Research Briefs Is Methylation a Shared Cancer Biomarker?
Is there a universal cancer fingerprint? National Institutes of Health researchers believe they may have found a potential common biomarker for five tumor types. The clue is a “methylation signature”—evidence of a chemical modification of DNA. Methylation controls the expression of genes: Higher amounts of DNA methylation reduce a gene’s activity. In an earlier study, using DNA from solid tumors, the researchers found a methylation signature around the gene ZNF154 in 15 tumor types in 13 different organs. In the new study, the researchers uncovered methylation in colon, lung, breast, stomach, and endometrial cancers. All the tumor types and subtypes consistently produced the same methylation mark around ZNF154. The researchers developed a computer program that looked at methylation marks in the DNA of people with and without cancer and were able to predict a threshold for detecting tumor DNA. Because tumors often shed DNA into the bloodstream, they were able to calculate the proportions of circulating tumor DNA. They hope their results may lead to a blood test that can diagnose cancers at early stages. Current blood tests are specific to a known tumor type: Clinicians must first find the tumor, then sequence a sample from it before they can track the tumor-specific mutations in the blood. By contrast, a method derived from methylation signatures would require no prior knowledge of the cancer. The tests would be less invasive than other screening methods and could be used to follow high-risk patients or monitor the activity of a tumor during treatment. Source: National Institutes of Health, February 5, 2016
A Call for More Autopsies to “Audit” Diagnoses
In the last 50 years, the number of autopsies at most U.S. hospitals has dropped drastically. The decline is due partly to a “widespread perception” that new imaging techniques and laboratory tests have improved diagnostic accuracy so much that autopsies are obsolete, say Temple University Hospital researchers. But that’s not the case, they say: Autopsies are still relevant and “a valuable tool to evaluate diagnostic accuracy.” Autopsy studies, the researchers found, show that proportions of clinical misdiagnosis have remained largely unchanged. In their study, autopsies performed over 10 years of 821 adults showed 8% had clinically undiagnosed malignancies—similar to the numbers found in studies 10 years earlier. Of 66 cases, 26 revealed undiagnosed malignancies directly related to the primary cause of death. In 16 autopsies, there was no clinical suspicion of malignancy, but the primary cause of death (such as acute bronchopneumonia and gastrointestinal perforation) was directly related to an undiagnosed neoplasm. In 10 cases, there was clinical suspicion of malignancy, based on history, radiological studies, and laboratory tests, but no definite tissue diagnosis. The researchers note that some studies have suggested
a link between short hospital stays and missed diagnoses. But in their study, length of stay had no bearing on a patient having an unsuspected malignancy. In fact, the cases with no clinical suspicion involved longer hospital stays. Moreover, computed tomography scans of the thorax/abdomen raised no suspicion of cancer. Their findings make a “strong case for a vigorous hospital autopsy program,” the researchers say, and for using autopsy data to improve performance in clinical, radiological, and laboratory services. Their study “reiterates the value of the hospital autopsy as an auditing tool for diagnostic accuracy.” Source: Human Pathology, February 2016
Excessive Bleeding After Cardiac Surgery
Cardiac surgery patients have a high risk of excessive postoperative bleeding, in part a consequence of procoagulant blood products, vasoconstrictors, and poor organ perfusion. To prepare for timely interventions, it helps if clinicians know which patients to watch—and when to identify the risk factors, say researchers at University Hospital, São Paulo, Brazil. In their prospective study of 323 patients, episodes of excessive bleeding were concentrated in the first and second postoperative hours, with 21% of complications requiring interventions, such as vasoactive medication titration, protamine supplementation, and transfusions of blood products. During the immediate postoperative period, 105 patients developed excessive bleeding: 39 in the first hour, 36 in the second hour, and eight in the third hour. Men had a significantly higher risk. Other risk factors were chronic hypertension, greater height, body mass index (BMI) of less than 26.35 kg/m2, higher hematocrit, and intraoperative heparin dose more than 312.5 mg without subsequent platelet transfusion. (Platelet transfusions may have been protective, the researchers say.) Certain variables, such as lower BMI and male gender, may have been explained by greater clot strength and faster rate of fibrin formation in women. Patients at risk for excessive bleeding also had lower preoperative platelet count, although the mean value was within the normal range. But given that more than half of the study group used aspirin and 11% used an adenosine diphosphatereceptor blocker, the researchers say they may have had a higher prevalence of unknown platelet dysfunctions. Source: Heart & Lung: The Journal of Acute and Critical Care, January–February 2016
Biomarker “Multiplex” to Detect Prostate Cancer
Because prostate cancer (PCa) is a heterogeneous disease, it stands to reason that a combination of biomarkers would outperform single markers in detection, say researchers from Universitat de Barcelona in Spain. The researchers had previously identified new putative
Vol. 41 No. 4 • April 2016 • P&T 261 ®
Research Briefs mRNA markers for PCa diagnosis, and they conducted a study to test some of them. They also validated the commercially available test based on urine PCA3 expression, as well as the best-performing mRNA panels of biomarkers reported in the literature. They used urine samples from 224 men; 10 patients with PSA levels greater than 4 were included as controls. Seven of the 42 genes the researchers evaluated were independent predictors for PCa. From those, the researchers developed a four-gene expression signature—HIST1H2BG, SPP1, ELF3, and PCA3—that had a sensitivity of 77% and specificity of 67% for discriminating between tumor and control urines, with a positive predictive value of 83%. That’s higher than PCA3, the only noninvasive urinary biomarker commercially available. The findings suggest that a urinary biomarker panel could improve detection of prostate cancer, the researchers say. However, they add that the accuracy of available urinary panels— including theirs—is not yet high enough to warrant routine use. Source: BMC Cancer, February 2016
The New Antiretroviral Therapy and HCV
Antiretroviral drugs can have toxic effects on the liver—problems that may be exacerbated by coinfection with hepatitis C virus (HCV), say researchers from the HEPAVIR SEG-HEP2007 Study Group of the Sociedad Andaluza de Enfermedades Infecciosas in Spain. But most earlier studies were retrospective and focused on specific antiretroviral therapy (ART) regimens, the researchers note, including some drugs that are no longer recommended. Thus, the research on ART in coinfected patients had not kept up with the rapidly changing strategies used in clinical practice. According to findings from their own recent study, deferring ART until chronic HCV infection is treated is no longer justified in coinfected patients. In 2011, these researchers reported a frequency of 7.6% of grade 3 to 4 transaminase elevation (TE) among coinfected patients, with no impact on the ART. However, they note, the study only included efavirenz and ritonavir-boosted protease inhibitor (PI/r). The more recent study enrolled 192 pretreated or treatment-naïve human immunodeficiency virus (HIV)infected patients who also had HCV and were starting one or more antiretroviral drugs. Most were on triple therapy. Of those, 114 remained with the new ART until the end of follow-up. The researchers recorded 342 drug initiations. Roughly half of the regimens involved a PI/r, 40% involved a nucleoside analogue reverse transcriptase inhibitor, and 40% involved a non-nucleoside analogue reverse transcriptase inhibitor. Clinical visits and blood tests were scheduled when the patient started the new ART, and at weeks 4, 12, 24, 36, and 48. The outcome variable was development of grade 3 or 4 TE. Nine HIV/HCV-coinfected patients developed grade 3 TE, as did one HIV/HBV-coinfected patient. Eight HIV/HCVcoinfected patients had total bilirubin elevations (due largely to
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ritonavir-boosted atazanavir). However, the hyperbilirubinemia did not lead to treatment interruptions and was not associated with the clinical outcome of ART. No patient discontinued therapy due to hepatotoxic effects. The researchers say the findings imply that the frequency of hepatotoxic events in HIV/ hepatitis coinfected patients has declined with newer regimens. Source: PLOS One, February 2016
Pot May Aid Leukemia Treatment
