MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

Medical Education Library

A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.

• Introduction 
• Treatment with ELIDEL ® (pimecrolimus) Cream 1%
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas

Dr. Hebert  reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.

Copyright © by Frontline Medical Communications Inc.

Medical Education Library

A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.

• Introduction 
• Treatment with ELIDEL ® (pimecrolimus) Cream 1%
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas

Dr. Hebert  reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.

Copyright © by Frontline Medical Communications Inc.

Medical Education Library

A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.

• Introduction 
• Treatment with ELIDEL ® (pimecrolimus) Cream 1%
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas

Dr. Hebert  reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.

Copyright © by Frontline Medical Communications Inc.

Recently, I put up a post on our main Shrink Rap blog titled, "Is it okay to shrink your sister in an emergency?" Given how difficult it can be to get an appointment with a psychiatrist, I wondered about the ethics of prescribing psychotropics to a distressed family member when other options are limited.

First, I created a fictional scenario. Sister Lucy was treated for panic disorder 5 years ago. She took a benzodiazepine for a few weeks, an SSRI for a year, and went to psychotherapy. Her symptoms resolved, and she was able to terminate treatment with the blessing of her psychiatrist. Last year, Lucy moved to a new state and, being generally healthy, she has not yet established relationships with primary care providers. So with no physician, in a new state, Lucy had a recurrence of her panic disorder. She was initially seen in an emergency department, given a small supply of Ativan (lorazepam), and instructions to see a psychiatrist.

Lucy called around, and the earliest appointment she could get was 6 weeks away. She tried a handful of psychiatrists, but she did not call every psychiatrist in town. Most of the ones she tried were not taking new patients, and the voice mail systems of each mental health group were time consuming and frustrating, some cut her off, and no one had any more immediate response than to go to the ED if it were an emergency, and Lucy had already done that. Her brother, a psychiatrist in another state, came to visit for the weekend, and he witnessed several of her panic attacks. He had no more luck finding a psychiatrist for her. Lucy visited an urgent care center, where she was restarted on the SSRI and given more of the Ativan. But at the drugstore, she noticed she was given a 2-week supply and this would not last until the scheduled appointment.

So I asked our blog readers if it was okay for the brother to write prescriptions to hold his sister over until her scheduled appointment. The other options would have been for her to continue to suffer, to see if she could find another form of treatment more quickly, to return to the urgent care center on a continual basis and hope they would provide more medication, or to find a new primary care doctor who could prescribe in the meantime. Lucy didn’t know if this would be any easier. The psychiatrist who saw her 5 years ago before she moved would not be comfortable resuming medications without seeing her, but just in case there was any doubt, he retired, moved to North Korea, and died in a freak accident where he was swept up by a street cleaner so that option was not on the table (fictional characters can lead interesting and tragic lives).

Readers wrote in with a variety of thoughts. One psychiatrist empathized; she had a very depressed relative, and she debated providing medication samples in the interim while the relative waited to get in with a mental health professional. Another psychiatrist had seen too many patients become addicted to prescription benzodiazepines and suggested that this might start a cycle where Sister Lucy would pester brother psychiatrist for more medication in the future. Most of the psychiatrists felt that if a reasonable effort were made to obtain care and the barriers were valid, then it was a tough situation, but ultimately they felt it was okay to resume medications that previously had worked and been tolerated, for a limited period of time, since Lucy was symptomatic and this constituted an emergency.

The patients who wrote in were less forgiving, overall. Several insisted it was easy enough to find a primary care doctor within days, and a primary care doctor would certainly prescribe the medications. I was told that all one has to do is call one’s insurance company, so, curious, I called mine and got two names. The first one had a message saying staff was not in on Wednesday and the caller should try back tomorrow. I didn’t. The second one instructed me to leave a message that would be returned within 24 hours. It wasn’t. I e-mailed my own primary care doctor to ask when the next new patient appointment was – this physician charges a practice fee (too low to be considered "concierge," but high enough to enable a lower caseload). The response I received is that the practice is full. I e-mailed a friend who is a wonderful primary care doctor but takes no health insurance and has opted out of Medicare, and he had an opening the following week. I, however, had insider knowledge that a random newcomer to town might not have, and the insurance companies would certainly not be referring urgent cases to this out-of-network doctor. And all this assumes that any doc will do; there is no allowance here for the idea of waiting for a psychiatrist or internist who might come highly recommended or have subspecialty training.

I was left to say that it wasn’t easy to find a psychiatrist or a primary care doctor on demand when one is new in town and in a state of emotional distress. Again, I was told otherwise! I learned about a service called ZocDoc.com where you can make a next day appointment with a physician, simply by giving your Zip code, insurance, and specialty desired. Interesting, as I do this all the time with an App called OpenTable to schedule reservations at restaurants. Why not doctors’ appointments?

So it was late, and I tried to schedule a next day appointment with a primary care doc. It worked! Only I didn’t really want the appointment; what I wanted was information to write my article for Clinical Psychiatry News this week. I dialed the doctor to cancel the appointment, and instead of getting an office machine, I got the actual doctor – and he even sounded like a nice guy. He couldn’t cancel my appointment, but I then realized that, like OpenTable, there was a button to push to cancel the appointment, and I did that. I looked for psychiatrists, and there weren’t many with next day appointments – perhaps one – nearby, but if I would drive 30 miles or so to the next major city, I could get an appointment very soon, and certainly within a couple of weeks. Interesting. I learned something new!

So I wondered about Sister Lucy, and I decided she lives in Boise, Idaho, a place I’ve never been to and whose availability of medical care I know nothing about. The ZocDoc site there is not active, and so poor Lucy is back to her original problem, and I am left to the original question: Should her brother prescribe her medications?

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).

Recently, I put up a post on our main Shrink Rap blog titled, "Is it okay to shrink your sister in an emergency?" Given how difficult it can be to get an appointment with a psychiatrist, I wondered about the ethics of prescribing psychotropics to a distressed family member when other options are limited.

