By analyzing the whole genomes of 3-year-old twin sisters—one healthy and one with multi-lineage leukemia (MLL)—researchers have identified a possible therapeutic target for leukemias.

Their research pointed to a molecular pathway involving the gene SETD2, which can mutate in blood cells as DNA is being transcribed and replicated.

The team confirmed the importance of this pathway via follow-up experiments using samples from leukemia patients and mouse models of the disease.

“We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events,” said Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells.”

Dr Huang and his colleagues recounted this discovery in Nature Genetics.

The team showed that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple genetic mutations and chromosomal translocations.

In comparing data from the twins, the researchers identified a chromosomal translocation in the MLL-NRIP3 fusion gene.

When they activated MLL-NRIP3 in mouse models, the animals developed MLL, but it took a long period of time. This suggests that additional epigenetic and molecular events must be involved to induce full-blown leukemia.

The researchers went on to show that activation of MLL-NRIP3 cooperated with the molecular cascade (including mutations in SETD2) to cause leukemia.

The initial clue came when the team was looking for additional genomic alterations in the leukemic cells of the sick twin. They discovered that activation of MLL-NRIP3 started the molecular cascade that led to bi-allelic mutations in SETD2, a tumor suppressor that regulates the histone modification protein H3K36me3.

During transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin, the mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and MLL.

To confirm the importance of these findings, the researchers analyzed blood samples from 241 patients—134 with acute myeloid leukemia and 107 with acute lymphoblastic leukemia. This revealed 19 somatic SETD2 mutations in 15 patients (6.2%).

SETD2 mutations were more common in patients with MLL rearrangements than those without—22.6% (6/27) and 4.6% (8/173), respectively. And patients with SETD2 mutations had decreased levels of global H3K36me3.

In follow-up tests on cell cultures of pre-leukemic cells and mouse models, the researchers saw the same progression of genetic mutations and related molecular events fuel the growth of leukemic cells.

The team also noticed that SETD2 mutation activated 2 genes—mTOR and JAK-STAT—that are known to contribute to leukemia and other cancers. So the researchers decided to test 2 mTOR inhibitors—Torin1 and rapamycin—on pre-leukemic cells generated by SETD2 mutations.

That treatment prompted a marked decrease in cell growth, indicating that SETD2 mutations activate numerous molecular pathways to generate leukemia.

Dr Huang said the tests also suggest there are multiple opportunities to find new molecular targets for developing more effective drugs—in particular, those that would target the MLL fusion-SETD2-H3K36me3 pathway to treat acute and aggressive leukemias.

The researchers are following up their current study by identifying additional pathways activated by mutations of SETD2. They also are looking for possible new molecular targets and therapeutic strategies to block disruptions in the SETD2-H3K36me3 pathway.

By analyzing the whole genomes of 3-year-old twin sisters—one healthy and one with multi-lineage leukemia (MLL)—researchers have identified a possible therapeutic target for leukemias.

Their research pointed to a molecular pathway involving the gene SETD2, which can mutate in blood cells as DNA is being transcribed and replicated.

The team confirmed the importance of this pathway via follow-up experiments using samples from leukemia patients and mouse models of the disease.

“We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events,” said Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells.”

Dr Huang and his colleagues recounted this discovery in Nature Genetics.

The team showed that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple genetic mutations and chromosomal translocations.

In comparing data from the twins, the researchers identified a chromosomal translocation in the MLL-NRIP3 fusion gene.

When they activated MLL-NRIP3 in mouse models, the animals developed MLL, but it took a long period of time. This suggests that additional epigenetic and molecular events must be involved to induce full-blown leukemia.

The researchers went on to show that activation of MLL-NRIP3 cooperated with the molecular cascade (including mutations in SETD2) to cause leukemia.

The initial clue came when the team was looking for additional genomic alterations in the leukemic cells of the sick twin. They discovered that activation of MLL-NRIP3 started the molecular cascade that led to bi-allelic mutations in SETD2, a tumor suppressor that regulates the histone modification protein H3K36me3.

During transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin, the mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and MLL.

To confirm the importance of these findings, the researchers analyzed blood samples from 241 patients—134 with acute myeloid leukemia and 107 with acute lymphoblastic leukemia. This revealed 19 somatic SETD2 mutations in 15 patients (6.2%).

SETD2 mutations were more common in patients with MLL rearrangements than those without—22.6% (6/27) and 4.6% (8/173), respectively. And patients with SETD2 mutations had decreased levels of global H3K36me3.

In follow-up tests on cell cultures of pre-leukemic cells and mouse models, the researchers saw the same progression of genetic mutations and related molecular events fuel the growth of leukemic cells.

The team also noticed that SETD2 mutation activated 2 genes—mTOR and JAK-STAT—that are known to contribute to leukemia and other cancers. So the researchers decided to test 2 mTOR inhibitors—Torin1 and rapamycin—on pre-leukemic cells generated by SETD2 mutations.

That treatment prompted a marked decrease in cell growth, indicating that SETD2 mutations activate numerous molecular pathways to generate leukemia.

Dr Huang said the tests also suggest there are multiple opportunities to find new molecular targets for developing more effective drugs—in particular, those that would target the MLL fusion-SETD2-H3K36me3 pathway to treat acute and aggressive leukemias.

The researchers are following up their current study by identifying additional pathways activated by mutations of SETD2. They also are looking for possible new molecular targets and therapeutic strategies to block disruptions in the SETD2-H3K36me3 pathway.

By analyzing the whole genomes of 3-year-old twin sisters—one healthy and one with multi-lineage leukemia (MLL)—researchers have identified a possible therapeutic target for leukemias.

Their research pointed to a molecular pathway involving the gene SETD2, which can mutate in blood cells as DNA is being transcribed and replicated.

The team confirmed the importance of this pathway via follow-up experiments using samples from leukemia patients and mouse models of the disease.

“We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events,” said Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells.”

Dr Huang and his colleagues recounted this discovery in Nature Genetics.

The team showed that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple genetic mutations and chromosomal translocations.

In comparing data from the twins, the researchers identified a chromosomal translocation in the MLL-NRIP3 fusion gene.

When they activated MLL-NRIP3 in mouse models, the animals developed MLL, but it took a long period of time. This suggests that additional epigenetic and molecular events must be involved to induce full-blown leukemia.

The researchers went on to show that activation of MLL-NRIP3 cooperated with the molecular cascade (including mutations in SETD2) to cause leukemia.

The initial clue came when the team was looking for additional genomic alterations in the leukemic cells of the sick twin. They discovered that activation of MLL-NRIP3 started the molecular cascade that led to bi-allelic mutations in SETD2, a tumor suppressor that regulates the histone modification protein H3K36me3.

During transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin, the mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and MLL.

To confirm the importance of these findings, the researchers analyzed blood samples from 241 patients—134 with acute myeloid leukemia and 107 with acute lymphoblastic leukemia. This revealed 19 somatic SETD2 mutations in 15 patients (6.2%).

SETD2 mutations were more common in patients with MLL rearrangements than those without—22.6% (6/27) and 4.6% (8/173), respectively. And patients with SETD2 mutations had decreased levels of global H3K36me3.

In follow-up tests on cell cultures of pre-leukemic cells and mouse models, the researchers saw the same progression of genetic mutations and related molecular events fuel the growth of leukemic cells.

The team also noticed that SETD2 mutation activated 2 genes—mTOR and JAK-STAT—that are known to contribute to leukemia and other cancers. So the researchers decided to test 2 mTOR inhibitors—Torin1 and rapamycin—on pre-leukemic cells generated by SETD2 mutations.

That treatment prompted a marked decrease in cell growth, indicating that SETD2 mutations activate numerous molecular pathways to generate leukemia.

Dr Huang said the tests also suggest there are multiple opportunities to find new molecular targets for developing more effective drugs—in particular, those that would target the MLL fusion-SETD2-H3K36me3 pathway to treat acute and aggressive leukemias.

The researchers are following up their current study by identifying additional pathways activated by mutations of SETD2. They also are looking for possible new molecular targets and therapeutic strategies to block disruptions in the SETD2-H3K36me3 pathway.

Scientists say they have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad proteins necessary for life.

The group’s work shows that the protein ADR-1 binds to mRNA and then enhances RNA editing.

This process allows a gene to be present as multiple mRNAs that can each affect gene expression differently.

The research appears in Cell Reports.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer, and blood disorders,” said study author Gene Yeo, PhD, of the University of California, San Diego.

“This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides

a method to screen for them and opens up new ways to study human biology and disease.”

Using the model organism Caenorhabditis elegans, Dr Yeo and his colleagues identified more than 400 new mRNA editing sites. As the majority of them were regulated by ADR-1, the team declared the protein the first global regulator of RNA editing.

“What we’ve determined is that this protein’s ability to alter editing of mRNAs is not specific to just a few genes, but, instead, its ability to bind to mRNAs is required for proper RNA editing of most mRNAs,” said study author Michael C. Washburn, of Indiana University in Bloomington.

The group found that the region of ADR-1 protein that binds to target mRNAs in C elegans is required for regulating editing. This region is present in many human proteins, and a protein similar to ADR-1 is specifically expressed in human neurons.