Dronabinol, a cannabinoid derivative, has been shown to have antitumor potential for several cancers, although the data for acute leukemia are “controversial,” say researchers from University Hospital Tübingen, Germany. However, when they tested THC in several leukemia cell lines and native leukemia blasts cultured ex vivo, they found “meaningful” antiproliferative and proapoptotic effects. Cannabinoid receptor agonists may be useful as low-toxicity agents, especially for patients who are “heavily pretreated,” elderly, or have refractory disease, the researchers say. They cite evidence that dronabinol retained antileukemic activity in a sample from a patient with otherwise chemotherapy- and steroid-refractory acute lymphocytic leukemia (ALL). Due to dronabinol’s excellent safety profile, the researchers say, effective doses are achievable in vivo, although tolerable doses may vary widely. They suggest starting with a sub effective dose, increased gradually, to help the patient build tolerance to the well-known psychoactive effects, which the researchers say have been a drawback to widespread use of THC for cancer patients. They add that, due to sparse densities of cannabinoid receptors in lower brainstem areas, severe intoxications with THC have rarely been reported. Source: BMC Cancer, January 2016
Allopurinol’s Effect on Cardiovascular Risk
Allopurinol, a urate-reducing drug, has been shown to have positive effects on cardiovascular risk factors, such as hypertension. Researchers from Odense University Hospital and University of Southern Denmark say allopurinol may also reduce risk in patients with hyperuricemia. They looked at cardiovascular outcomes among 65,971 patients with high urate levels, of whom 7,127 were taking allopurinol. The overall rate of major cardiovascular events was 44 per 1,000 person-years. For allopurinol users, the rate was 43.3 versus 44.2 for nonusers. All-cause mortality was significantly and consistently lower among allopurinol users. The researchers note that, in small randomized trials, allopurinol has increased working capacity in angina patients, reduced hypertension and vascular oxidative stress, and lowered the cardiovascular event rate in nongout kidney patients. These and other findings led them to suggest a protective effect of allopurinol. Source: American Journal of Medicine, March 2016 n
Is there a universal cancer fingerprint? National Institutes of Health researchers believe they may have found a potential common biomarker for five tumor types. The clue is a “methylation signature”—evidence of a chemical modification of DNA. Methylation controls the expression of genes: Higher amounts of DNA methylation reduce a gene’s activity. In an earlier study, using DNA from solid tumors, the researchers found a methylation signature around the gene ZNF154 in 15 tumor types in 13 different organs. In the new study, the researchers uncovered methylation in colon, lung, breast, stomach, and endometrial cancers. All the tumor types and subtypes consistently produced the same methylation mark around ZNF154. The researchers developed a computer program that looked at methylation marks in the DNA of people with and without cancer and were able to predict a threshold for detecting tumor DNA. Because tumors often shed DNA into the bloodstream, they were able to calculate the proportions of circulating tumor DNA. They hope their results may lead to a blood test that can diagnose cancers at early stages. Current blood tests are specific to a known tumor type: Clinicians must first find the tumor, then sequence a sample from it before they can track the tumor-specific mutations in the blood. By contrast, a method derived from methylation signatures would require no prior knowledge of the cancer. The tests would be less invasive than other screening methods and could be used to follow high-risk patients or monitor the activity of a tumor during treatment. Source: National Institutes of Health, February 5, 2016
A Call for More Autopsies to “Audit” Diagnoses