First, I created a fictional scenario. Sister Lucy was treated for panic disorder 5 years ago. She took a benzodiazepine for a few weeks, an SSRI for a year, and went to psychotherapy. Her symptoms resolved, and she was able to terminate treatment with the blessing of her psychiatrist. Last year, Lucy moved to a new state and, being generally healthy, she has not yet established relationships with primary care providers. So with no physician, in a new state, Lucy had a recurrence of her panic disorder. She was initially seen in an emergency department, given a small supply of Ativan (lorazepam), and instructions to see a psychiatrist.

Lucy called around, and the earliest appointment she could get was 6 weeks away. She tried a handful of psychiatrists, but she did not call every psychiatrist in town. Most of the ones she tried were not taking new patients, and the voice mail systems of each mental health group were time consuming and frustrating, some cut her off, and no one had any more immediate response than to go to the ED if it were an emergency, and Lucy had already done that. Her brother, a psychiatrist in another state, came to visit for the weekend, and he witnessed several of her panic attacks. He had no more luck finding a psychiatrist for her. Lucy visited an urgent care center, where she was restarted on the SSRI and given more of the Ativan. But at the drugstore, she noticed she was given a 2-week supply and this would not last until the scheduled appointment.

So I asked our blog readers if it was okay for the brother to write prescriptions to hold his sister over until her scheduled appointment. The other options would have been for her to continue to suffer, to see if she could find another form of treatment more quickly, to return to the urgent care center on a continual basis and hope they would provide more medication, or to find a new primary care doctor who could prescribe in the meantime. Lucy didn’t know if this would be any easier. The psychiatrist who saw her 5 years ago before she moved would not be comfortable resuming medications without seeing her, but just in case there was any doubt, he retired, moved to North Korea, and died in a freak accident where he was swept up by a street cleaner so that option was not on the table (fictional characters can lead interesting and tragic lives).

Readers wrote in with a variety of thoughts. One psychiatrist empathized; she had a very depressed relative, and she debated providing medication samples in the interim while the relative waited to get in with a mental health professional. Another psychiatrist had seen too many patients become addicted to prescription benzodiazepines and suggested that this might start a cycle where Sister Lucy would pester brother psychiatrist for more medication in the future. Most of the psychiatrists felt that if a reasonable effort were made to obtain care and the barriers were valid, then it was a tough situation, but ultimately they felt it was okay to resume medications that previously had worked and been tolerated, for a limited period of time, since Lucy was symptomatic and this constituted an emergency.

The patients who wrote in were less forgiving, overall. Several insisted it was easy enough to find a primary care doctor within days, and a primary care doctor would certainly prescribe the medications. I was told that all one has to do is call one’s insurance company, so, curious, I called mine and got two names. The first one had a message saying staff was not in on Wednesday and the caller should try back tomorrow. I didn’t. The second one instructed me to leave a message that would be returned within 24 hours. It wasn’t. I e-mailed my own primary care doctor to ask when the next new patient appointment was – this physician charges a practice fee (too low to be considered "concierge," but high enough to enable a lower caseload). The response I received is that the practice is full. I e-mailed a friend who is a wonderful primary care doctor but takes no health insurance and has opted out of Medicare, and he had an opening the following week. I, however, had insider knowledge that a random newcomer to town might not have, and the insurance companies would certainly not be referring urgent cases to this out-of-network doctor. And all this assumes that any doc will do; there is no allowance here for the idea of waiting for a psychiatrist or internist who might come highly recommended or have subspecialty training.

I was left to say that it wasn’t easy to find a psychiatrist or a primary care doctor on demand when one is new in town and in a state of emotional distress. Again, I was told otherwise! I learned about a service called ZocDoc.com where you can make a next day appointment with a physician, simply by giving your Zip code, insurance, and specialty desired. Interesting, as I do this all the time with an App called OpenTable to schedule reservations at restaurants. Why not doctors’ appointments?

So it was late, and I tried to schedule a next day appointment with a primary care doc. It worked! Only I didn’t really want the appointment; what I wanted was information to write my article for Clinical Psychiatry News this week. I dialed the doctor to cancel the appointment, and instead of getting an office machine, I got the actual doctor – and he even sounded like a nice guy. He couldn’t cancel my appointment, but I then realized that, like OpenTable, there was a button to push to cancel the appointment, and I did that. I looked for psychiatrists, and there weren’t many with next day appointments – perhaps one – nearby, but if I would drive 30 miles or so to the next major city, I could get an appointment very soon, and certainly within a couple of weeks. Interesting. I learned something new!

So I wondered about Sister Lucy, and I decided she lives in Boise, Idaho, a place I’ve never been to and whose availability of medical care I know nothing about. The ZocDoc site there is not active, and so poor Lucy is back to her original problem, and I am left to the original question: Should her brother prescribe her medications?

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).

Recently, I put up a post on our main Shrink Rap blog titled, "Is it okay to shrink your sister in an emergency?" Given how difficult it can be to get an appointment with a psychiatrist, I wondered about the ethics of prescribing psychotropics to a distressed family member when other options are limited.

First, I created a fictional scenario. Sister Lucy was treated for panic disorder 5 years ago. She took a benzodiazepine for a few weeks, an SSRI for a year, and went to psychotherapy. Her symptoms resolved, and she was able to terminate treatment with the blessing of her psychiatrist. Last year, Lucy moved to a new state and, being generally healthy, she has not yet established relationships with primary care providers. So with no physician, in a new state, Lucy had a recurrence of her panic disorder. She was initially seen in an emergency department, given a small supply of Ativan (lorazepam), and instructions to see a psychiatrist.

Lucy called around, and the earliest appointment she could get was 6 weeks away. She tried a handful of psychiatrists, but she did not call every psychiatrist in town. Most of the ones she tried were not taking new patients, and the voice mail systems of each mental health group were time consuming and frustrating, some cut her off, and no one had any more immediate response than to go to the ED if it were an emergency, and Lucy had already done that. Her brother, a psychiatrist in another state, came to visit for the weekend, and he witnessed several of her panic attacks. He had no more luck finding a psychiatrist for her. Lucy visited an urgent care center, where she was restarted on the SSRI and given more of the Ativan. But at the drugstore, she noticed she was given a 2-week supply and this would not last until the scheduled appointment.