“So it is likely that a similar mechanism exists to regulate editing in humans,” said study author Heather A. Hundley, PhD, also of Indiana University.

“Further work in our lab will be aimed at understanding the detailed mechanism of how these proteins regulate editing, in turn providing an inroad to developing therapeutics that modulate editing for the treatment of human diseases.”

C elegans, like humans, highly expresses a family of proteins in the nervous system called adenosine deaminases acting on RNA (ADARs), a family that includes ADR-1.

ADARs change specific nucleotides in RNA in a process called adenosine-to-inosine editing (A-to-I editing) that diversifies genetic information to specify different amino acids, splice sites, and structures.

Scientists currently estimate there are between 400,000 and 1 million A-to-I editing events in noncoding regions of the human transcriptome.

Newly synthesized RNA encodes the exact information found in DNA. But it’s when later RNA editing occurs that RNA gets altered, and this change is most often catalyzed by ADARs.

“One thing we also know is that ADAR protein levels are not altered in disease, implying that other mechanisms are also at work regulating ADAR-mediated RNA editing,” Dr Hundley said. “By identifying this major regulator of noncoding editing in C elegans, we can now focus on dissecting the regulatory mechanism and determining the conservation of this regulatory protein in human cells.”

Scientists say they have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad proteins necessary for life.

The group’s work shows that the protein ADR-1 binds to mRNA and then enhances RNA editing.

This process allows a gene to be present as multiple mRNAs that can each affect gene expression differently.

The research appears in Cell Reports.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer, and blood disorders,” said study author Gene Yeo, PhD, of the University of California, San Diego.

“This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides

a method to screen for them and opens up new ways to study human biology and disease.”

Using the model organism Caenorhabditis elegans, Dr Yeo and his colleagues identified more than 400 new mRNA editing sites. As the majority of them were regulated by ADR-1, the team declared the protein the first global regulator of RNA editing.

“What we’ve determined is that this protein’s ability to alter editing of mRNAs is not specific to just a few genes, but, instead, its ability to bind to mRNAs is required for proper RNA editing of most mRNAs,” said study author Michael C. Washburn, of Indiana University in Bloomington.

The group found that the region of ADR-1 protein that binds to target mRNAs in C elegans is required for regulating editing. This region is present in many human proteins, and a protein similar to ADR-1 is specifically expressed in human neurons.

“So it is likely that a similar mechanism exists to regulate editing in humans,” said study author Heather A. Hundley, PhD, also of Indiana University.

“Further work in our lab will be aimed at understanding the detailed mechanism of how these proteins regulate editing, in turn providing an inroad to developing therapeutics that modulate editing for the treatment of human diseases.”

C elegans, like humans, highly expresses a family of proteins in the nervous system called adenosine deaminases acting on RNA (ADARs), a family that includes ADR-1.

ADARs change specific nucleotides in RNA in a process called adenosine-to-inosine editing (A-to-I editing) that diversifies genetic information to specify different amino acids, splice sites, and structures.

Scientists currently estimate there are between 400,000 and 1 million A-to-I editing events in noncoding regions of the human transcriptome.

Newly synthesized RNA encodes the exact information found in DNA. But it’s when later RNA editing occurs that RNA gets altered, and this change is most often catalyzed by ADARs.

“One thing we also know is that ADAR protein levels are not altered in disease, implying that other mechanisms are also at work regulating ADAR-mediated RNA editing,” Dr Hundley said. “By identifying this major regulator of noncoding editing in C elegans, we can now focus on dissecting the regulatory mechanism and determining the conservation of this regulatory protein in human cells.”

Scientists say they have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad proteins necessary for life.

The group’s work shows that the protein ADR-1 binds to mRNA and then enhances RNA editing.

This process allows a gene to be present as multiple mRNAs that can each affect gene expression differently.

The research appears in Cell Reports.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer, and blood disorders,” said study author Gene Yeo, PhD, of the University of California, San Diego.

“This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides

a method to screen for them and opens up new ways to study human biology and disease.”

Using the model organism Caenorhabditis elegans, Dr Yeo and his colleagues identified more than 400 new mRNA editing sites. As the majority of them were regulated by ADR-1, the team declared the protein the first global regulator of RNA editing.

“What we’ve determined is that this protein’s ability to alter editing of mRNAs is not specific to just a few genes, but, instead, its ability to bind to mRNAs is required for proper RNA editing of most mRNAs,” said study author Michael C. Washburn, of Indiana University in Bloomington.

The group found that the region of ADR-1 protein that binds to target mRNAs in C elegans is required for regulating editing. This region is present in many human proteins, and a protein similar to ADR-1 is specifically expressed in human neurons.

“So it is likely that a similar mechanism exists to regulate editing in humans,” said study author Heather A. Hundley, PhD, also of Indiana University.

“Further work in our lab will be aimed at understanding the detailed mechanism of how these proteins regulate editing, in turn providing an inroad to developing therapeutics that modulate editing for the treatment of human diseases.”

C elegans, like humans, highly expresses a family of proteins in the nervous system called adenosine deaminases acting on RNA (ADARs), a family that includes ADR-1.

ADARs change specific nucleotides in RNA in a process called adenosine-to-inosine editing (A-to-I editing) that diversifies genetic information to specify different amino acids, splice sites, and structures.

Scientists currently estimate there are between 400,000 and 1 million A-to-I editing events in noncoding regions of the human transcriptome.

Newly synthesized RNA encodes the exact information found in DNA. But it’s when later RNA editing occurs that RNA gets altered, and this change is most often catalyzed by ADARs.

“One thing we also know is that ADAR protein levels are not altered in disease, implying that other mechanisms are also at work regulating ADAR-mediated RNA editing,” Dr Hundley said. “By identifying this major regulator of noncoding editing in C elegans, we can now focus on dissecting the regulatory mechanism and determining the conservation of this regulatory protein in human cells.”

Leaders from the US Senate and House of Representatives have agreed on a plan to replace the Medicare sustainable growth rate (SGR) formula, but they must still agree on how to pay for it.

The group’s bill, called the SGR Repeal and Medicare Provider Payment Modernization Act of 2014, would remove the threat of a 23.7% cut in Medicare payments that is set to take effect on April 1.

And it would provide annual payment updates of 0.5% for the next 5 years, as Medicare transitions to a payment system designed to reward physicians based on care quality, not quantity.

“This is a significant step forward in our long-standing effort to replace the flawed physician update formula with a 21st-century system focused on quality and value rather than the quantity of services,” said House Ways and Means Committee Ranking Member Sander Levin (D-Mich.).

“For the first time in many years, we have agreement among the bipartisan leadership of the 3 committees that oversee Medicare. Now, we have to turn to the thorny issue of offsets.”

The Congressional Budget Office has estimated that the new plan would increase direct spending by $150.4 billion from 2014 to 2023, although other sources have said the cost would be about $126 billion for the same time period.

Repealing the SGR

The SGR calls for annual, automatic cuts in Medicare payments to physicians. It was established in 1997 to control physician spending, but, over the years, the necessary cuts have not occurred.

Since 2003, Congress has spent about $150 billion to provide short-term fixes to spare physicians from the cuts. Without another short-term fix or legislation to permanently eliminate the SGR, physicians would see a 23.7% cut in Medicare payments starting April 1.

For years, Congress has been trying to eliminate the SGR, but agreeing on a plan to do so—and a way to pay for it—has proven difficult. Now, Congress says it has brought “renewed commitment to repealing and replacing the flawed SGR update mechanism.”

Provisions of the bill

The SGR Repeal and Medicare Provider Payment Modernization Act of 2014 would institute a 0.5% annual payment increase for physicians from 2014 through 2018. According to Congress, this would help the transition to a merit-based incentive payment system (MIPS), beginning in 2018.

The MIPS consolidates the 3 existing incentive programs—the Physician Quality Reporting System, the Value-Based Payment Modifier, and the Meaningful Use of Electronic Health Records—into a single program that would reward providers who meet performance thresholds.

The bill would also give a 5% bonus to providers who receive a significant portion of their revenue from an alternative payment model (APM) or patient-centered medical home (PCMH). Participants would need to receive at least 25% of their Medicare revenue through an APM in 2018-2019, and this threshold would increase over time.

The bill would provide incentives for participation in private-payer APMs as well. And it would establish a technical advisory committee to review and recommend physician-developed APMs based on criteria developed through an open-comment process.

Finally, the bill would expand the use of Medicare data. Quality and utilization data would be posted on the Physician Compare website with the goal of helping patients to make more informed decisions about their care.

Furthermore, “qualified entities” would be allowed to provide analyses and underlying data to providers, although this provision is subject to privacy and security laws. And qualified clinical data registries would be allowed to purchase claims data.

To read the bill in full, visit Congress.gov.

Leaders from the US Senate and House of Representatives have agreed on a plan to replace the Medicare sustainable growth rate (SGR) formula, but they must still agree on how to pay for it.

The group’s bill, called the SGR Repeal and Medicare Provider Payment Modernization Act of 2014, would remove the threat of a 23.7% cut in Medicare payments that is set to take effect on April 1.

And it would provide annual payment updates of 0.5% for the next 5 years, as Medicare transitions to a payment system designed to reward physicians based on care quality, not quantity.