In the last 50 years, the number of autopsies at most U.S. hospitals has dropped drastically. The decline is due partly to a “widespread perception” that new imaging techniques and laboratory tests have improved diagnostic accuracy so much that autopsies are obsolete, say Temple University Hospital researchers. But that’s not the case, they say: Autopsies are still relevant and “a valuable tool to evaluate diagnostic accuracy.” Autopsy studies, the researchers found, show that proportions of clinical misdiagnosis have remained largely unchanged. In their study, autopsies performed over 10 years of 821 adults showed 8% had clinically undiagnosed malignancies—similar to the numbers found in studies 10 years earlier. Of 66 cases, 26 revealed undiagnosed malignancies directly related to the primary cause of death. In 16 autopsies, there was no clinical suspicion of malignancy, but the primary cause of death (such as acute bronchopneumonia and gastrointestinal perforation) was directly related to an undiagnosed neoplasm. In 10 cases, there was clinical suspicion of malignancy, based on history, radiological studies, and laboratory tests, but no definite tissue diagnosis. The researchers note that some studies have suggested
a link between short hospital stays and missed diagnoses. But in their study, length of stay had no bearing on a patient having an unsuspected malignancy. In fact, the cases with no clinical suspicion involved longer hospital stays. Moreover, computed tomography scans of the thorax/abdomen raised no suspicion of cancer. Their findings make a “strong case for a vigorous hospital autopsy program,” the researchers say, and for using autopsy data to improve performance in clinical, radiological, and laboratory services. Their study “reiterates the value of the hospital autopsy as an auditing tool for diagnostic accuracy.” Source: Human Pathology, February 2016
Excessive Bleeding After Cardiac Surgery
Cardiac surgery patients have a high risk of excessive postoperative bleeding, in part a consequence of procoagulant blood products, vasoconstrictors, and poor organ perfusion. To prepare for timely interventions, it helps if clinicians know which patients to watch—and when to identify the risk factors, say researchers at University Hospital, São Paulo, Brazil. In their prospective study of 323 patients, episodes of excessive bleeding were concentrated in the first and second postoperative hours, with 21% of complications requiring interventions, such as vasoactive medication titration, protamine supplementation, and transfusions of blood products. During the immediate postoperative period, 105 patients developed excessive bleeding: 39 in the first hour, 36 in the second hour, and eight in the third hour. Men had a significantly higher risk. Other risk factors were chronic hypertension, greater height, body mass index (BMI) of less than 26.35 kg/m2, higher hematocrit, and intraoperative heparin dose more than 312.5 mg without subsequent platelet transfusion. (Platelet transfusions may have been protective, the researchers say.) Certain variables, such as lower BMI and male gender, may have been explained by greater clot strength and faster rate of fibrin formation in women. Patients at risk for excessive bleeding also had lower preoperative platelet count, although the mean value was within the normal range. But given that more than half of the study group used aspirin and 11% used an adenosine diphosphatereceptor blocker, the researchers say they may have had a higher prevalence of unknown platelet dysfunctions. Source: Heart & Lung: The Journal of Acute and Critical Care, January–February 2016
Biomarker “Multiplex” to Detect Prostate Cancer
Because prostate cancer (PCa) is a heterogeneous disease, it stands to reason that a combination of biomarkers would outperform single markers in detection, say researchers from Universitat de Barcelona in Spain. The researchers had previously identified new putative
Vol. 41 No. 4 • April 2016 • P&T 261 ®
Research Briefs mRNA markers for PCa diagnosis, and they conducted a study to test some of them. They also validated the commercially available test based on urine PCA3 expression, as well as the best-performing mRNA panels of biomarkers reported in the literature. They used urine samples from 224 men; 10 patients with PSA levels greater than 4 were included as controls. Seven of the 42 genes the researchers evaluated were independent predictors for PCa. From those, the researchers developed a four-gene expression signature—HIST1H2BG, SPP1, ELF3, and PCA3—that had a sensitivity of 77% and specificity of 67% for discriminating between tumor and control urines, with a positive predictive value of 83%. That’s higher than PCA3, the only noninvasive urinary biomarker commercially available. The findings suggest that a urinary biomarker panel could improve detection of prostate cancer, the researchers say. However, they add that the accuracy of available urinary panels— including theirs—is not yet high enough to warrant routine use. Source: BMC Cancer, February 2016
The New Antiretroviral Therapy and HCV