So I asked our blog readers if it was okay for the brother to write prescriptions to hold his sister over until her scheduled appointment. The other options would have been for her to continue to suffer, to see if she could find another form of treatment more quickly, to return to the urgent care center on a continual basis and hope they would provide more medication, or to find a new primary care doctor who could prescribe in the meantime. Lucy didn’t know if this would be any easier. The psychiatrist who saw her 5 years ago before she moved would not be comfortable resuming medications without seeing her, but just in case there was any doubt, he retired, moved to North Korea, and died in a freak accident where he was swept up by a street cleaner so that option was not on the table (fictional characters can lead interesting and tragic lives).

Readers wrote in with a variety of thoughts. One psychiatrist empathized; she had a very depressed relative, and she debated providing medication samples in the interim while the relative waited to get in with a mental health professional. Another psychiatrist had seen too many patients become addicted to prescription benzodiazepines and suggested that this might start a cycle where Sister Lucy would pester brother psychiatrist for more medication in the future. Most of the psychiatrists felt that if a reasonable effort were made to obtain care and the barriers were valid, then it was a tough situation, but ultimately they felt it was okay to resume medications that previously had worked and been tolerated, for a limited period of time, since Lucy was symptomatic and this constituted an emergency.

The patients who wrote in were less forgiving, overall. Several insisted it was easy enough to find a primary care doctor within days, and a primary care doctor would certainly prescribe the medications. I was told that all one has to do is call one’s insurance company, so, curious, I called mine and got two names. The first one had a message saying staff was not in on Wednesday and the caller should try back tomorrow. I didn’t. The second one instructed me to leave a message that would be returned within 24 hours. It wasn’t. I e-mailed my own primary care doctor to ask when the next new patient appointment was – this physician charges a practice fee (too low to be considered "concierge," but high enough to enable a lower caseload). The response I received is that the practice is full. I e-mailed a friend who is a wonderful primary care doctor but takes no health insurance and has opted out of Medicare, and he had an opening the following week. I, however, had insider knowledge that a random newcomer to town might not have, and the insurance companies would certainly not be referring urgent cases to this out-of-network doctor. And all this assumes that any doc will do; there is no allowance here for the idea of waiting for a psychiatrist or internist who might come highly recommended or have subspecialty training.

I was left to say that it wasn’t easy to find a psychiatrist or a primary care doctor on demand when one is new in town and in a state of emotional distress. Again, I was told otherwise! I learned about a service called ZocDoc.com where you can make a next day appointment with a physician, simply by giving your Zip code, insurance, and specialty desired. Interesting, as I do this all the time with an App called OpenTable to schedule reservations at restaurants. Why not doctors’ appointments?

So it was late, and I tried to schedule a next day appointment with a primary care doc. It worked! Only I didn’t really want the appointment; what I wanted was information to write my article for Clinical Psychiatry News this week. I dialed the doctor to cancel the appointment, and instead of getting an office machine, I got the actual doctor – and he even sounded like a nice guy. He couldn’t cancel my appointment, but I then realized that, like OpenTable, there was a button to push to cancel the appointment, and I did that. I looked for psychiatrists, and there weren’t many with next day appointments – perhaps one – nearby, but if I would drive 30 miles or so to the next major city, I could get an appointment very soon, and certainly within a couple of weeks. Interesting. I learned something new!

So I wondered about Sister Lucy, and I decided she lives in Boise, Idaho, a place I’ve never been to and whose availability of medical care I know nothing about. The ZocDoc site there is not active, and so poor Lucy is back to her original problem, and I am left to the original question: Should her brother prescribe her medications?

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: the Johns Hopkins University Press, 2011).

Postdischarge, the patient was febrile and developed abdominal pain and an odorous vaginal discharge. A month later, exploratory surgery revealed a retained blue towel that had been used for bowel retraction. The patient required open healing of the surgical wound and a temporary colostomy. She developed an incisional hernia after colostomy reversal, and hernia repair required resection of a small portion of the bowel.

PATIENT’S CLAIM It was negligent to use a blue towel to retract the bowel. The towel should have been removed from her abdomen before closure.

DEFENDANTS’ DEFENSE The technician claimed that she did not provide the towel, did not see the towel used, and that she was not told that the towel had to be tracked. She noted that its color indicated that it lacked a radiopaque tag, and that hospital policy forbade use of untagged towels in an open wound.

Dr. A claimed that he specifically requested a blue towel because it was absorbent, that the technician provided the towel, and that the towel’s use prevented the patient from bleeding to death.

VERDICT A $7.2 million New York verdict was returned against both gynecologists and the hospital as the technician’s employer.

MISCARRIAGE AFTER D&C
A few days after a woman thought she miscarried, her family practi-tioner (FP) performed a dilation and curettage (D&C). 

The patient was at work 12 days later when she expelled a fully formed 14-week fetus into a toilet. She was taken to the emergency department (ED), where the cord was cut. Later that day, she passed placental tissue; a repeat D&C was performed the next day.

PATIENT'S CLAIM The FP did not properly perform the first D&C. Although the pathology report was available to the FP prior to the patient’s postoperative visit, the FP failed to inform the patient that no fetal parts had been extracted.

PHYSICIAN’S DEFENSE Because the FP thought that the fetus had been passed prior to the D&C, she believed the pathology report was appropriate.

The patient had been informed of the possibility of retained products of conception after the D&C. The FP had ordered a blood pregnancy test that would have revealed the presence of retained products of conception, but the patient did not have the test. The patient did not contact the FP to report symptoms that felt like labor pains on the day that she passed the fetus.

VERDICT A bench trial resulted in a $51,000 California verdict.

PREGNANT WOMAN COMPLAINS OF LEG PAIN; DIES OF DVT
A 23-year-old woman went to the ED with pain and swelling in her lower left leg and calf. The symptoms were reported to her ObGyn, who examined and then discharged her within a few hours, with instructions to come for her regularly scheduled prenatal visit.

The patient died 2 weeks later. The cause of death was determined to be a pulmonary embolus from a thrombus of the left popliteal vein.

ESTATE’S CLAIM The ObGyn was negligent in failing to test the patient for thrombosis in her left leg when she was in the ED or several days later at the office, when she continued to report leg pain.

PHYSICIAN’S DEFENSE The patient did not have signs of thrombosis at the ED or at the subsequent office visit. The pathologist reported that the clot that caused the embolus appeared fresh. The ObGyn surmised that it had formed after the patient’s last appointment.