“This is a significant step forward in our long-standing effort to replace the flawed physician update formula with a 21st-century system focused on quality and value rather than the quantity of services,” said House Ways and Means Committee Ranking Member Sander Levin (D-Mich.).

“For the first time in many years, we have agreement among the bipartisan leadership of the 3 committees that oversee Medicare. Now, we have to turn to the thorny issue of offsets.”

The Congressional Budget Office has estimated that the new plan would increase direct spending by $150.4 billion from 2014 to 2023, although other sources have said the cost would be about $126 billion for the same time period.

Repealing the SGR

The SGR calls for annual, automatic cuts in Medicare payments to physicians. It was established in 1997 to control physician spending, but, over the years, the necessary cuts have not occurred.

Since 2003, Congress has spent about $150 billion to provide short-term fixes to spare physicians from the cuts. Without another short-term fix or legislation to permanently eliminate the SGR, physicians would see a 23.7% cut in Medicare payments starting April 1.

For years, Congress has been trying to eliminate the SGR, but agreeing on a plan to do so—and a way to pay for it—has proven difficult. Now, Congress says it has brought “renewed commitment to repealing and replacing the flawed SGR update mechanism.”

Provisions of the bill

The SGR Repeal and Medicare Provider Payment Modernization Act of 2014 would institute a 0.5% annual payment increase for physicians from 2014 through 2018. According to Congress, this would help the transition to a merit-based incentive payment system (MIPS), beginning in 2018.

The MIPS consolidates the 3 existing incentive programs—the Physician Quality Reporting System, the Value-Based Payment Modifier, and the Meaningful Use of Electronic Health Records—into a single program that would reward providers who meet performance thresholds.

The bill would also give a 5% bonus to providers who receive a significant portion of their revenue from an alternative payment model (APM) or patient-centered medical home (PCMH). Participants would need to receive at least 25% of their Medicare revenue through an APM in 2018-2019, and this threshold would increase over time.

The bill would provide incentives for participation in private-payer APMs as well. And it would establish a technical advisory committee to review and recommend physician-developed APMs based on criteria developed through an open-comment process.

Finally, the bill would expand the use of Medicare data. Quality and utilization data would be posted on the Physician Compare website with the goal of helping patients to make more informed decisions about their care.

Furthermore, “qualified entities” would be allowed to provide analyses and underlying data to providers, although this provision is subject to privacy and security laws. And qualified clinical data registries would be allowed to purchase claims data.

To read the bill in full, visit Congress.gov.

Leaders from the US Senate and House of Representatives have agreed on a plan to replace the Medicare sustainable growth rate (SGR) formula, but they must still agree on how to pay for it.

The group’s bill, called the SGR Repeal and Medicare Provider Payment Modernization Act of 2014, would remove the threat of a 23.7% cut in Medicare payments that is set to take effect on April 1.

And it would provide annual payment updates of 0.5% for the next 5 years, as Medicare transitions to a payment system designed to reward physicians based on care quality, not quantity.

“This is a significant step forward in our long-standing effort to replace the flawed physician update formula with a 21st-century system focused on quality and value rather than the quantity of services,” said House Ways and Means Committee Ranking Member Sander Levin (D-Mich.).

“For the first time in many years, we have agreement among the bipartisan leadership of the 3 committees that oversee Medicare. Now, we have to turn to the thorny issue of offsets.”

The Congressional Budget Office has estimated that the new plan would increase direct spending by $150.4 billion from 2014 to 2023, although other sources have said the cost would be about $126 billion for the same time period.

Repealing the SGR

The SGR calls for annual, automatic cuts in Medicare payments to physicians. It was established in 1997 to control physician spending, but, over the years, the necessary cuts have not occurred.

Since 2003, Congress has spent about $150 billion to provide short-term fixes to spare physicians from the cuts. Without another short-term fix or legislation to permanently eliminate the SGR, physicians would see a 23.7% cut in Medicare payments starting April 1.

For years, Congress has been trying to eliminate the SGR, but agreeing on a plan to do so—and a way to pay for it—has proven difficult. Now, Congress says it has brought “renewed commitment to repealing and replacing the flawed SGR update mechanism.”

Provisions of the bill

The SGR Repeal and Medicare Provider Payment Modernization Act of 2014 would institute a 0.5% annual payment increase for physicians from 2014 through 2018. According to Congress, this would help the transition to a merit-based incentive payment system (MIPS), beginning in 2018.

The MIPS consolidates the 3 existing incentive programs—the Physician Quality Reporting System, the Value-Based Payment Modifier, and the Meaningful Use of Electronic Health Records—into a single program that would reward providers who meet performance thresholds.

The bill would also give a 5% bonus to providers who receive a significant portion of their revenue from an alternative payment model (APM) or patient-centered medical home (PCMH). Participants would need to receive at least 25% of their Medicare revenue through an APM in 2018-2019, and this threshold would increase over time.

The bill would provide incentives for participation in private-payer APMs as well. And it would establish a technical advisory committee to review and recommend physician-developed APMs based on criteria developed through an open-comment process.

Finally, the bill would expand the use of Medicare data. Quality and utilization data would be posted on the Physician Compare website with the goal of helping patients to make more informed decisions about their care.

Furthermore, “qualified entities” would be allowed to provide analyses and underlying data to providers, although this provision is subject to privacy and security laws. And qualified clinical data registries would be allowed to purchase claims data.

To read the bill in full, visit Congress.gov.

My object all sublime

I shall achieve in time –

To let the punishment fit the crime –

The punishment fit the crime.

–The Mikado

Gilbert and Sullivan

The Mikado’s ambition to give back in a jocular, but apt, way to the subjects who annoyed him is well known. Although I am no Mikado and don’t give back to anybody, aptly or otherwise, I have to admit that the impulse to do so does cross my mind. Maybe it crosses yours, too. Here are some people I sometimes meet. You might recognize them, and perhaps approve some of my suggested just deserts; punishments that fit the crime (PTFTC).

• The imaginary voice mail. "Call John Doe back right away," reads the message. "Use this number."

"You have reached 617-555-1234. This voice-mailbox has not yet been set up and cannot accept calls. Goodbye."

PTFTC: New outgoing message: "Dr. Rockoff is not actually a dermatologist yet. He will get back to you as soon as he becomes one."

• Playing with a full box. "You have reached 617-555-4321. This mailbox is full and cannot accept messages. Goodbye."

PTFTC: Outgoing message: "You have reached the doctor’s office. The doctor has filled his monthly quota of advice giving. Please call back next month, preferably before the 9th."

• Never mind who this is. "Doctor, please call me back right away. My itch is terrible and the medicine you prescribed doesn’t work at all." Click.

PTFTC: Outgoing message: Heavy breathing for 30 seconds. (Has to be for everyone, since we don’t know the number to call.)

• Mumbles. "Doctor, zy... Zyglub ... really need frtunsn mnidioos ... You ... to dhrsrsrs ... 617-96dlubgx ... Again, the number is zigd ... 52879 ... cloy."

PTFTC: Outgoing message. "Hello, Zyg! Glub Dr. Roc ... Bfflp! Yucca grapetz! ... Brgl nice day!"

• The anonymous e-mailer. "Hi, Doc! That cream is great! Can you call more into my pharmacy? Thanks! Skip ([email protected].)

PTFTC: Return e-mail: "Hey, Skip! Take care on that skateboard! Could I have your name? Thanks!"

• The mailed-scrip requester. "Please mail a prescription to Mr. Bean’s house," says the message. "It can’t be called or faxed in. It has to be mailed, with a 90-day supply and three refills."

PTFTC: "Dear Mr. Bean, Kindly send a detailed prescription request typed on an Underwood manual manufactured no later than 1936. Please include a stamped, self-addressed envelope with correct postage. Thank you."

• The walk-in scrip requester. "Doctor," says my front-desk person, catching me in the hall between patients. "Dimitriy is in the waiting room. He says he needs you to write out refills for the three medicines you gave him – the one for the scalp, the one for the body, and the one for the other part that he doesn’t want to tell me about. He says he’ll wait."

PTFTC: "Tell Dimitriy that I need to review his record in detail. I should be done first thing tomorrow morning."

• The highly-detailed-scrip requester. "Doctor, my insurer requires that my prescription be written in a specific way: ‘SuperDerm cream, six 45-gram tunes for a 90-day supply, apply twice a day, morning and night, substitution mandated on penalty of reporting to the Highest Authorities.’ After you’re done with that, I’ll instruct you on the correct way to write my three other prescriptions."

PTFTC: "Here are four blank prescription forms. Please fill them out exactly as your insurer requires. I will return in 21 minutes to review and sign them."

Turnabout is of course fair play. I am sure that many patients, mine and yours, could readily generate lists of our infractions along with appropriate penalties. For instance:

• The doctor kept me waiting so long that I got a parking ticket.

• He called in the solution when I specifically asked for the cream.

• I rearranged my whole schedule and hired a babysitter to keep my appointment, and then her office called the day before and canceled it.

To show my even-handedness, I have set up a Let-the-Punishment-Fit-the-Crime hotline for any patients reading this article. To take these calls, I have rented a special office just outside Fargo, North Dakota, at 701-555-6789, although I’m rarely there.