Antiretroviral drugs can have toxic effects on the liver—problems that may be exacerbated by coinfection with hepatitis C virus (HCV), say researchers from the HEPAVIR SEG-HEP2007 Study Group of the Sociedad Andaluza de Enfermedades Infecciosas in Spain. But most earlier studies were retrospective and focused on specific antiretroviral therapy (ART) regimens, the researchers note, including some drugs that are no longer recommended. Thus, the research on ART in coinfected patients had not kept up with the rapidly changing strategies used in clinical practice. According to findings from their own recent study, deferring ART until chronic HCV infection is treated is no longer justified in coinfected patients. In 2011, these researchers reported a frequency of 7.6% of grade 3 to 4 transaminase elevation (TE) among coinfected patients, with no impact on the ART. However, they note, the study only included efavirenz and ritonavir-boosted protease inhibitor (PI/r). The more recent study enrolled 192 pretreated or treatment-naïve human immunodeficiency virus (HIV)infected patients who also had HCV and were starting one or more antiretroviral drugs. Most were on triple therapy. Of those, 114 remained with the new ART until the end of follow-up. The researchers recorded 342 drug initiations. Roughly half of the regimens involved a PI/r, 40% involved a nucleoside analogue reverse transcriptase inhibitor, and 40% involved a non-nucleoside analogue reverse transcriptase inhibitor. Clinical visits and blood tests were scheduled when the patient started the new ART, and at weeks 4, 12, 24, 36, and 48. The outcome variable was development of grade 3 or 4 TE. Nine HIV/HCV-coinfected patients developed grade 3 TE, as did one HIV/HBV-coinfected patient. Eight HIV/HCVcoinfected patients had total bilirubin elevations (due largely to
262 P&T • ®
April 2016 • Vol. 41 No. 4
ritonavir-boosted atazanavir). However, the hyperbilirubinemia did not lead to treatment interruptions and was not associated with the clinical outcome of ART. No patient discontinued therapy due to hepatotoxic effects. The researchers say the findings imply that the frequency of hepatotoxic events in HIV/ hepatitis coinfected patients has declined with newer regimens. Source: PLOS One, February 2016
Pot May Aid Leukemia Treatment
Dronabinol, a cannabinoid derivative, has been shown to have antitumor potential for several cancers, although the data for acute leukemia are “controversial,” say researchers from University Hospital Tübingen, Germany. However, when they tested THC in several leukemia cell lines and native leukemia blasts cultured ex vivo, they found “meaningful” antiproliferative and proapoptotic effects. Cannabinoid receptor agonists may be useful as low-toxicity agents, especially for patients who are “heavily pretreated,” elderly, or have refractory disease, the researchers say. They cite evidence that dronabinol retained antileukemic activity in a sample from a patient with otherwise chemotherapy- and steroid-refractory acute lymphocytic leukemia (ALL). Due to dronabinol’s excellent safety profile, the researchers say, effective doses are achievable in vivo, although tolerable doses may vary widely. They suggest starting with a sub effective dose, increased gradually, to help the patient build tolerance to the well-known psychoactive effects, which the researchers say have been a drawback to widespread use of THC for cancer patients. They add that, due to sparse densities of cannabinoid receptors in lower brainstem areas, severe intoxications with THC have rarely been reported. Source: BMC Cancer, January 2016
Allopurinol’s Effect on Cardiovascular Risk
Allopurinol, a urate-reducing drug, has been shown to have positive effects on cardiovascular risk factors, such as hypertension. Researchers from Odense University Hospital and University of Southern Denmark say allopurinol may also reduce risk in patients with hyperuricemia. They looked at cardiovascular outcomes among 65,971 patients with high urate levels, of whom 7,127 were taking allopurinol. The overall rate of major cardiovascular events was 44 per 1,000 person-years. For allopurinol users, the rate was 43.3 versus 44.2 for nonusers. All-cause mortality was significantly and consistently lower among allopurinol users. The researchers note that, in small randomized trials, allopurinol has increased working capacity in angina patients, reduced hypertension and vascular oxidative stress, and lowered the cardiovascular event rate in nongout kidney patients. These and other findings led them to suggest a protective effect of allopurinol. Source: American Journal of Medicine, March 2016 n