VERDICT A Texas defense verdict was returned.

Mother took topiramate; child born with cleft lip and palate: $3M verdict
When a woman learned she was pregnant in December 2007, she was taking topiramate (Topamax) to treat migraine headaches. She discussed tapering off but not discontinuing topiramate usage with her neurologist. The patient’s ObGyn told her that topiramate was safe to take during pregnancy. The child was born with a cleft lip and palate.

PARENTS’ CLAIM Janssen Pharmaceuticals, manufacturer of Topamax, failed to provide adequate warnings about the potential risks associated with Topamax until labeling was changed in March 2011. Janssen knew of potential birth defects associated with Topamax use during pregnancy more than a decade before the labeling change; Janssen’s associate director of regulatory affairs had testified in an earlier hearing that there was knowledge of related birth defects as early as 1996.

DEFENDANTS’ DEFENSE There is uncertainty as to whether exposure to Topamax during pregnancy causes birth defects. The neurologist had warned the patient of possible risks associated with taking Topamax during pregnancy, but the patient had refused to discontinue the drug.

VERDICT A $3 million Pennsylvania verdict was returned.

Related articles:
• Is it time to rethink the use of oral contraceptives in premenopausal women with migraine? Anne H. Calhoun, MD (Audiocast; October 2013)
• How to choose a contraceptive for a patient who has headaches. Kristina M. Tocce, MD; Stephanie B. Teal, MD, MPH (February 2011)
• The gynecologist’s role in managing menstrual migraine. Anne H. Calhoun, MD (April 2010)

WAS MOTHER’S HISTORY OF INCOMPETENT CERVIX IGNORED?
Early in her second pregnancy, a woman told her ObGyn that she had previously miscarried due to an incompetent cervix.

At 24 weeks’ gestation, the patient was admitted to the hospital with back and pelvic pain and vaginal bleeding. Shortly after admission, the ObGyn performed a vaginal examination and ordered ultrasonography (US), which showed that the fetus was in the transverse position and the membranes were bulging.

The ObGyn performed an emergency cesarean delivery, but the premature infant died within 2 hours.

PARENTS’ CLAIM The ObGyn should have performed a cervical cerclage because of the mother’s history of an incompetent cervix. The mother should have been placed on bed rest and monitored every 2 weeks for cervical dilation.

PHYSICIAN’S DEFENSE The patient underwent regular prenatal evaluations for an incompetent cervix, and the findings were always normal.

VERDICT A Florida defense verdict was returned.

Related article:
A stepwise approach to cervical cerclage. Katrin Karl, MD; Michael Katz, MD (Surgical Technique; June 2012)

ObGyn unresponsive to patient’s postsurgical phone calls
In 2009, a 50-year-old woman reported occasional right lower quadrant pain to her ObGyn. US results were normal. The menopausal patient’s history included three cesarean deliveries, a total abdominal hysterectomy, and a laparoscopic ovarian cystectomy. 

When the patient saw her ObGyn in December 2010, she reported intermittent, progressive right lower quadrant pain that radiated down her right leg. She also reported urine loss with coughing or sneezing, and slight pain on intercourse. The ObGyn prescribed oxybutynin chloride (Ditropan) to treat the patient’s incontinence.

Three weeks later, the patient reported bilateral lower quadrant pain to her ObGyn, with minor improvement in incontinence.

The ObGyn performed bilateral salpingo-oophorectomy (BSO) in January 2011. Surgery took 3.5 hours due to extensive adhesiolysis.

After discharge, the patient felt ill and vomited. She attempted to reach the ObGyn by phone several times. That evening, the ObGyn prescribed a suppository to treat nausea and vomiting.

The patient went to the ED later that night and was found to have a perforated colon. Emergency surgery to repair the injury included creation of a colostomy, which was repaired 20 months later.

PATIENT’S CLAIM A proper workup of her symptoms was not performed; BSO was unnecessary. The ObGyn was negligent for failing to respond in a timely manner to her post-discharge phone calls, and did not properly evaluate her postoperative symptoms.

PHYSICIAN’S DEFENSE BSO was warranted. Colon injury is a known complication of the procedure.

VERDICT A $716,976 California verdict was returned, but was reduced to $591,967 under the state cap.

Who delayed delivery? $32.8M verdict for child with CP
An 18-year-old woman at 38 weeks’ gestation went to the hospital in labor. After 3.5 hours, the fetal heart rate dropped to 60 bpm. A nurse repositioned the patient, administered oxygen, and increased intravenous fluids. When the nurse rang the emergency call bell, a second nurse responded. Eighteen minutes after the fetal heart rate first dropped, a nurse rang the call bell again and the on-call ObGyn appeared.

The ObGyn performed a vaginal examination and repositioned the patient. She noted that the fetal heart-rate monitor was not working correctly, and called for an emergency cesarean delivery. The baby was born 42 minutes after the fetal heart rate initially dropped.

The child received a diagnosis of spastic-quadriplegia cerebral palsy (CP). She requires a wheelchair and has severe speech deficits and developmental delays.

PARENT’S CLAIM Cesarean delivery was not performed in a timely manner; the delivery delay was responsible for the injury that caused CP. The ObGyn was negligent in not responding to the initial emergency call. The nurses should have summoned the ObGyn earlier.

DEFENDANTS’ DEFENSE The hospital argued that the nurses followed proper protocol. Furthermore, the hospital noted that the ObGyn did not respond to the first call, and did not request a cesarean delivery for 17 minutes.

The ObGyn claimed that she made the decision to perform cesarean delivery within 5 minutes of her arrival, but it took another 15 minutes to gather the surgical team.

VERDICT A $32,882,860 Pennsylvania verdict was returned against the hospital. The ObGyn was vindicated. 

DIFFICULT DELIVERY: ZAVANELLI MANEUVER
At 38 5/7 weeks’ gestation, a woman went to the hospital for induction of labor. Twenty-four hours later, she began to push. After an hour of pushing, the mother was exhausted and had a low-grade fever, and the fetal heart rate was slowing. Her ObGyn, Dr. A, attempted vacuum extraction and performed a midline episiotomy. Shoulder dystocia was encountered and maneuvers were used, but without success. Another ObGyn, Dr. B, arrived to assist and also attempted the maneuvers.