Oh yes, the voice mail hasn’t been set up yet.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

My object all sublime

I shall achieve in time –

To let the punishment fit the crime –

The punishment fit the crime.

–The Mikado

Gilbert and Sullivan

The Mikado’s ambition to give back in a jocular, but apt, way to the subjects who annoyed him is well known. Although I am no Mikado and don’t give back to anybody, aptly or otherwise, I have to admit that the impulse to do so does cross my mind. Maybe it crosses yours, too. Here are some people I sometimes meet. You might recognize them, and perhaps approve some of my suggested just deserts; punishments that fit the crime (PTFTC).

• The imaginary voice mail. "Call John Doe back right away," reads the message. "Use this number."

"You have reached 617-555-1234. This voice-mailbox has not yet been set up and cannot accept calls. Goodbye."

PTFTC: New outgoing message: "Dr. Rockoff is not actually a dermatologist yet. He will get back to you as soon as he becomes one."

• Playing with a full box. "You have reached 617-555-4321. This mailbox is full and cannot accept messages. Goodbye."

PTFTC: Outgoing message: "You have reached the doctor’s office. The doctor has filled his monthly quota of advice giving. Please call back next month, preferably before the 9th."

• Never mind who this is. "Doctor, please call me back right away. My itch is terrible and the medicine you prescribed doesn’t work at all." Click.

PTFTC: Outgoing message: Heavy breathing for 30 seconds. (Has to be for everyone, since we don’t know the number to call.)

• Mumbles. "Doctor, zy... Zyglub ... really need frtunsn mnidioos ... You ... to dhrsrsrs ... 617-96dlubgx ... Again, the number is zigd ... 52879 ... cloy."

PTFTC: Outgoing message. "Hello, Zyg! Glub Dr. Roc ... Bfflp! Yucca grapetz! ... Brgl nice day!"

• The anonymous e-mailer. "Hi, Doc! That cream is great! Can you call more into my pharmacy? Thanks! Skip ([email protected].)

PTFTC: Return e-mail: "Hey, Skip! Take care on that skateboard! Could I have your name? Thanks!"

• The mailed-scrip requester. "Please mail a prescription to Mr. Bean’s house," says the message. "It can’t be called or faxed in. It has to be mailed, with a 90-day supply and three refills."

PTFTC: "Dear Mr. Bean, Kindly send a detailed prescription request typed on an Underwood manual manufactured no later than 1936. Please include a stamped, self-addressed envelope with correct postage. Thank you."

• The walk-in scrip requester. "Doctor," says my front-desk person, catching me in the hall between patients. "Dimitriy is in the waiting room. He says he needs you to write out refills for the three medicines you gave him – the one for the scalp, the one for the body, and the one for the other part that he doesn’t want to tell me about. He says he’ll wait."

PTFTC: "Tell Dimitriy that I need to review his record in detail. I should be done first thing tomorrow morning."

• The highly-detailed-scrip requester. "Doctor, my insurer requires that my prescription be written in a specific way: ‘SuperDerm cream, six 45-gram tunes for a 90-day supply, apply twice a day, morning and night, substitution mandated on penalty of reporting to the Highest Authorities.’ After you’re done with that, I’ll instruct you on the correct way to write my three other prescriptions."

PTFTC: "Here are four blank prescription forms. Please fill them out exactly as your insurer requires. I will return in 21 minutes to review and sign them."

Turnabout is of course fair play. I am sure that many patients, mine and yours, could readily generate lists of our infractions along with appropriate penalties. For instance:

• The doctor kept me waiting so long that I got a parking ticket.

• He called in the solution when I specifically asked for the cream.

• I rearranged my whole schedule and hired a babysitter to keep my appointment, and then her office called the day before and canceled it.

To show my even-handedness, I have set up a Let-the-Punishment-Fit-the-Crime hotline for any patients reading this article. To take these calls, I have rented a special office just outside Fargo, North Dakota, at 701-555-6789, although I’m rarely there.

Oh yes, the voice mail hasn’t been set up yet.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

My object all sublime

I shall achieve in time –

To let the punishment fit the crime –

The punishment fit the crime.

–The Mikado

Gilbert and Sullivan

The Mikado’s ambition to give back in a jocular, but apt, way to the subjects who annoyed him is well known. Although I am no Mikado and don’t give back to anybody, aptly or otherwise, I have to admit that the impulse to do so does cross my mind. Maybe it crosses yours, too. Here are some people I sometimes meet. You might recognize them, and perhaps approve some of my suggested just deserts; punishments that fit the crime (PTFTC).

• The imaginary voice mail. "Call John Doe back right away," reads the message. "Use this number."

"You have reached 617-555-1234. This voice-mailbox has not yet been set up and cannot accept calls. Goodbye."

PTFTC: New outgoing message: "Dr. Rockoff is not actually a dermatologist yet. He will get back to you as soon as he becomes one."

• Playing with a full box. "You have reached 617-555-4321. This mailbox is full and cannot accept messages. Goodbye."

PTFTC: Outgoing message: "You have reached the doctor’s office. The doctor has filled his monthly quota of advice giving. Please call back next month, preferably before the 9th."

• Never mind who this is. "Doctor, please call me back right away. My itch is terrible and the medicine you prescribed doesn’t work at all." Click.

PTFTC: Outgoing message: Heavy breathing for 30 seconds. (Has to be for everyone, since we don’t know the number to call.)

• Mumbles. "Doctor, zy... Zyglub ... really need frtunsn mnidioos ... You ... to dhrsrsrs ... 617-96dlubgx ... Again, the number is zigd ... 52879 ... cloy."

PTFTC: Outgoing message. "Hello, Zyg! Glub Dr. Roc ... Bfflp! Yucca grapetz! ... Brgl nice day!"

• The anonymous e-mailer. "Hi, Doc! That cream is great! Can you call more into my pharmacy? Thanks! Skip ([email protected].)

PTFTC: Return e-mail: "Hey, Skip! Take care on that skateboard! Could I have your name? Thanks!"

• The mailed-scrip requester. "Please mail a prescription to Mr. Bean’s house," says the message. "It can’t be called or faxed in. It has to be mailed, with a 90-day supply and three refills."

PTFTC: "Dear Mr. Bean, Kindly send a detailed prescription request typed on an Underwood manual manufactured no later than 1936. Please include a stamped, self-addressed envelope with correct postage. Thank you."

• The walk-in scrip requester. "Doctor," says my front-desk person, catching me in the hall between patients. "Dimitriy is in the waiting room. He says he needs you to write out refills for the three medicines you gave him – the one for the scalp, the one for the body, and the one for the other part that he doesn’t want to tell me about. He says he’ll wait."

PTFTC: "Tell Dimitriy that I need to review his record in detail. I should be done first thing tomorrow morning."

• The highly-detailed-scrip requester. "Doctor, my insurer requires that my prescription be written in a specific way: ‘SuperDerm cream, six 45-gram tunes for a 90-day supply, apply twice a day, morning and night, substitution mandated on penalty of reporting to the Highest Authorities.’ After you’re done with that, I’ll instruct you on the correct way to write my three other prescriptions."

PTFTC: "Here are four blank prescription forms. Please fill them out exactly as your insurer requires. I will return in 21 minutes to review and sign them."

Turnabout is of course fair play. I am sure that many patients, mine and yours, could readily generate lists of our infractions along with appropriate penalties. For instance:

• The doctor kept me waiting so long that I got a parking ticket.

• He called in the solution when I specifically asked for the cream.

• I rearranged my whole schedule and hired a babysitter to keep my appointment, and then her office called the day before and canceled it.

To show my even-handedness, I have set up a Let-the-Punishment-Fit-the-Crime hotline for any patients reading this article. To take these calls, I have rented a special office just outside Fargo, North Dakota, at 701-555-6789, although I’m rarely there.

Oh yes, the voice mail hasn’t been set up yet.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

The U.S. immunization program has been one of the country’s most successful initiatives and best investments. Prior to 2005, vaccines were targeted for administration to infants and young children. Adolescence was a period for catch-up immunizations. All that changed in 2005 when the first meningococcal conjugate vaccine (MCV) was recommended for administration to preteens at 11-12 years and college freshmen residing in dormitories by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP). Shortly thereafter in 2006, a new tetanus toxoid, diphtheria, and acellular pertussis vaccine (Tdap) was recommended, and in March 2007 the quadrivalent human papillomavirus vaccine (HPV4: types 6, 11, 16, and 18) was recommended for use in girls, starting at age 11-12 years, and young women up to 26 years of age. In 2009, a bivalent HPV vaccine (HPV2: types 16 and 18) was licensed, and in 2010, ACIP recommendations indicated that either HPV4 or HPV2 vaccine could be administered to girls and young women. In addition, the use of HPV4 vaccine in males was permitted. In 2011, ACIP recommended routine administration of HPV4 to boys and young adult males up to 21 years of age. Adolescents were the target population for these vaccines, and administration was recommended at the 11- to 12-year wellness visit. The primary role of the adolescent encounter was no longer to provide catch-up immunizations. A definitive adolescent immunization schedule had been established.

Why introduce the HPV vaccine so early?

