The location of ligament tears within a pitcher’s elbow can be key to predicting the success of non-operative treatment for injuries, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers examined 38 pitchers from one professional baseball organization (both major and minor league teams) who sustained ulnar collateral ligament (UCL) injuries between 2006 and 2015,. Thirty-two players (84%) received non-operative treatment for partial ligament tears. A proximal tear of the UCL was identified in 81% of the patients who were successfully treated non-operatively. By contrast, a distal tear of the UCL was detected in 90% of patients who failed non-operative treatment and required surgery.

The location of ligament tears within a pitcher’s elbow can be key to predicting the success of non-operative treatment for injuries, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers examined 38 pitchers from one professional baseball organization (both major and minor league teams) who sustained ulnar collateral ligament (UCL) injuries between 2006 and 2015,. Thirty-two players (84%) received non-operative treatment for partial ligament tears. A proximal tear of the UCL was identified in 81% of the patients who were successfully treated non-operatively. By contrast, a distal tear of the UCL was detected in 90% of patients who failed non-operative treatment and required surgery.

The location of ligament tears within a pitcher’s elbow can be key to predicting the success of non-operative treatment for injuries, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers examined 38 pitchers from one professional baseball organization (both major and minor league teams) who sustained ulnar collateral ligament (UCL) injuries between 2006 and 2015,. Thirty-two players (84%) received non-operative treatment for partial ligament tears. A proximal tear of the UCL was identified in 81% of the patients who were successfully treated non-operatively. By contrast, a distal tear of the UCL was detected in 90% of patients who failed non-operative treatment and required surgery.

After anterior cruciate ligament (ACL) reconstruction, women younger than age 25 with a graft size of <8 mm have an increased change of re-tearing their ACL, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers studied 503 athletes (235 women and 268 men; average age 27) undergoing primary, autograft hamstring ACL reconstruction. The surgeries were all performed at a single center by a single surgeon between September through December 2012. Patients were followed for 2 years. Overall, the rate of re-tears was 6% and the mean graft size was 7.9 mm.

Graft size <8 mm and age < 25 years were significantly predictive of re‐tear. Female sex was correlated with re‐tear but was not significant.

After anterior cruciate ligament (ACL) reconstruction, women younger than age 25 with a graft size of <8 mm have an increased change of re-tearing their ACL, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers studied 503 athletes (235 women and 268 men; average age 27) undergoing primary, autograft hamstring ACL reconstruction. The surgeries were all performed at a single center by a single surgeon between September through December 2012. Patients were followed for 2 years. Overall, the rate of re-tears was 6% and the mean graft size was 7.9 mm.

Graft size <8 mm and age < 25 years were significantly predictive of re‐tear. Female sex was correlated with re‐tear but was not significant.

After anterior cruciate ligament (ACL) reconstruction, women younger than age 25 with a graft size of <8 mm have an increased change of re-tearing their ACL, according to the results of a study presented at the 2016 annual meeting of the American Orthopedic Society of Sports Medicine.

Researchers studied 503 athletes (235 women and 268 men; average age 27) undergoing primary, autograft hamstring ACL reconstruction. The surgeries were all performed at a single center by a single surgeon between September through December 2012. Patients were followed for 2 years. Overall, the rate of re-tears was 6% and the mean graft size was 7.9 mm.

Graft size <8 mm and age < 25 years were significantly predictive of re‐tear. Female sex was correlated with re‐tear but was not significant.

Although both men and women generally do well after having arthroscopic surgery for hip impingement, patients over age 45, particularly women over 45, don’t fare quite as well, according to a study published May 18 in The Journal of Bone and Joint Surgery.

Researchers examined 150 men and women of various ages, who underwent hip arthroscopy to treat femoroacetabular impingement (FAI). Patients were divided into groups based on age and sex. Outcomes were evaluated based on results from several instruments, include the Hip Outcome Score Activities of Daily Living Subscale, Hip Outcome Score Sport-Specific Subscale, and modified Harris hip score, as well as by clinical improvement at follow-up.

Researchers found that while all patients had significant improvements after hip arthroscopy for FAI, patients under age 45 had better overall results and fewer complications compared with people over age 45. Women older than age 45 had lower outcome scores than their male counterparts.

