals and diagnostic tests per participant. The agreement between physicians about suitability for follow-up of findings was fair, the investigators reported.
In the end, 1 of the 12 participants went on to take action as a result of the findings. A BRCA1 mutation was found in a woman with no family history of breast or ovarian cancer, and she subsequently underwent prophylactic bilateral salpingo-oophorectomy.
Overall, the results illustrate several challenges to clinical adoption of whole-genome sequencing, the authors suggested. Although the analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. The finding of only one-third of insertion/deletion genetic variants in inherited disease genes confirmed by the second sequencing platform suggests that variants likely to be pathogenic are more often inconsistently identified, Dr. Dewey and his associates said.
"In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings," they wrote.
The research was supported by grants from the National Institutes of Health, the Breetwor Family Foundation, and the LeDucq Foundation. Dr. Dewey reported being a stockholder and member of the scientific advisory board of Personalis, a privately held genome interpretation company, and receiving royalties for patented technology related to genome sequencing. Some of his associates were scientific advisers for companies involved in genomics or received royalties for patented technologies related to genome sequencing.
On Twitter @nikolaideslaura
Clinicians and the public have held great hope for years that genomic analysis would transform the prevention and treatment of disease, but although costs may be plummeting, challenges persist, investigators reported March 12th in JAMA.
Sequencing the genome of individuals has become much less expensive, but translating those results into clinically useful information is labor intensive, and fraught with inconsistencies and uncertainties, reported Dr. Frederick E. Dewey of the Stanford (Calif.) Center for Inherited Cardiovascular Disease and his associates (JAMA 2014;311:1035-44).
Three academic primary care physicians and two academic medical geneticists separately reviewed whole-genome sequencing (WGS) results from 12 adult participants, and each proposed clinical follow-up based on the findings. The DNA from whole-blood samples obtained from five men and seven women without any known inherited disease risk was sequenced by commonly used platforms (all 12 at Illumina, with confirmatory sequencing performed for 9 of the participants by Complete Genomics). Two of the primary care physicians had no previous experience with genomic medicine or genetics training, the investigators reported.
Up to one-fifth of gene variants known to be associated with disease risk were not covered at a minimum threshold for discovery, meaning there could be significant gaps in predicting individual risk. For those genetic variants that met the threshold, concordance between the two sequencing platforms was high for common variants (99%), but was substantially lower for genetic variants that were candidates for inherited disease risk (median, 33%; range, 10%-75%), Dr. Dewey and his associates said.
For each participant, the WGS identified between 90 and 127 novel or rare genetic variations, and between 12 and 20 commonly reported variations, all candidates for curation with respect to personal risk and carrier status for inherited disease. The geneticists’ review of the evidence for pathogenicity for each variant required a median time of 54 minutes (range, 5-223 minutes). Based on this finding, investigators estimated the median cost for sequencing and variant interpretation for each participant was $14,815.
Review of the medical genomics report by the three primary care physicians prompted consideration of a median one to three initial follow-up referrals and diagnostic tests per participant. The agreement between physicians about suitability for follow-up of findings was fair, the investigators reported.
In the end, 1 of the 12 participants went on to take action as a result of the findings. A BRCA1 mutation was found in a woman with no family history of breast or ovarian cancer, and she subsequently underwent prophylactic bilateral salpingo-oophorectomy.
Overall, the results illustrate several challenges to clinical adoption of whole-genome sequencing, the authors suggested. Although the analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. The finding of only one-third of insertion/deletion genetic variants in inherited disease genes confirmed by the second sequencing platform suggests that variants likely to be pathogenic are more often inconsistently identified, Dr. Dewey and his associates said.
"In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings," they wrote.
The research was supported by grants from the National Institutes of Health, the Breetwor Family Foundation, and the LeDucq Foundation. Dr. Dewey reported being a stockholder and member of the scientific advisory board of Personalis, a privately held genome interpretation company, and receiving royalties for patented technology related to genome sequencing. Some of his associates were scientific advisers for companies involved in genomics or received royalties for patented technologies related to genome sequencing.
On Twitter @nikolaideslaura
FROM JAMA
Major finding: For each participant, whole-genome sequencing identified between 90 and 127 novel or rare genetic variations, and between 12 and 20 commonly reported variations.
Data source: Whole-genome sequencing was performed from whole-blood samples of 12 adult volunteers, and reports were analyzed by geneticists and primary care physicians for follow-up.
Disclosures: The research was supported by grants from the National Institutes of Health, the Breetwor Family Foundation, and the LeDucq Foundation. Dr. Dewey reported being a stockholder and member of the scientific advisory board of Personalis, a privately held genome interpretation company, and receiving royalties for patented technology related to genome sequencing. Some of his associates were scientific advisers for companies involved in genomics or received royalties for patented technologies related to genome sequencing.
Bevacizumab fails to improve survival in newly diagnosed glioblastoma
The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.
Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.
Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)
Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.
Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).
Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.
Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.
On Twitter @NikolaidesLaura
The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.
Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.
Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)
Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.
Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).
Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.
Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.
On Twitter @NikolaidesLaura
The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.
Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.
Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)
Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.
Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).
Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.
Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.
On Twitter @NikolaidesLaura
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Two similar studies found no difference in median survival with the addition of bevacizumab to standard therapy for patients with newly diagnosed glioblastoma. Median overall survival was 15.7 months in the bevacizumab arm vs. 16.1 months in the placebo arm in one study, and16.8 months in the bevacizumab arm vs. 16.7 months in the placebo arm in a second, similar study.
Data source: Two randomized, double-blind placebo-controlled phase III trials; the Radiation Therapy Oncology Group (RCOG) 0825 trial included 637 patients and the Avastin in Glioblastoma (Avaglia) trial involved 921 patients.