HPV is the most common sexually transmitted infection in both men and women. Recent data suggest that approximately 79 million individuals are infected (Sex. Transm. Dis. 2013;40:187-93). Annually, about 14 million, mostly young adults are infected. Most sexually active individuals will acquire HPV. It is most common in teens and young adults, and intercourse is not required for transmission. It can be transmitted with any type of intimate sexual contact, and it has been isolated from virgins. The majority of these infections are asymptomatic and self- limited. However, persistent infection is associated with cervical and other types of anogenital cancer, and genital warts in both men and women. Complications of these infections may take years to manifest.

HPV is categorized by its epidemiologic association with cervical cancer. High-risk types cause cervical cancer, and HPV types 16 and 18 account for the majority of cervical cancers (66%) These two types are also associated with vaginal (55%), anal (79%), and oropharyngeal (62%) cancer (MMWR 2014 Jan. 31;63;69-72). It is estimated that each year there are 26,000 HPV-related cancers including 8,800 cases in men and 17,000 in women, 4,000 of whom will die of cervical cancer, according to the CDC. Low-risk types including HPV types 6 and 11 cause benign/low-grade cervical cell changes, recurrent papillomatosis, and 90% of the cases of genital warts.

Once a person is infected, HPV usually clears. If not, cervical intraepithelial neoplasia (CIN) may occur. The infection may still resolve spontaneously. If it persists, the degree of dysplasia can progress. Several years may pass before progression to invasive cancer. HPV vaccines are prophylactic like other vaccines. They cannot prevent disease progression and need to be administered before exposure to the viruses.

Compared with the introduction of other vaccines, such as Haemophilus influenzae type b and Prevnar7, some pediatric care providers may feel we may not have the benefit of realizing our efforts as immediately as in the past. However, encouraging vaccine effectiveness data in U.S. teens has been published. In one study, the investigators compared HPV prevalence data from the pre- and postvaccine era collected during the National Health and Nutrition Examination Survey. Among females aged 14-19 years, HPV prevalence (HPV-6, -11, -16, or -18 ) decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010. That is a 56% reduction in vaccine type HPV prevalence. This decrease in prevalence occurred within 4 years of vaccine introduction and low vaccine uptake. (J. Infect. Dis. 2013;208:385-93). Studies conducted in Denmark, Australia, Germany, and New Zealand also have shown significant declines in HPV4 vaccine type infection prevalence.

Vaccination coverage

The CDC tracks vaccination coverage annually in the National Immunization Survey–Teen (NIS-Teen), with data obtained from the 50 states, the District of Columbia, the U.S. Virgin Islands, and six major urban areas (MMWR 2013;62:685-93). Vaccination coverage differed significantly although each vaccine is recommended to be routinely administered at the 11- to 12-year visit. Although an increase from 25% to 53% had been noted between 2007 and 2011, in 2012, coverage for receiving at least one dose of HPV among females was almost 54%, essentially unchanged since 2011. The number who had received the recommended three doses was also essentially unchanged from 2011 to 2012 (34.8% in 2011 and 33.4% in 2012). Receipt of a single dose of HPV in boys was 8.3% in 2011 and 20.8% in 2012, the first year after the vaccine was recommended. Completion of the series in boys was 6.3%, an increase from 1.3% in 2011.

 

In contrast, the 2012 coverage for Tdap increased to 85% and MCV4, to 74%. It has been suggested that the higher coverage of Tdap and MCV may be due to the 40 and 13 states, respectively, that require them for middle school entry.

The disparity in coverage between Tdap and other vaccines suggests there are numerous missed opportunities to vaccinate adolescents. Data revealed that missed opportunities for girls increased from 20.8% in 2007 to 84% in 2012. If all missed opportunities had been eliminated, HPV coverage for at least one dose could have reached 92.6%.Almost 25% of parents indicated that they had no plan to immunize their daughter. The top reasons parents stated for not immunizing their daughters included: not needed or necessary, 19.1%; not recommended by provider, 14.2%; safety concerns, 13.3%; lack of knowledge, 12.6%; and not sexually active, 10.1%. (MMWR 2013;62:591-5).

Vaccine safety also was addressed. All reported adverse events were consistent with prelicensure clinical trial data. Ninety two percent of all adverse events were nonserious and included syncope, dizziness, nausea, and fever. Reports peaked in 2008 and have declined each year thereafter.

Challenges for HPV prevention

Improving immunization coverage is critical. There are numerous strategies to increase coverage including reminder recall systems, standing orders, and educating parents, patients, health care providers, and office staff who interact with parents. Education should reemphasize why immunization is initiated at 11-12 years and that completion of the series is recommended by 13 years. School requirements have always led to an increase in vaccination coverage. Only the District of Columbia has one for HPV. In this case, eliminating missed opportunities is crucial. It is estimated that for every year coverage is delayed, an additional 4,400 women will develop cervical cancer. The reality is that the burden of HPV-related cancers will persist if coverage is not increased.

As Louis Pasteur once said, "When meditating over a disease, I never think of finding a remedy for it, but, instead a means of preventing it."

For additional resources to assist with discussions about HPV, click here.

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures. E-mail her at [email protected]. Scan this QR code or visit pediatricnews.com.

The U.S. immunization program has been one of the country’s most successful initiatives and best investments. Prior to 2005, vaccines were targeted for administration to infants and young children. Adolescence was a period for catch-up immunizations. All that changed in 2005 when the first meningococcal conjugate vaccine (MCV) was recommended for administration to preteens at 11-12 years and college freshmen residing in dormitories by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP). Shortly thereafter in 2006, a new tetanus toxoid, diphtheria, and acellular pertussis vaccine (Tdap) was recommended, and in March 2007 the quadrivalent human papillomavirus vaccine (HPV4: types 6, 11, 16, and 18) was recommended for use in girls, starting at age 11-12 years, and young women up to 26 years of age. In 2009, a bivalent HPV vaccine (HPV2: types 16 and 18) was licensed, and in 2010, ACIP recommendations indicated that either HPV4 or HPV2 vaccine could be administered to girls and young women. In addition, the use of HPV4 vaccine in males was permitted. In 2011, ACIP recommended routine administration of HPV4 to boys and young adult males up to 21 years of age. Adolescents were the target population for these vaccines, and administration was recommended at the 11- to 12-year wellness visit. The primary role of the adolescent encounter was no longer to provide catch-up immunizations. A definitive adolescent immunization schedule had been established.

Why introduce the HPV vaccine so early?

HPV is the most common sexually transmitted infection in both men and women. Recent data suggest that approximately 79 million individuals are infected (Sex. Transm. Dis. 2013;40:187-93). Annually, about 14 million, mostly young adults are infected. Most sexually active individuals will acquire HPV. It is most common in teens and young adults, and intercourse is not required for transmission. It can be transmitted with any type of intimate sexual contact, and it has been isolated from virgins. The majority of these infections are asymptomatic and self- limited. However, persistent infection is associated with cervical and other types of anogenital cancer, and genital warts in both men and women. Complications of these infections may take years to manifest.

HPV is categorized by its epidemiologic association with cervical cancer. High-risk types cause cervical cancer, and HPV types 16 and 18 account for the majority of cervical cancers (66%) These two types are also associated with vaginal (55%), anal (79%), and oropharyngeal (62%) cancer (MMWR 2014 Jan. 31;63;69-72). It is estimated that each year there are 26,000 HPV-related cancers including 8,800 cases in men and 17,000 in women, 4,000 of whom will die of cervical cancer, according to the CDC. Low-risk types including HPV types 6 and 11 cause benign/low-grade cervical cell changes, recurrent papillomatosis, and 90% of the cases of genital warts.

Once a person is infected, HPV usually clears. If not, cervical intraepithelial neoplasia (CIN) may occur. The infection may still resolve spontaneously. If it persists, the degree of dysplasia can progress. Several years may pass before progression to invasive cancer. HPV vaccines are prophylactic like other vaccines. They cannot prevent disease progression and need to be administered before exposure to the viruses.

Compared with the introduction of other vaccines, such as Haemophilus influenzae type b and Prevnar7, some pediatric care providers may feel we may not have the benefit of realizing our efforts as immediately as in the past. However, encouraging vaccine effectiveness data in U.S. teens has been published. In one study, the investigators compared HPV prevalence data from the pre- and postvaccine era collected during the National Health and Nutrition Examination Survey. Among females aged 14-19 years, HPV prevalence (HPV-6, -11, -16, or -18 ) decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010. That is a 56% reduction in vaccine type HPV prevalence. This decrease in prevalence occurred within 4 years of vaccine introduction and low vaccine uptake. (J. Infect. Dis. 2013;208:385-93). Studies conducted in Denmark, Australia, Germany, and New Zealand also have shown significant declines in HPV4 vaccine type infection prevalence.

Vaccination coverage

The CDC tracks vaccination coverage annually in the National Immunization Survey–Teen (NIS-Teen), with data obtained from the 50 states, the District of Columbia, the U.S. Virgin Islands, and six major urban areas (MMWR 2013;62:685-93). Vaccination coverage differed significantly although each vaccine is recommended to be routinely administered at the 11- to 12-year visit. Although an increase from 25% to 53% had been noted between 2007 and 2011, in 2012, coverage for receiving at least one dose of HPV among females was almost 54%, essentially unchanged since 2011. The number who had received the recommended three doses was also essentially unchanged from 2011 to 2012 (34.8% in 2011 and 33.4% in 2012). Receipt of a single dose of HPV in boys was 8.3% in 2011 and 20.8% in 2012, the first year after the vaccine was recommended. Completion of the series in boys was 6.3%, an increase from 1.3% in 2011.