The physicians agreed to try the Zavanelli maneuver, which involves pushing the baby’s head back inside the vagina and performing a cesarean delivery.

The baby was sent to the neonatal intensive care unit, where her breathing quickly normalized without supplemental oxygen. The child has a brachial plexus injury.

PARENTS’ CLAIM Dr. A should have performed an earlier cesarean delivery. Excessive traction was used when shoulder dystocia maneuvers were attempted.

PHYSICIANS’ DEFENSE The ObGyns’ actions saved the baby’s life and prevented serious injury to both mother and baby. 

VERDICT An Alabama defense verdict was returned.

Related article:
You are the second responder to a shoulder dystocia emergency. What do you do first? Robert L. Barbieri, MD (Editorial; May 2013)

PLACENTA PREVIA FOUND EARLY, BUT FETUS DIES
A woman's first pregnancy was complicated by complete placenta previa. A cesarean delivery was scheduled at 36 weeks’ gestation. However, before that date, the mother developed vaginal bleeding and was taken to the ED. The covering ObGyn was notified of the mother’s arrival within 15 minutes, but did not come to the hospital for 2.5 hours. After examining her, the ObGyn ordered US evaluation and transferred the mother to the obstetric floor. Nursing notes indicate that the fetal heart rate was 120 bpm at that time.

There are no notes from the ObGyn between 5:30 am and mid-afternoon. There is no record of the fetal heart rate when the mother was taken for US in the afternoon, which revealed fetal demise and a large extraovular hematoma. A cesarean delivery was performed. It was determined that the fetus died from placental abruption.

PARENTS’ CLAIM The mother was not adequately evaluated and monitored, which led to fetal demise. Delivery could have proceeded while the fetus was still alive.

PHYSICIAN’S DEFENSE The case was settled during the trial.

VERDICT A $495,000 Massachusetts settlement was reached.

Related articles:
• What is the optimal time to deliver a woman who has placenta previa? John T. Repke, MD (Examining the Evidence; April 2011)
• Act fast when confronted by a coagulopathy postpartum. Robert L. Barbieri, MD (Editorial; March 2012)

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

TELL US WHAT YOU THINK! Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, city and state. Stay in touch! Your feedback is important to us!

Postdischarge, the patient was febrile and developed abdominal pain and an odorous vaginal discharge. A month later, exploratory surgery revealed a retained blue towel that had been used for bowel retraction. The patient required open healing of the surgical wound and a temporary colostomy. She developed an incisional hernia after colostomy reversal, and hernia repair required resection of a small portion of the bowel.

PATIENT’S CLAIM It was negligent to use a blue towel to retract the bowel. The towel should have been removed from her abdomen before closure.

DEFENDANTS’ DEFENSE The technician claimed that she did not provide the towel, did not see the towel used, and that she was not told that the towel had to be tracked. She noted that its color indicated that it lacked a radiopaque tag, and that hospital policy forbade use of untagged towels in an open wound.

Dr. A claimed that he specifically requested a blue towel because it was absorbent, that the technician provided the towel, and that the towel’s use prevented the patient from bleeding to death.

VERDICT A $7.2 million New York verdict was returned against both gynecologists and the hospital as the technician’s employer.

MISCARRIAGE AFTER D&C
A few days after a woman thought she miscarried, her family practi-tioner (FP) performed a dilation and curettage (D&C). 

The patient was at work 12 days later when she expelled a fully formed 14-week fetus into a toilet. She was taken to the emergency department (ED), where the cord was cut. Later that day, she passed placental tissue; a repeat D&C was performed the next day.

PATIENT'S CLAIM The FP did not properly perform the first D&C. Although the pathology report was available to the FP prior to the patient’s postoperative visit, the FP failed to inform the patient that no fetal parts had been extracted.

PHYSICIAN’S DEFENSE Because the FP thought that the fetus had been passed prior to the D&C, she believed the pathology report was appropriate.

The patient had been informed of the possibility of retained products of conception after the D&C. The FP had ordered a blood pregnancy test that would have revealed the presence of retained products of conception, but the patient did not have the test. The patient did not contact the FP to report symptoms that felt like labor pains on the day that she passed the fetus.

VERDICT A bench trial resulted in a $51,000 California verdict.

PREGNANT WOMAN COMPLAINS OF LEG PAIN; DIES OF DVT
A 23-year-old woman went to the ED with pain and swelling in her lower left leg and calf. The symptoms were reported to her ObGyn, who examined and then discharged her within a few hours, with instructions to come for her regularly scheduled prenatal visit.

The patient died 2 weeks later. The cause of death was determined to be a pulmonary embolus from a thrombus of the left popliteal vein.

ESTATE’S CLAIM The ObGyn was negligent in failing to test the patient for thrombosis in her left leg when she was in the ED or several days later at the office, when she continued to report leg pain.

PHYSICIAN’S DEFENSE The patient did not have signs of thrombosis at the ED or at the subsequent office visit. The pathologist reported that the clot that caused the embolus appeared fresh. The ObGyn surmised that it had formed after the patient’s last appointment.

VERDICT A Texas defense verdict was returned.

Mother took topiramate; child born with cleft lip and palate: $3M verdict
When a woman learned she was pregnant in December 2007, she was taking topiramate (Topamax) to treat migraine headaches. She discussed tapering off but not discontinuing topiramate usage with her neurologist. The patient’s ObGyn told her that topiramate was safe to take during pregnancy. The child was born with a cleft lip and palate.

PARENTS’ CLAIM Janssen Pharmaceuticals, manufacturer of Topamax, failed to provide adequate warnings about the potential risks associated with Topamax until labeling was changed in March 2011. Janssen knew of potential birth defects associated with Topamax use during pregnancy more than a decade before the labeling change; Janssen’s associate director of regulatory affairs had testified in an earlier hearing that there was knowledge of related birth defects as early as 1996.

DEFENDANTS’ DEFENSE There is uncertainty as to whether exposure to Topamax during pregnancy causes birth defects. The neurologist had warned the patient of possible risks associated with taking Topamax during pregnancy, but the patient had refused to discontinue the drug.