Although both men and women generally do well after having arthroscopic surgery for hip impingement, patients over age 45, particularly women over 45, don’t fare quite as well, according to a study published May 18 in The Journal of Bone and Joint Surgery.

Researchers examined 150 men and women of various ages, who underwent hip arthroscopy to treat femoroacetabular impingement (FAI). Patients were divided into groups based on age and sex. Outcomes were evaluated based on results from several instruments, include the Hip Outcome Score Activities of Daily Living Subscale, Hip Outcome Score Sport-Specific Subscale, and modified Harris hip score, as well as by clinical improvement at follow-up.

Researchers found that while all patients had significant improvements after hip arthroscopy for FAI, patients under age 45 had better overall results and fewer complications compared with people over age 45. Women older than age 45 had lower outcome scores than their male counterparts.

Although both men and women generally do well after having arthroscopic surgery for hip impingement, patients over age 45, particularly women over 45, don’t fare quite as well, according to a study published May 18 in The Journal of Bone and Joint Surgery.

Researchers examined 150 men and women of various ages, who underwent hip arthroscopy to treat femoroacetabular impingement (FAI). Patients were divided into groups based on age and sex. Outcomes were evaluated based on results from several instruments, include the Hip Outcome Score Activities of Daily Living Subscale, Hip Outcome Score Sport-Specific Subscale, and modified Harris hip score, as well as by clinical improvement at follow-up.

Researchers found that while all patients had significant improvements after hip arthroscopy for FAI, patients under age 45 had better overall results and fewer complications compared with people over age 45. Women older than age 45 had lower outcome scores than their male counterparts.

The C6 Lyme enzyme immunoassay is an effective diagnostic tool for children who are being tested for Lyme disease, according to Susan C. Lipsett, MD, and her associates.

Of the 944 samples collected for the study, 114 were positive for Lyme disease. The sensitivity of C6 enzyme immunoassay (EIA) testing alone was 79.8% and the specificity was 94.2%, slightly less than the standard two-tiered testing approach, which had a sensitivity of 81.6% and a specificity of 98.8%. The specificity of C6 EIA testing was increased to 98.6% when a supplemental immunoblot was added to testing.

©KUO CHUN HUNG/Thinkstock

The specificity of C6 EIA testing alone was significantly lower than standard testing in the control group. When the supplemental immunoblot was added to testing, the specificity of C6 EIA testing did match the specificity of standard testing in children who did not have Lyme disease.

“Although supplemental immunoblots are still required to confirm a Lyme disease diagnosis, our study supports using the C6 EIA as a first-line diagnostic test in children undergoing evaluation for Lyme disease. In the appropriate clinical scenario, the C6 EIA could limit unnecessary procedures and allow for prompt initiation of appropriate therapy,” the investigators concluded.

Find the full study in Clinical Infectious Diseases (doi:10.1093/cid/ciw427).

[email protected]

The C6 Lyme enzyme immunoassay is an effective diagnostic tool for children who are being tested for Lyme disease, according to Susan C. Lipsett, MD, and her associates.

Of the 944 samples collected for the study, 114 were positive for Lyme disease. The sensitivity of C6 enzyme immunoassay (EIA) testing alone was 79.8% and the specificity was 94.2%, slightly less than the standard two-tiered testing approach, which had a sensitivity of 81.6% and a specificity of 98.8%. The specificity of C6 EIA testing was increased to 98.6% when a supplemental immunoblot was added to testing.

©KUO CHUN HUNG/Thinkstock

The specificity of C6 EIA testing alone was significantly lower than standard testing in the control group. When the supplemental immunoblot was added to testing, the specificity of C6 EIA testing did match the specificity of standard testing in children who did not have Lyme disease.

“Although supplemental immunoblots are still required to confirm a Lyme disease diagnosis, our study supports using the C6 EIA as a first-line diagnostic test in children undergoing evaluation for Lyme disease. In the appropriate clinical scenario, the C6 EIA could limit unnecessary procedures and allow for prompt initiation of appropriate therapy,” the investigators concluded.

Find the full study in Clinical Infectious Diseases (doi:10.1093/cid/ciw427).