 

In contrast, the 2012 coverage for Tdap increased to 85% and MCV4, to 74%. It has been suggested that the higher coverage of Tdap and MCV may be due to the 40 and 13 states, respectively, that require them for middle school entry.

The disparity in coverage between Tdap and other vaccines suggests there are numerous missed opportunities to vaccinate adolescents. Data revealed that missed opportunities for girls increased from 20.8% in 2007 to 84% in 2012. If all missed opportunities had been eliminated, HPV coverage for at least one dose could have reached 92.6%.Almost 25% of parents indicated that they had no plan to immunize their daughter. The top reasons parents stated for not immunizing their daughters included: not needed or necessary, 19.1%; not recommended by provider, 14.2%; safety concerns, 13.3%; lack of knowledge, 12.6%; and not sexually active, 10.1%. (MMWR 2013;62:591-5).

Vaccine safety also was addressed. All reported adverse events were consistent with prelicensure clinical trial data. Ninety two percent of all adverse events were nonserious and included syncope, dizziness, nausea, and fever. Reports peaked in 2008 and have declined each year thereafter.

Challenges for HPV prevention

Improving immunization coverage is critical. There are numerous strategies to increase coverage including reminder recall systems, standing orders, and educating parents, patients, health care providers, and office staff who interact with parents. Education should reemphasize why immunization is initiated at 11-12 years and that completion of the series is recommended by 13 years. School requirements have always led to an increase in vaccination coverage. Only the District of Columbia has one for HPV. In this case, eliminating missed opportunities is crucial. It is estimated that for every year coverage is delayed, an additional 4,400 women will develop cervical cancer. The reality is that the burden of HPV-related cancers will persist if coverage is not increased.

As Louis Pasteur once said, "When meditating over a disease, I never think of finding a remedy for it, but, instead a means of preventing it."

For additional resources to assist with discussions about HPV, click here.

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures. E-mail her at [email protected]. Scan this QR code or visit pediatricnews.com.

The U.S. immunization program has been one of the country’s most successful initiatives and best investments. Prior to 2005, vaccines were targeted for administration to infants and young children. Adolescence was a period for catch-up immunizations. All that changed in 2005 when the first meningococcal conjugate vaccine (MCV) was recommended for administration to preteens at 11-12 years and college freshmen residing in dormitories by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP). Shortly thereafter in 2006, a new tetanus toxoid, diphtheria, and acellular pertussis vaccine (Tdap) was recommended, and in March 2007 the quadrivalent human papillomavirus vaccine (HPV4: types 6, 11, 16, and 18) was recommended for use in girls, starting at age 11-12 years, and young women up to 26 years of age. In 2009, a bivalent HPV vaccine (HPV2: types 16 and 18) was licensed, and in 2010, ACIP recommendations indicated that either HPV4 or HPV2 vaccine could be administered to girls and young women. In addition, the use of HPV4 vaccine in males was permitted. In 2011, ACIP recommended routine administration of HPV4 to boys and young adult males up to 21 years of age. Adolescents were the target population for these vaccines, and administration was recommended at the 11- to 12-year wellness visit. The primary role of the adolescent encounter was no longer to provide catch-up immunizations. A definitive adolescent immunization schedule had been established.

Why introduce the HPV vaccine so early?

HPV is the most common sexually transmitted infection in both men and women. Recent data suggest that approximately 79 million individuals are infected (Sex. Transm. Dis. 2013;40:187-93). Annually, about 14 million, mostly young adults are infected. Most sexually active individuals will acquire HPV. It is most common in teens and young adults, and intercourse is not required for transmission. It can be transmitted with any type of intimate sexual contact, and it has been isolated from virgins. The majority of these infections are asymptomatic and self- limited. However, persistent infection is associated with cervical and other types of anogenital cancer, and genital warts in both men and women. Complications of these infections may take years to manifest.

HPV is categorized by its epidemiologic association with cervical cancer. High-risk types cause cervical cancer, and HPV types 16 and 18 account for the majority of cervical cancers (66%) These two types are also associated with vaginal (55%), anal (79%), and oropharyngeal (62%) cancer (MMWR 2014 Jan. 31;63;69-72). It is estimated that each year there are 26,000 HPV-related cancers including 8,800 cases in men and 17,000 in women, 4,000 of whom will die of cervical cancer, according to the CDC. Low-risk types including HPV types 6 and 11 cause benign/low-grade cervical cell changes, recurrent papillomatosis, and 90% of the cases of genital warts.

Once a person is infected, HPV usually clears. If not, cervical intraepithelial neoplasia (CIN) may occur. The infection may still resolve spontaneously. If it persists, the degree of dysplasia can progress. Several years may pass before progression to invasive cancer. HPV vaccines are prophylactic like other vaccines. They cannot prevent disease progression and need to be administered before exposure to the viruses.

Compared with the introduction of other vaccines, such as Haemophilus influenzae type b and Prevnar7, some pediatric care providers may feel we may not have the benefit of realizing our efforts as immediately as in the past. However, encouraging vaccine effectiveness data in U.S. teens has been published. In one study, the investigators compared HPV prevalence data from the pre- and postvaccine era collected during the National Health and Nutrition Examination Survey. Among females aged 14-19 years, HPV prevalence (HPV-6, -11, -16, or -18 ) decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010. That is a 56% reduction in vaccine type HPV prevalence. This decrease in prevalence occurred within 4 years of vaccine introduction and low vaccine uptake. (J. Infect. Dis. 2013;208:385-93). Studies conducted in Denmark, Australia, Germany, and New Zealand also have shown significant declines in HPV4 vaccine type infection prevalence.

Vaccination coverage

The CDC tracks vaccination coverage annually in the National Immunization Survey–Teen (NIS-Teen), with data obtained from the 50 states, the District of Columbia, the U.S. Virgin Islands, and six major urban areas (MMWR 2013;62:685-93). Vaccination coverage differed significantly although each vaccine is recommended to be routinely administered at the 11- to 12-year visit. Although an increase from 25% to 53% had been noted between 2007 and 2011, in 2012, coverage for receiving at least one dose of HPV among females was almost 54%, essentially unchanged since 2011. The number who had received the recommended three doses was also essentially unchanged from 2011 to 2012 (34.8% in 2011 and 33.4% in 2012). Receipt of a single dose of HPV in boys was 8.3% in 2011 and 20.8% in 2012, the first year after the vaccine was recommended. Completion of the series in boys was 6.3%, an increase from 1.3% in 2011.

 

In contrast, the 2012 coverage for Tdap increased to 85% and MCV4, to 74%. It has been suggested that the higher coverage of Tdap and MCV may be due to the 40 and 13 states, respectively, that require them for middle school entry.

The disparity in coverage between Tdap and other vaccines suggests there are numerous missed opportunities to vaccinate adolescents. Data revealed that missed opportunities for girls increased from 20.8% in 2007 to 84% in 2012. If all missed opportunities had been eliminated, HPV coverage for at least one dose could have reached 92.6%.Almost 25% of parents indicated that they had no plan to immunize their daughter. The top reasons parents stated for not immunizing their daughters included: not needed or necessary, 19.1%; not recommended by provider, 14.2%; safety concerns, 13.3%; lack of knowledge, 12.6%; and not sexually active, 10.1%. (MMWR 2013;62:591-5).

Vaccine safety also was addressed. All reported adverse events were consistent with prelicensure clinical trial data. Ninety two percent of all adverse events were nonserious and included syncope, dizziness, nausea, and fever. Reports peaked in 2008 and have declined each year thereafter.

Challenges for HPV prevention

Improving immunization coverage is critical. There are numerous strategies to increase coverage including reminder recall systems, standing orders, and educating parents, patients, health care providers, and office staff who interact with parents. Education should reemphasize why immunization is initiated at 11-12 years and that completion of the series is recommended by 13 years. School requirements have always led to an increase in vaccination coverage. Only the District of Columbia has one for HPV. In this case, eliminating missed opportunities is crucial. It is estimated that for every year coverage is delayed, an additional 4,400 women will develop cervical cancer. The reality is that the burden of HPV-related cancers will persist if coverage is not increased.

As Louis Pasteur once said, "When meditating over a disease, I never think of finding a remedy for it, but, instead a means of preventing it."

For additional resources to assist with discussions about HPV, click here.

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures. E-mail her at [email protected]. Scan this QR code or visit pediatricnews.com.

Researchers say they’ve discovered a distinct bone-marrow-failure syndrome and the genetic defect that causes it.

In its natural form, the gene ERCC6L2 plays a role in DNA repair and mitochondrial function.

But investigators found evidence to suggest that mutations in ERCC6L2, and the subsequent DNA damage, were the underlying cause of tri-lineage bone marrow failure in a pair of patients with neurological dysfunction.

“New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure,” said Inderjeet Dokal, MD, of Queen Mary University of London in the UK.

“Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.”

Dr Dokal and his colleagues described this research in The American Journal of Human Genetics.

The team performed exome sequencing in 3 patients with genetically uncharacterized, tri-lineage bone marrow failure.