VERDICT A $3 million Pennsylvania verdict was returned.

Related articles:
• Is it time to rethink the use of oral contraceptives in premenopausal women with migraine? Anne H. Calhoun, MD (Audiocast; October 2013)
• How to choose a contraceptive for a patient who has headaches. Kristina M. Tocce, MD; Stephanie B. Teal, MD, MPH (February 2011)
• The gynecologist’s role in managing menstrual migraine. Anne H. Calhoun, MD (April 2010)

WAS MOTHER’S HISTORY OF INCOMPETENT CERVIX IGNORED?
Early in her second pregnancy, a woman told her ObGyn that she had previously miscarried due to an incompetent cervix.

At 24 weeks’ gestation, the patient was admitted to the hospital with back and pelvic pain and vaginal bleeding. Shortly after admission, the ObGyn performed a vaginal examination and ordered ultrasonography (US), which showed that the fetus was in the transverse position and the membranes were bulging.

The ObGyn performed an emergency cesarean delivery, but the premature infant died within 2 hours.

PARENTS’ CLAIM The ObGyn should have performed a cervical cerclage because of the mother’s history of an incompetent cervix. The mother should have been placed on bed rest and monitored every 2 weeks for cervical dilation.

PHYSICIAN’S DEFENSE The patient underwent regular prenatal evaluations for an incompetent cervix, and the findings were always normal.

VERDICT A Florida defense verdict was returned.

Related article:
A stepwise approach to cervical cerclage. Katrin Karl, MD; Michael Katz, MD (Surgical Technique; June 2012)

ObGyn unresponsive to patient’s postsurgical phone calls
In 2009, a 50-year-old woman reported occasional right lower quadrant pain to her ObGyn. US results were normal. The menopausal patient’s history included three cesarean deliveries, a total abdominal hysterectomy, and a laparoscopic ovarian cystectomy. 

When the patient saw her ObGyn in December 2010, she reported intermittent, progressive right lower quadrant pain that radiated down her right leg. She also reported urine loss with coughing or sneezing, and slight pain on intercourse. The ObGyn prescribed oxybutynin chloride (Ditropan) to treat the patient’s incontinence.

Three weeks later, the patient reported bilateral lower quadrant pain to her ObGyn, with minor improvement in incontinence.

The ObGyn performed bilateral salpingo-oophorectomy (BSO) in January 2011. Surgery took 3.5 hours due to extensive adhesiolysis.

After discharge, the patient felt ill and vomited. She attempted to reach the ObGyn by phone several times. That evening, the ObGyn prescribed a suppository to treat nausea and vomiting.

The patient went to the ED later that night and was found to have a perforated colon. Emergency surgery to repair the injury included creation of a colostomy, which was repaired 20 months later.

PATIENT’S CLAIM A proper workup of her symptoms was not performed; BSO was unnecessary. The ObGyn was negligent for failing to respond in a timely manner to her post-discharge phone calls, and did not properly evaluate her postoperative symptoms.

PHYSICIAN’S DEFENSE BSO was warranted. Colon injury is a known complication of the procedure.

VERDICT A $716,976 California verdict was returned, but was reduced to $591,967 under the state cap.

Who delayed delivery? $32.8M verdict for child with CP
An 18-year-old woman at 38 weeks’ gestation went to the hospital in labor. After 3.5 hours, the fetal heart rate dropped to 60 bpm. A nurse repositioned the patient, administered oxygen, and increased intravenous fluids. When the nurse rang the emergency call bell, a second nurse responded. Eighteen minutes after the fetal heart rate first dropped, a nurse rang the call bell again and the on-call ObGyn appeared.

The ObGyn performed a vaginal examination and repositioned the patient. She noted that the fetal heart-rate monitor was not working correctly, and called for an emergency cesarean delivery. The baby was born 42 minutes after the fetal heart rate initially dropped.

The child received a diagnosis of spastic-quadriplegia cerebral palsy (CP). She requires a wheelchair and has severe speech deficits and developmental delays.

PARENT’S CLAIM Cesarean delivery was not performed in a timely manner; the delivery delay was responsible for the injury that caused CP. The ObGyn was negligent in not responding to the initial emergency call. The nurses should have summoned the ObGyn earlier.

DEFENDANTS’ DEFENSE The hospital argued that the nurses followed proper protocol. Furthermore, the hospital noted that the ObGyn did not respond to the first call, and did not request a cesarean delivery for 17 minutes.

The ObGyn claimed that she made the decision to perform cesarean delivery within 5 minutes of her arrival, but it took another 15 minutes to gather the surgical team.

VERDICT A $32,882,860 Pennsylvania verdict was returned against the hospital. The ObGyn was vindicated. 

DIFFICULT DELIVERY: ZAVANELLI MANEUVER
At 38 5/7 weeks’ gestation, a woman went to the hospital for induction of labor. Twenty-four hours later, she began to push. After an hour of pushing, the mother was exhausted and had a low-grade fever, and the fetal heart rate was slowing. Her ObGyn, Dr. A, attempted vacuum extraction and performed a midline episiotomy. Shoulder dystocia was encountered and maneuvers were used, but without success. Another ObGyn, Dr. B, arrived to assist and also attempted the maneuvers.

The physicians agreed to try the Zavanelli maneuver, which involves pushing the baby’s head back inside the vagina and performing a cesarean delivery.

The baby was sent to the neonatal intensive care unit, where her breathing quickly normalized without supplemental oxygen. The child has a brachial plexus injury.

PARENTS’ CLAIM Dr. A should have performed an earlier cesarean delivery. Excessive traction was used when shoulder dystocia maneuvers were attempted.

PHYSICIANS’ DEFENSE The ObGyns’ actions saved the baby’s life and prevented serious injury to both mother and baby. 

VERDICT An Alabama defense verdict was returned.

Related article:
You are the second responder to a shoulder dystocia emergency. What do you do first? Robert L. Barbieri, MD (Editorial; May 2013)

PLACENTA PREVIA FOUND EARLY, BUT FETUS DIES
A woman's first pregnancy was complicated by complete placenta previa. A cesarean delivery was scheduled at 36 weeks’ gestation. However, before that date, the mother developed vaginal bleeding and was taken to the ED. The covering ObGyn was notified of the mother’s arrival within 15 minutes, but did not come to the hospital for 2.5 hours. After examining her, the ObGyn ordered US evaluation and transferred the mother to the obstetric floor. Nursing notes indicate that the fetal heart rate was 120 bpm at that time.