[email protected]

The C6 Lyme enzyme immunoassay is an effective diagnostic tool for children who are being tested for Lyme disease, according to Susan C. Lipsett, MD, and her associates.

Of the 944 samples collected for the study, 114 were positive for Lyme disease. The sensitivity of C6 enzyme immunoassay (EIA) testing alone was 79.8% and the specificity was 94.2%, slightly less than the standard two-tiered testing approach, which had a sensitivity of 81.6% and a specificity of 98.8%. The specificity of C6 EIA testing was increased to 98.6% when a supplemental immunoblot was added to testing.

©KUO CHUN HUNG/Thinkstock

The specificity of C6 EIA testing alone was significantly lower than standard testing in the control group. When the supplemental immunoblot was added to testing, the specificity of C6 EIA testing did match the specificity of standard testing in children who did not have Lyme disease.

“Although supplemental immunoblots are still required to confirm a Lyme disease diagnosis, our study supports using the C6 EIA as a first-line diagnostic test in children undergoing evaluation for Lyme disease. In the appropriate clinical scenario, the C6 EIA could limit unnecessary procedures and allow for prompt initiation of appropriate therapy,” the investigators concluded.

Find the full study in Clinical Infectious Diseases (doi:10.1093/cid/ciw427).

[email protected]

Question: In July 2002, a patient in California underwent surgery for a herniated T8-9 disk, but the surgeon instead removed the T6-7 and T7-8 disks. On Sept. 11, 2002, the surgeon discussed with the patient the MRI findings showing his mistake. On Sept. 17, 2003, the patient filed a malpractice lawsuit, just 6 days beyond California’s 1-year limitations period. California subscribes to the discovery rule, that is, a cause of action accrues only when a claimant discovers or should have discovered injury was the result of negligence.

Which of the following choices is best?

A. The lawsuit filed Sept. 17, 2003, is time barred, as the negligent surgery took place in July 2002.

B. On its face, the lawsuit was filed too late, being 1 year and 6 days after the Sept. 11, 2002, discussion date.

C. The lawsuit was timely filed, so long as the claimant can prove he was out of town for more than 6 days of that year.

D. The patient should sue as an action in battery, which has a longer statute of limitations.

E. All choices except A are correct.

Answer: E. At common law, there was no time limit that barred a plaintiff from bringing a claim, although an equitable doctrine of laches existed to foreclose an action that had long lapsed. Statutory changes in the law now require that lawsuits be brought in a timely manner so that the evidence remains fresh, accurate, and reliable.

Another reason is to provide repose to the wrongdoer, that is, relief from worrying for an indefinite period of time whether a lawsuit will be brought. This time period, during which a lawsuit must be filed or it will be barred, is termed the statute of limitations. It is 2 years for the tort of negligence in most jurisdictions, with states such as California and Tennessee placing a 1-year limit on medical malpractice claims. In California, the running of the statute is tolled (temporarily halted) for the days a claimant is out of state.

The above case scenario is taken from Kaplan v. Mamelak,¹ where the plaintiff’s lawsuit was not barred to allow him to identify the number of days he was out of town. The court also permitted a cause of action in battery, which is covered under a longer statute of limitations, as well as one sounding in malpractice.

Patients who are injured from malpractice may not always be aware that a negligent act had taken place, and some injuries may remain latent for a long period. Recognizing this, statutes of limitation emphasize the date when the plaintiff first discovered that the injury resulted from negligence. This is termed the discovery rule.

Stated more formally, the limitations period commences at the time the cause of action (negligence or other wrongs) accrues, and this usually means when the claimant knew (actual knowledge) or should have known (constructive knowledge).

The rule, in the words of one court, is meant to balance the need for “prompt assertion of claims” against a policy “favoring adjudication of claims on the merits and ensuring that a party with a valid claim will be given an opportunity to present it.”

As is typical of other jurisdictions, Hawaii sought to clarify the discovery rule in a series of court cases, beginning with Yoshizaki v. Hilo Hospital,² where the court deemed a cause of action “does not begin to run until the plaintiff knew or should have known of the defendant’s negligence.”