The patients came from consanguineous families (their parents were first-degree cousins), they had developmental delays characterized by learning disabilities, and 2 of the patients had microcephaly.

The sequencing did not uncover variations in any of the known genes associated with bone marrow failure. And the researchers could not find any obvious disease-causing variants in 1 of the patients.

However, the other 2 patients shared homozygous truncating mutations in ERCC6L2—c.1963C>T (p.Arg655*) and c.1236_1239delAACA (p.Thr413Cysfs*2). The c.1963C>T variant had already been identified, but, to the researchers’ knowledge, the other variant had not.

Additional experiments suggested that these mutations affect the subcellular localization and stability of ERCC6L2.

The investigators then speculated that ERCC6L2 plays a role in the DNA-damage response. To test that theory, they mimicked the truncating mutations by knocking down ERCC6L2 expression in human A549 cells.

This significantly reduced cell viability when the cells were exposed to the DNA-damaging agents mitomycin C and irofulven.

To further confirm their theory, the researchers looked at another marker of DNA damage. Previous research had suggested that Snf2 protein complexes are involved in the recruitment of γH2AX, a phosphorylated form of histone 2A, to sites of DNA damage.

So the team performed immunostaining with a γH2AX-specific antibody. And they found that ERCC6L2-knockdown cells displayed H2AX phosphorylation, an effect that increased upon genotoxic stress (treatment with irofulven).

These results indicate that ERCC6L2 plays a role in the DNA-damage-response pathway, and knockdown of this gene sensitizes cells to genotoxic agents.

Additional experiments showed that ERCC6L2 translocated to the mitochondria and the nucleus in response to DNA damage. And ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS).

But introducing the ROS scavenger N-acetyl cysteine diminished the cytotoxicity induced by irofulven, and it halted ERCCGL2 traffic to the mitochondria and nucleus.

The investigators said these results point to a distinct bone-marrow-failure syndrome resulting from mutations in ERCC6L2.

“This is a promising finding which we hope, one day, could lead to finding an effective treatment for this type of gene defect,” Dr Dokal said. “Now [that] we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.”

Researchers say they’ve discovered a distinct bone-marrow-failure syndrome and the genetic defect that causes it.

In its natural form, the gene ERCC6L2 plays a role in DNA repair and mitochondrial function.

But investigators found evidence to suggest that mutations in ERCC6L2, and the subsequent DNA damage, were the underlying cause of tri-lineage bone marrow failure in a pair of patients with neurological dysfunction.

“New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure,” said Inderjeet Dokal, MD, of Queen Mary University of London in the UK.

“Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.”

Dr Dokal and his colleagues described this research in The American Journal of Human Genetics.

The team performed exome sequencing in 3 patients with genetically uncharacterized, tri-lineage bone marrow failure.

The patients came from consanguineous families (their parents were first-degree cousins), they had developmental delays characterized by learning disabilities, and 2 of the patients had microcephaly.

The sequencing did not uncover variations in any of the known genes associated with bone marrow failure. And the researchers could not find any obvious disease-causing variants in 1 of the patients.

However, the other 2 patients shared homozygous truncating mutations in ERCC6L2—c.1963C>T (p.Arg655*) and c.1236_1239delAACA (p.Thr413Cysfs*2). The c.1963C>T variant had already been identified, but, to the researchers’ knowledge, the other variant had not.

Additional experiments suggested that these mutations affect the subcellular localization and stability of ERCC6L2.

The investigators then speculated that ERCC6L2 plays a role in the DNA-damage response. To test that theory, they mimicked the truncating mutations by knocking down ERCC6L2 expression in human A549 cells.

This significantly reduced cell viability when the cells were exposed to the DNA-damaging agents mitomycin C and irofulven.

To further confirm their theory, the researchers looked at another marker of DNA damage. Previous research had suggested that Snf2 protein complexes are involved in the recruitment of γH2AX, a phosphorylated form of histone 2A, to sites of DNA damage.

So the team performed immunostaining with a γH2AX-specific antibody. And they found that ERCC6L2-knockdown cells displayed H2AX phosphorylation, an effect that increased upon genotoxic stress (treatment with irofulven).

These results indicate that ERCC6L2 plays a role in the DNA-damage-response pathway, and knockdown of this gene sensitizes cells to genotoxic agents.

Additional experiments showed that ERCC6L2 translocated to the mitochondria and the nucleus in response to DNA damage. And ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS).

But introducing the ROS scavenger N-acetyl cysteine diminished the cytotoxicity induced by irofulven, and it halted ERCCGL2 traffic to the mitochondria and nucleus.

The investigators said these results point to a distinct bone-marrow-failure syndrome resulting from mutations in ERCC6L2.

“This is a promising finding which we hope, one day, could lead to finding an effective treatment for this type of gene defect,” Dr Dokal said. “Now [that] we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.”

Researchers say they’ve discovered a distinct bone-marrow-failure syndrome and the genetic defect that causes it.

In its natural form, the gene ERCC6L2 plays a role in DNA repair and mitochondrial function.

But investigators found evidence to suggest that mutations in ERCC6L2, and the subsequent DNA damage, were the underlying cause of tri-lineage bone marrow failure in a pair of patients with neurological dysfunction.

“New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure,” said Inderjeet Dokal, MD, of Queen Mary University of London in the UK.

“Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.”

Dr Dokal and his colleagues described this research in The American Journal of Human Genetics.

The team performed exome sequencing in 3 patients with genetically uncharacterized, tri-lineage bone marrow failure.

The patients came from consanguineous families (their parents were first-degree cousins), they had developmental delays characterized by learning disabilities, and 2 of the patients had microcephaly.

The sequencing did not uncover variations in any of the known genes associated with bone marrow failure. And the researchers could not find any obvious disease-causing variants in 1 of the patients.

However, the other 2 patients shared homozygous truncating mutations in ERCC6L2—c.1963C>T (p.Arg655*) and c.1236_1239delAACA (p.Thr413Cysfs*2). The c.1963C>T variant had already been identified, but, to the researchers’ knowledge, the other variant had not.

Additional experiments suggested that these mutations affect the subcellular localization and stability of ERCC6L2.

The investigators then speculated that ERCC6L2 plays a role in the DNA-damage response. To test that theory, they mimicked the truncating mutations by knocking down ERCC6L2 expression in human A549 cells.

This significantly reduced cell viability when the cells were exposed to the DNA-damaging agents mitomycin C and irofulven.

To further confirm their theory, the researchers looked at another marker of DNA damage. Previous research had suggested that Snf2 protein complexes are involved in the recruitment of γH2AX, a phosphorylated form of histone 2A, to sites of DNA damage.

So the team performed immunostaining with a γH2AX-specific antibody. And they found that ERCC6L2-knockdown cells displayed H2AX phosphorylation, an effect that increased upon genotoxic stress (treatment with irofulven).

These results indicate that ERCC6L2 plays a role in the DNA-damage-response pathway, and knockdown of this gene sensitizes cells to genotoxic agents.

Additional experiments showed that ERCC6L2 translocated to the mitochondria and the nucleus in response to DNA damage. And ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS).

But introducing the ROS scavenger N-acetyl cysteine diminished the cytotoxicity induced by irofulven, and it halted ERCCGL2 traffic to the mitochondria and nucleus.

The investigators said these results point to a distinct bone-marrow-failure syndrome resulting from mutations in ERCC6L2.

“This is a promising finding which we hope, one day, could lead to finding an effective treatment for this type of gene defect,” Dr Dokal said. “Now [that] we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.”

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

 

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

 

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

 

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

New research indicates that, toward the end of the century, climate change may make tropical highland regions suitable breeding grounds for malaria. And this could greatly increase the incidence of the disease.

Scientists compared the latest predictions for global warming with a range of statistical models commonly used to predict the spread of malaria.

And the models suggested that the changing climate will allow malaria to move into higher altitudes during warmer seasons and become permanently resident in larger areas.

This would mainly affect Africa but would also have an impact in Asia and South America.

In eastern Africa, the change could result in an additional 100 million people being exposed to malaria by the end of the 2080s, the researchers calculated.

However, they noted that the size of the impact is highly variable, as it can be affected by a number of factors.

“[W]e expect increased urbanization in these areas over the next 70 years,” said study author Cyril Caminade, PhD, of the University of Liverpool in the UK.

“Other developments, such as land use changes, population movements, and economic growth, will also have to be accounted for in future studies. What is clear is that diseases such as malaria are going to be moving, and this is a crucial element of how we prepare for the effects of climate change.”

The comparison of these models has not been carried out before, and by doing so, the researchers were able to find that malaria spreading to tropical highland areas was the one area in which the models agreed.

There was distinct variation in other parts of the world. Two of the models predicted that malaria would move northward, eventually spreading into Europe, Russia, and North America. Others showed that malaria would move north, but only as far as North Africa, where it was eliminated in the 20th century.

For more details, see the paper in PNAS.

New research indicates that, toward the end of the century, climate change may make tropical highland regions suitable breeding grounds for malaria. And this could greatly increase the incidence of the disease.

Scientists compared the latest predictions for global warming with a range of statistical models commonly used to predict the spread of malaria.