There are no notes from the ObGyn between 5:30 am and mid-afternoon. There is no record of the fetal heart rate when the mother was taken for US in the afternoon, which revealed fetal demise and a large extraovular hematoma. A cesarean delivery was performed. It was determined that the fetus died from placental abruption.

PARENTS’ CLAIM The mother was not adequately evaluated and monitored, which led to fetal demise. Delivery could have proceeded while the fetus was still alive.

PHYSICIAN’S DEFENSE The case was settled during the trial.

VERDICT A $495,000 Massachusetts settlement was reached.

Related articles:
• What is the optimal time to deliver a woman who has placenta previa? John T. Repke, MD (Examining the Evidence; April 2011)
• Act fast when confronted by a coagulopathy postpartum. Robert L. Barbieri, MD (Editorial; March 2012)

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

TELL US WHAT YOU THINK! Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, city and state. Stay in touch! Your feedback is important to us!

Postdischarge, the patient was febrile and developed abdominal pain and an odorous vaginal discharge. A month later, exploratory surgery revealed a retained blue towel that had been used for bowel retraction. The patient required open healing of the surgical wound and a temporary colostomy. She developed an incisional hernia after colostomy reversal, and hernia repair required resection of a small portion of the bowel.

PATIENT’S CLAIM It was negligent to use a blue towel to retract the bowel. The towel should have been removed from her abdomen before closure.

DEFENDANTS’ DEFENSE The technician claimed that she did not provide the towel, did not see the towel used, and that she was not told that the towel had to be tracked. She noted that its color indicated that it lacked a radiopaque tag, and that hospital policy forbade use of untagged towels in an open wound.

Dr. A claimed that he specifically requested a blue towel because it was absorbent, that the technician provided the towel, and that the towel’s use prevented the patient from bleeding to death.

VERDICT A $7.2 million New York verdict was returned against both gynecologists and the hospital as the technician’s employer.

MISCARRIAGE AFTER D&C
A few days after a woman thought she miscarried, her family practi-tioner (FP) performed a dilation and curettage (D&C). 

The patient was at work 12 days later when she expelled a fully formed 14-week fetus into a toilet. She was taken to the emergency department (ED), where the cord was cut. Later that day, she passed placental tissue; a repeat D&C was performed the next day.

PATIENT'S CLAIM The FP did not properly perform the first D&C. Although the pathology report was available to the FP prior to the patient’s postoperative visit, the FP failed to inform the patient that no fetal parts had been extracted.

PHYSICIAN’S DEFENSE Because the FP thought that the fetus had been passed prior to the D&C, she believed the pathology report was appropriate.

The patient had been informed of the possibility of retained products of conception after the D&C. The FP had ordered a blood pregnancy test that would have revealed the presence of retained products of conception, but the patient did not have the test. The patient did not contact the FP to report symptoms that felt like labor pains on the day that she passed the fetus.

VERDICT A bench trial resulted in a $51,000 California verdict.

PREGNANT WOMAN COMPLAINS OF LEG PAIN; DIES OF DVT
A 23-year-old woman went to the ED with pain and swelling in her lower left leg and calf. The symptoms were reported to her ObGyn, who examined and then discharged her within a few hours, with instructions to come for her regularly scheduled prenatal visit.

The patient died 2 weeks later. The cause of death was determined to be a pulmonary embolus from a thrombus of the left popliteal vein.

ESTATE’S CLAIM The ObGyn was negligent in failing to test the patient for thrombosis in her left leg when she was in the ED or several days later at the office, when she continued to report leg pain.

PHYSICIAN’S DEFENSE The patient did not have signs of thrombosis at the ED or at the subsequent office visit. The pathologist reported that the clot that caused the embolus appeared fresh. The ObGyn surmised that it had formed after the patient’s last appointment.

VERDICT A Texas defense verdict was returned.

Mother took topiramate; child born with cleft lip and palate: $3M verdict
When a woman learned she was pregnant in December 2007, she was taking topiramate (Topamax) to treat migraine headaches. She discussed tapering off but not discontinuing topiramate usage with her neurologist. The patient’s ObGyn told her that topiramate was safe to take during pregnancy. The child was born with a cleft lip and palate.

PARENTS’ CLAIM Janssen Pharmaceuticals, manufacturer of Topamax, failed to provide adequate warnings about the potential risks associated with Topamax until labeling was changed in March 2011. Janssen knew of potential birth defects associated with Topamax use during pregnancy more than a decade before the labeling change; Janssen’s associate director of regulatory affairs had testified in an earlier hearing that there was knowledge of related birth defects as early as 1996.

DEFENDANTS’ DEFENSE There is uncertainty as to whether exposure to Topamax during pregnancy causes birth defects. The neurologist had warned the patient of possible risks associated with taking Topamax during pregnancy, but the patient had refused to discontinue the drug.

VERDICT A $3 million Pennsylvania verdict was returned.

Related articles:
• Is it time to rethink the use of oral contraceptives in premenopausal women with migraine? Anne H. Calhoun, MD (Audiocast; October 2013)
• How to choose a contraceptive for a patient who has headaches. Kristina M. Tocce, MD; Stephanie B. Teal, MD, MPH (February 2011)
• The gynecologist’s role in managing menstrual migraine. Anne H. Calhoun, MD (April 2010)

WAS MOTHER’S HISTORY OF INCOMPETENT CERVIX IGNORED?
Early in her second pregnancy, a woman told her ObGyn that she had previously miscarried due to an incompetent cervix.

At 24 weeks’ gestation, the patient was admitted to the hospital with back and pelvic pain and vaginal bleeding. Shortly after admission, the ObGyn performed a vaginal examination and ordered ultrasonography (US), which showed that the fetus was in the transverse position and the membranes were bulging.

The ObGyn performed an emergency cesarean delivery, but the premature infant died within 2 hours.

PARENTS’ CLAIM The ObGyn should have performed a cervical cerclage because of the mother’s history of an incompetent cervix. The mother should have been placed on bed rest and monitored every 2 weeks for cervical dilation.