Subsequently, Hawaii’s Intermediate Court of Appeals explained that the state’s 2-year limitations statute commences when the plaintiff discovers, or through the use of reasonable diligence should have discovered, 1) the damage; 2) the violation of the duty; and 3) the causal connection between the violation of the duty and the damage.³

The court subsequently held that the rule prevents the running of the limitations period until “the plaintiff [has] knowledge of those facts which are necessary for an actionable claim.”⁴ In 1999, the Hawaii Supreme Court clarified that it was “factual knowledge,” rather than “legal knowledge,” that starts the clock running, and that legal knowledge of a defendant’s negligence was not required.⁵

More recently, litigation over the time barring of claims was evident in Moon v. Rhode,⁶ where Dr. Clarissa Rhode and Central Illinois Radiological Associates were sued for negligently misreading a patient’s CT scans.

The 90-year-old patient, Kathryn Moon, was admitted to Proctor Hospital May 18, 2009, and died 11 days later following surgery and complications of fluid overload and a pneumoperitoneum. Dr. Rhode, a radiologist, interpreted two CT scans, which an independent expert in 2013 determined were negligently misread. A lawsuit was then brought against Dr. Rhode, who was not a named defendant when the plaintiff had timely filed a medical negligence action back in 2011 against the surgeon and the attending doctor.

The court of appeals held that the discovery rule can be applied to wrongful death and survival actions, and that the statute of limitations begins to run when the plaintiff knows or should have known that the death was “wrongfully caused.” However, this did not necessarily mean knowledge of a specific defendant’s negligent conduct or knowledge of the existence of a cause of action.

The court stated: “Plaintiff filed his complaint long after he became possessed with sufficient information, which put him on inquiry to determine whether actionable conduct was involved.” The court ruled that the relevant inquiry was not when the plaintiff became aware that Dr. Rhode may have committed medical negligence, but when any defendant may have committed medical negligence against the patient Kathryn. The case is currently on appeal to the Supreme Court of Illinois.

In addition to the discovery rule, other situations may toll the limitations period. One example is fraudulent concealment of a right of action, where the statute may be tolled during the period of concealment. And in all jurisdictions, the running of the time period is halted in malpractice complaints involving treatment of a minor until that minor reaches a certain age, such as age of majority, or after a stipulated number of years, for example, 6 years.

Occasionally, a health care provider may overlook an important tolling provision. California, for example, has a rule that any “payment” made to an injured party must be accompanied by a written statement regarding the applicable statute of limitations.

In the recent Coastal Surgical Institute v. Blevins case,⁷ the defendant surgeon made a payment of $4,118.23 for medical expenses incurred by an unrepresented plaintiff, but had neglected to attach a release or a written notice regarding the statute of limitations. The plaintiff subsequently decided to file a lawsuit, even though more than a year – the statutory period – had lapsed.

Under the facts, the limitation period was tolled, and the trial court allowed the case to go forward, ultimately finding liability and awarding damages of $500,000, later reduced to $285,114. The court of appeals affirmed the decision.

This case has prompted MIEC, a malpractice insurance carrier, to emphasize putting in writing the restrictions imposed by the limitations statute to any unrepresented patient. MIEC also warned that the term “payment” might be construed liberally, citing case examples that include a free counseling session and the provision of specialized care for a student injured by a school’s gym equipment.

References

1. Kaplan v. Mamelak, 162 Cal. App. 4th 637 (2008).

2. Yoshizaki v. Hilo Hospital, 433 P.2d 220 (1967).

3. Jacoby v. Kaiser Foundation Hospital, 622 P.2d 613 (1981).

4. Yamaguchi v. Queen’s Medical Center, 648 P.2d 689 (1982).

5. Buck v. Miles, 971 P.2d 717 (1999).

6. Moon v. Rhode, IL. 2015 App. 3d 130613.

7. Coastal Surgical Institute v. Blevins, 232 Cal. App. 4th 1321 (2015).

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, “Medical Malpractice: Understanding the Law, Managing the Risk” (2006). For additional information, readers may contact the author at [email protected].

Question: In July 2002, a patient in California underwent surgery for a herniated T8-9 disk, but the surgeon instead removed the T6-7 and T7-8 disks. On Sept. 11, 2002, the surgeon discussed with the patient the MRI findings showing his mistake. On Sept. 17, 2003, the patient filed a malpractice lawsuit, just 6 days beyond California’s 1-year limitations period. California subscribes to the discovery rule, that is, a cause of action accrues only when a claimant discovers or should have discovered injury was the result of negligence.