And the models suggested that the changing climate will allow malaria to move into higher altitudes during warmer seasons and become permanently resident in larger areas.

This would mainly affect Africa but would also have an impact in Asia and South America.

In eastern Africa, the change could result in an additional 100 million people being exposed to malaria by the end of the 2080s, the researchers calculated.

However, they noted that the size of the impact is highly variable, as it can be affected by a number of factors.

“[W]e expect increased urbanization in these areas over the next 70 years,” said study author Cyril Caminade, PhD, of the University of Liverpool in the UK.

“Other developments, such as land use changes, population movements, and economic growth, will also have to be accounted for in future studies. What is clear is that diseases such as malaria are going to be moving, and this is a crucial element of how we prepare for the effects of climate change.”

The comparison of these models has not been carried out before, and by doing so, the researchers were able to find that malaria spreading to tropical highland areas was the one area in which the models agreed.

There was distinct variation in other parts of the world. Two of the models predicted that malaria would move northward, eventually spreading into Europe, Russia, and North America. Others showed that malaria would move north, but only as far as North Africa, where it was eliminated in the 20th century.

For more details, see the paper in PNAS.

New research indicates that, toward the end of the century, climate change may make tropical highland regions suitable breeding grounds for malaria. And this could greatly increase the incidence of the disease.

Scientists compared the latest predictions for global warming with a range of statistical models commonly used to predict the spread of malaria.

And the models suggested that the changing climate will allow malaria to move into higher altitudes during warmer seasons and become permanently resident in larger areas.

This would mainly affect Africa but would also have an impact in Asia and South America.

In eastern Africa, the change could result in an additional 100 million people being exposed to malaria by the end of the 2080s, the researchers calculated.

However, they noted that the size of the impact is highly variable, as it can be affected by a number of factors.

“[W]e expect increased urbanization in these areas over the next 70 years,” said study author Cyril Caminade, PhD, of the University of Liverpool in the UK.

“Other developments, such as land use changes, population movements, and economic growth, will also have to be accounted for in future studies. What is clear is that diseases such as malaria are going to be moving, and this is a crucial element of how we prepare for the effects of climate change.”

The comparison of these models has not been carried out before, and by doing so, the researchers were able to find that malaria spreading to tropical highland areas was the one area in which the models agreed.

There was distinct variation in other parts of the world. Two of the models predicted that malaria would move northward, eventually spreading into Europe, Russia, and North America. Others showed that malaria would move north, but only as far as North Africa, where it was eliminated in the 20th century.

For more details, see the paper in PNAS.

A new microscopy method allows scientists to image many cellular components at once, according to a paper published in Nature Methods.

Such images could shed light on complex cellular pathways and might lead to new ways to diagnose disease, track its progress, or monitor treatment effectiveness at a cellular level, the researchers said.

They noted that today’s imaging methods typically spot, at most, 3 or 4 types of biomolecules simultaneously.

But to truly understand complex cellular functions, it’s important to be able to visualize most or all of the molecules at once, said study author Peng Yin, PhD, of the Wyss Institute at Harvard Medical School in Boston.

“If you can see only a few things at a time, you are missing the big picture,” Dr Yin said.

So he and his colleagues sought a way to take aerial views of cells that could show dozens of types of biomolecules. They decided to build upon a method called DNA-PAINT, which can create snapshots of up to 3 molecules at once by labeling them with different colored dyes.

The team modified DNA-PAINT to create a method called Exchange-PAINT. Exchange-PAINT relies on the fact that DNA strands with the correct sequence of nucleotides bind specifically to partner strands with complementary sequences.

The researchers label a biomolecule they want to visualize with a short DNA tag. Then, they add to the solution a partner strand carrying a fluorescent dye that lights up only when the 2 strands pair up.

When that partner strand binds the tagged biomolecule, it lights up, then lets go, causing the biomolecule to “blink” at a precise rate the researchers can control. The team uses this blinking to obtain ultra-sharp images.

They repeat the process to visualize a second target, a third, and so on. Then, they overlay the resulting images to create a composite image in which each biomolecule is assigned a different color.

This allows them to create false-color images that simultaneously show many types of biomolecules—far more than they could simultaneously visualize by labeling them with different colored dyes. And these false-color images allow them to spot enough biomolecules at once to capture the entire scene.

To test Exchange-PAINT, the researchers created 10 unique pieces of folded DNA that resembled the numerals 0 through 9. These numerals could be resolved with less than 10 nanometers resolution, or 1/20th of the diffraction limit.

The team was able to use Exchange-PAINT to capture clear images of the 10 different DNA origami structures in one image. They also used the method to capture images of fixed human cells, with each color tagging a different cellular component—microtubules, mitochondria, Golgi apparatus, or peroxisomes.

Dr Yin expects that, with further development, this method could be used to visualize dozens of cellular components at once.

A new microscopy method allows scientists to image many cellular components at once, according to a paper published in Nature Methods.

Such images could shed light on complex cellular pathways and might lead to new ways to diagnose disease, track its progress, or monitor treatment effectiveness at a cellular level, the researchers said.

They noted that today’s imaging methods typically spot, at most, 3 or 4 types of biomolecules simultaneously.

But to truly understand complex cellular functions, it’s important to be able to visualize most or all of the molecules at once, said study author Peng Yin, PhD, of the Wyss Institute at Harvard Medical School in Boston.

“If you can see only a few things at a time, you are missing the big picture,” Dr Yin said.

So he and his colleagues sought a way to take aerial views of cells that could show dozens of types of biomolecules. They decided to build upon a method called DNA-PAINT, which can create snapshots of up to 3 molecules at once by labeling them with different colored dyes.

The team modified DNA-PAINT to create a method called Exchange-PAINT. Exchange-PAINT relies on the fact that DNA strands with the correct sequence of nucleotides bind specifically to partner strands with complementary sequences.

The researchers label a biomolecule they want to visualize with a short DNA tag. Then, they add to the solution a partner strand carrying a fluorescent dye that lights up only when the 2 strands pair up.

When that partner strand binds the tagged biomolecule, it lights up, then lets go, causing the biomolecule to “blink” at a precise rate the researchers can control. The team uses this blinking to obtain ultra-sharp images.

They repeat the process to visualize a second target, a third, and so on. Then, they overlay the resulting images to create a composite image in which each biomolecule is assigned a different color.

This allows them to create false-color images that simultaneously show many types of biomolecules—far more than they could simultaneously visualize by labeling them with different colored dyes. And these false-color images allow them to spot enough biomolecules at once to capture the entire scene.

To test Exchange-PAINT, the researchers created 10 unique pieces of folded DNA that resembled the numerals 0 through 9. These numerals could be resolved with less than 10 nanometers resolution, or 1/20th of the diffraction limit.

The team was able to use Exchange-PAINT to capture clear images of the 10 different DNA origami structures in one image. They also used the method to capture images of fixed human cells, with each color tagging a different cellular component—microtubules, mitochondria, Golgi apparatus, or peroxisomes.

Dr Yin expects that, with further development, this method could be used to visualize dozens of cellular components at once.

A new microscopy method allows scientists to image many cellular components at once, according to a paper published in Nature Methods.

Such images could shed light on complex cellular pathways and might lead to new ways to diagnose disease, track its progress, or monitor treatment effectiveness at a cellular level, the researchers said.

They noted that today’s imaging methods typically spot, at most, 3 or 4 types of biomolecules simultaneously.

But to truly understand complex cellular functions, it’s important to be able to visualize most or all of the molecules at once, said study author Peng Yin, PhD, of the Wyss Institute at Harvard Medical School in Boston.

“If you can see only a few things at a time, you are missing the big picture,” Dr Yin said.

So he and his colleagues sought a way to take aerial views of cells that could show dozens of types of biomolecules. They decided to build upon a method called DNA-PAINT, which can create snapshots of up to 3 molecules at once by labeling them with different colored dyes.

The team modified DNA-PAINT to create a method called Exchange-PAINT. Exchange-PAINT relies on the fact that DNA strands with the correct sequence of nucleotides bind specifically to partner strands with complementary sequences.

The researchers label a biomolecule they want to visualize with a short DNA tag. Then, they add to the solution a partner strand carrying a fluorescent dye that lights up only when the 2 strands pair up.

When that partner strand binds the tagged biomolecule, it lights up, then lets go, causing the biomolecule to “blink” at a precise rate the researchers can control. The team uses this blinking to obtain ultra-sharp images.

They repeat the process to visualize a second target, a third, and so on. Then, they overlay the resulting images to create a composite image in which each biomolecule is assigned a different color.

This allows them to create false-color images that simultaneously show many types of biomolecules—far more than they could simultaneously visualize by labeling them with different colored dyes. And these false-color images allow them to spot enough biomolecules at once to capture the entire scene.

To test Exchange-PAINT, the researchers created 10 unique pieces of folded DNA that resembled the numerals 0 through 9. These numerals could be resolved with less than 10 nanometers resolution, or 1/20th of the diffraction limit.

The team was able to use Exchange-PAINT to capture clear images of the 10 different DNA origami structures in one image. They also used the method to capture images of fixed human cells, with each color tagging a different cellular component—microtubules, mitochondria, Golgi apparatus, or peroxisomes.

Dr Yin expects that, with further development, this method could be used to visualize dozens of cellular components at once.