Disclosures: The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.
Bevacizumab improved survival in advanced cervical cancer
Adding bevacizumab to combination chemotherapy improved survival for women with advanced cervical cancer.
Women in the Gynecologic Oncology Group (GOG) trial who received bevacizumab in addition to chemotherapy lived about 4 months longer than their counterparts who received chemotherapy alone, Dr. Krishnansu S. Tewari and his associates reported Feb. 20 in the New England Journal of Medicine.
The trial was open to women who had chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer. A total of 452 women were randomized in dual factorial design according to chemotherapy doublet (cisplatin plus paclitaxel vs. topotecan plus paclitaxel) and receipt of bevacizumab (yes vs. no). Treatment was on an open-label basis, and crossover was not allowed (N. Engl. J. Med. 2014;370:734-43).
An interim analysis showed that the topotecan-paclitaxel regimen was neither superior nor inferior to the cisplatin-paclitaxel regimen that has been the standard in this setting.
With longer follow-up, to a median of 20.8 months, women who received added bevacizumab had a longer median overall survival than did their counterparts who received chemotherapy alone (17.0 vs. 13.3 months; hazard ratio, 0.71; P = .0035). Bevacizumab conferred a significant survival benefit when added to cisplatin-paclitaxel chemotherapy (HR, 0.68; P = .03) but not when added to topotecan-paclitaxel chemotherapy (HR, 0.74; P = .09).
Adverse effects were largely consistent with previous experience in other cancers with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, Dr. Tewari and his associates reported.
The study was presented last year at the annual meeting of the American Society of Clinical Oncology. See our full coverage here.
The trial was sponsored by the National Cancer Institute. Dr. Tewari disclosed no relevant conflicts of interest. Roche/Genentech provided bevacizumab for the trial.
Adding bevacizumab to combination chemotherapy improved survival for women with advanced cervical cancer.
Women in the Gynecologic Oncology Group (GOG) trial who received bevacizumab in addition to chemotherapy lived about 4 months longer than their counterparts who received chemotherapy alone, Dr. Krishnansu S. Tewari and his associates reported Feb. 20 in the New England Journal of Medicine.
The trial was open to women who had chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer. A total of 452 women were randomized in dual factorial design according to chemotherapy doublet (cisplatin plus paclitaxel vs. topotecan plus paclitaxel) and receipt of bevacizumab (yes vs. no). Treatment was on an open-label basis, and crossover was not allowed (N. Engl. J. Med. 2014;370:734-43).
An interim analysis showed that the topotecan-paclitaxel regimen was neither superior nor inferior to the cisplatin-paclitaxel regimen that has been the standard in this setting.
With longer follow-up, to a median of 20.8 months, women who received added bevacizumab had a longer median overall survival than did their counterparts who received chemotherapy alone (17.0 vs. 13.3 months; hazard ratio, 0.71; P = .0035). Bevacizumab conferred a significant survival benefit when added to cisplatin-paclitaxel chemotherapy (HR, 0.68; P = .03) but not when added to topotecan-paclitaxel chemotherapy (HR, 0.74; P = .09).
Adverse effects were largely consistent with previous experience in other cancers with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, Dr. Tewari and his associates reported.
The study was presented last year at the annual meeting of the American Society of Clinical Oncology. See our full coverage here.
The trial was sponsored by the National Cancer Institute. Dr. Tewari disclosed no relevant conflicts of interest. Roche/Genentech provided bevacizumab for the trial.
Adding bevacizumab to combination chemotherapy improved survival for women with advanced cervical cancer.
Women in the Gynecologic Oncology Group (GOG) trial who received bevacizumab in addition to chemotherapy lived about 4 months longer than their counterparts who received chemotherapy alone, Dr. Krishnansu S. Tewari and his associates reported Feb. 20 in the New England Journal of Medicine.
The trial was open to women who had chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer. A total of 452 women were randomized in dual factorial design according to chemotherapy doublet (cisplatin plus paclitaxel vs. topotecan plus paclitaxel) and receipt of bevacizumab (yes vs. no). Treatment was on an open-label basis, and crossover was not allowed (N. Engl. J. Med. 2014;370:734-43).
An interim analysis showed that the topotecan-paclitaxel regimen was neither superior nor inferior to the cisplatin-paclitaxel regimen that has been the standard in this setting.
With longer follow-up, to a median of 20.8 months, women who received added bevacizumab had a longer median overall survival than did their counterparts who received chemotherapy alone (17.0 vs. 13.3 months; hazard ratio, 0.71; P = .0035). Bevacizumab conferred a significant survival benefit when added to cisplatin-paclitaxel chemotherapy (HR, 0.68; P = .03) but not when added to topotecan-paclitaxel chemotherapy (HR, 0.74; P = .09).
Adverse effects were largely consistent with previous experience in other cancers with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, Dr. Tewari and his associates reported.
The study was presented last year at the annual meeting of the American Society of Clinical Oncology. See our full coverage here.
The trial was sponsored by the National Cancer Institute. Dr. Tewari disclosed no relevant conflicts of interest. Roche/Genentech provided bevacizumab for the trial.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Women who received added bevacizumab had a longer median overall survival than women who received chemotherapy alone (17.0 vs. 13.3 months).
Data source: Phase III, randomized, factorial design study of 452 women with chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer (GOG 240). Treatment was open label with no crossover.
Disclosures: The trial was sponsored by the National Cancer Institute. Dr. Tewari disclosed no relevant conflicts of interest. Roche/Genentech provided bevacizumab for the trial.