PHYSICIAN’S DEFENSE The patient underwent regular prenatal evaluations for an incompetent cervix, and the findings were always normal.

VERDICT A Florida defense verdict was returned.

Related article:
A stepwise approach to cervical cerclage. Katrin Karl, MD; Michael Katz, MD (Surgical Technique; June 2012)

ObGyn unresponsive to patient’s postsurgical phone calls
In 2009, a 50-year-old woman reported occasional right lower quadrant pain to her ObGyn. US results were normal. The menopausal patient’s history included three cesarean deliveries, a total abdominal hysterectomy, and a laparoscopic ovarian cystectomy. 

When the patient saw her ObGyn in December 2010, she reported intermittent, progressive right lower quadrant pain that radiated down her right leg. She also reported urine loss with coughing or sneezing, and slight pain on intercourse. The ObGyn prescribed oxybutynin chloride (Ditropan) to treat the patient’s incontinence.

Three weeks later, the patient reported bilateral lower quadrant pain to her ObGyn, with minor improvement in incontinence.

The ObGyn performed bilateral salpingo-oophorectomy (BSO) in January 2011. Surgery took 3.5 hours due to extensive adhesiolysis.

After discharge, the patient felt ill and vomited. She attempted to reach the ObGyn by phone several times. That evening, the ObGyn prescribed a suppository to treat nausea and vomiting.

The patient went to the ED later that night and was found to have a perforated colon. Emergency surgery to repair the injury included creation of a colostomy, which was repaired 20 months later.

PATIENT’S CLAIM A proper workup of her symptoms was not performed; BSO was unnecessary. The ObGyn was negligent for failing to respond in a timely manner to her post-discharge phone calls, and did not properly evaluate her postoperative symptoms.

PHYSICIAN’S DEFENSE BSO was warranted. Colon injury is a known complication of the procedure.

VERDICT A $716,976 California verdict was returned, but was reduced to $591,967 under the state cap.

Who delayed delivery? $32.8M verdict for child with CP
An 18-year-old woman at 38 weeks’ gestation went to the hospital in labor. After 3.5 hours, the fetal heart rate dropped to 60 bpm. A nurse repositioned the patient, administered oxygen, and increased intravenous fluids. When the nurse rang the emergency call bell, a second nurse responded. Eighteen minutes after the fetal heart rate first dropped, a nurse rang the call bell again and the on-call ObGyn appeared.

The ObGyn performed a vaginal examination and repositioned the patient. She noted that the fetal heart-rate monitor was not working correctly, and called for an emergency cesarean delivery. The baby was born 42 minutes after the fetal heart rate initially dropped.

The child received a diagnosis of spastic-quadriplegia cerebral palsy (CP). She requires a wheelchair and has severe speech deficits and developmental delays.

PARENT’S CLAIM Cesarean delivery was not performed in a timely manner; the delivery delay was responsible for the injury that caused CP. The ObGyn was negligent in not responding to the initial emergency call. The nurses should have summoned the ObGyn earlier.

DEFENDANTS’ DEFENSE The hospital argued that the nurses followed proper protocol. Furthermore, the hospital noted that the ObGyn did not respond to the first call, and did not request a cesarean delivery for 17 minutes.

The ObGyn claimed that she made the decision to perform cesarean delivery within 5 minutes of her arrival, but it took another 15 minutes to gather the surgical team.

VERDICT A $32,882,860 Pennsylvania verdict was returned against the hospital. The ObGyn was vindicated. 

DIFFICULT DELIVERY: ZAVANELLI MANEUVER
At 38 5/7 weeks’ gestation, a woman went to the hospital for induction of labor. Twenty-four hours later, she began to push. After an hour of pushing, the mother was exhausted and had a low-grade fever, and the fetal heart rate was slowing. Her ObGyn, Dr. A, attempted vacuum extraction and performed a midline episiotomy. Shoulder dystocia was encountered and maneuvers were used, but without success. Another ObGyn, Dr. B, arrived to assist and also attempted the maneuvers.

The physicians agreed to try the Zavanelli maneuver, which involves pushing the baby’s head back inside the vagina and performing a cesarean delivery.

The baby was sent to the neonatal intensive care unit, where her breathing quickly normalized without supplemental oxygen. The child has a brachial plexus injury.

PARENTS’ CLAIM Dr. A should have performed an earlier cesarean delivery. Excessive traction was used when shoulder dystocia maneuvers were attempted.

PHYSICIANS’ DEFENSE The ObGyns’ actions saved the baby’s life and prevented serious injury to both mother and baby. 

VERDICT An Alabama defense verdict was returned.

Related article:
You are the second responder to a shoulder dystocia emergency. What do you do first? Robert L. Barbieri, MD (Editorial; May 2013)

PLACENTA PREVIA FOUND EARLY, BUT FETUS DIES
A woman's first pregnancy was complicated by complete placenta previa. A cesarean delivery was scheduled at 36 weeks’ gestation. However, before that date, the mother developed vaginal bleeding and was taken to the ED. The covering ObGyn was notified of the mother’s arrival within 15 minutes, but did not come to the hospital for 2.5 hours. After examining her, the ObGyn ordered US evaluation and transferred the mother to the obstetric floor. Nursing notes indicate that the fetal heart rate was 120 bpm at that time.

There are no notes from the ObGyn between 5:30 am and mid-afternoon. There is no record of the fetal heart rate when the mother was taken for US in the afternoon, which revealed fetal demise and a large extraovular hematoma. A cesarean delivery was performed. It was determined that the fetus died from placental abruption.

PARENTS’ CLAIM The mother was not adequately evaluated and monitored, which led to fetal demise. Delivery could have proceeded while the fetus was still alive.

PHYSICIAN’S DEFENSE The case was settled during the trial.

VERDICT A $495,000 Massachusetts settlement was reached.

Related articles:
• What is the optimal time to deliver a woman who has placenta previa? John T. Repke, MD (Examining the Evidence; April 2011)
• Act fast when confronted by a coagulopathy postpartum. Robert L. Barbieri, MD (Editorial; March 2012)

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

TELL US WHAT YOU THINK! Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, city and state. Stay in touch! Your feedback is important to us!

Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.