Which of the following choices is best?

A. The lawsuit filed Sept. 17, 2003, is time barred, as the negligent surgery took place in July 2002.

B. On its face, the lawsuit was filed too late, being 1 year and 6 days after the Sept. 11, 2002, discussion date.

C. The lawsuit was timely filed, so long as the claimant can prove he was out of town for more than 6 days of that year.

D. The patient should sue as an action in battery, which has a longer statute of limitations.

E. All choices except A are correct.

Answer: E. At common law, there was no time limit that barred a plaintiff from bringing a claim, although an equitable doctrine of laches existed to foreclose an action that had long lapsed. Statutory changes in the law now require that lawsuits be brought in a timely manner so that the evidence remains fresh, accurate, and reliable.

Another reason is to provide repose to the wrongdoer, that is, relief from worrying for an indefinite period of time whether a lawsuit will be brought. This time period, during which a lawsuit must be filed or it will be barred, is termed the statute of limitations. It is 2 years for the tort of negligence in most jurisdictions, with states such as California and Tennessee placing a 1-year limit on medical malpractice claims. In California, the running of the statute is tolled (temporarily halted) for the days a claimant is out of state.

The above case scenario is taken from Kaplan v. Mamelak,¹ where the plaintiff’s lawsuit was not barred to allow him to identify the number of days he was out of town. The court also permitted a cause of action in battery, which is covered under a longer statute of limitations, as well as one sounding in malpractice.

Patients who are injured from malpractice may not always be aware that a negligent act had taken place, and some injuries may remain latent for a long period. Recognizing this, statutes of limitation emphasize the date when the plaintiff first discovered that the injury resulted from negligence. This is termed the discovery rule.

Stated more formally, the limitations period commences at the time the cause of action (negligence or other wrongs) accrues, and this usually means when the claimant knew (actual knowledge) or should have known (constructive knowledge).

The rule, in the words of one court, is meant to balance the need for “prompt assertion of claims” against a policy “favoring adjudication of claims on the merits and ensuring that a party with a valid claim will be given an opportunity to present it.”

As is typical of other jurisdictions, Hawaii sought to clarify the discovery rule in a series of court cases, beginning with Yoshizaki v. Hilo Hospital,² where the court deemed a cause of action “does not begin to run until the plaintiff knew or should have known of the defendant’s negligence.”

Subsequently, Hawaii’s Intermediate Court of Appeals explained that the state’s 2-year limitations statute commences when the plaintiff discovers, or through the use of reasonable diligence should have discovered, 1) the damage; 2) the violation of the duty; and 3) the causal connection between the violation of the duty and the damage.³

The court subsequently held that the rule prevents the running of the limitations period until “the plaintiff [has] knowledge of those facts which are necessary for an actionable claim.”⁴ In 1999, the Hawaii Supreme Court clarified that it was “factual knowledge,” rather than “legal knowledge,” that starts the clock running, and that legal knowledge of a defendant’s negligence was not required.⁵

More recently, litigation over the time barring of claims was evident in Moon v. Rhode,⁶ where Dr. Clarissa Rhode and Central Illinois Radiological Associates were sued for negligently misreading a patient’s CT scans.

The 90-year-old patient, Kathryn Moon, was admitted to Proctor Hospital May 18, 2009, and died 11 days later following surgery and complications of fluid overload and a pneumoperitoneum. Dr. Rhode, a radiologist, interpreted two CT scans, which an independent expert in 2013 determined were negligently misread. A lawsuit was then brought against Dr. Rhode, who was not a named defendant when the plaintiff had timely filed a medical negligence action back in 2011 against the surgeon and the attending doctor.

The court of appeals held that the discovery rule can be applied to wrongful death and survival actions, and that the statute of limitations begins to run when the plaintiff knows or should have known that the death was “wrongfully caused.” However, this did not necessarily mean knowledge of a specific defendant’s negligent conduct or knowledge of the existence of a cause of action.

The court stated: “Plaintiff filed his complaint long after he became possessed with sufficient information, which put him on inquiry to determine whether actionable conduct was involved.” The court ruled that the relevant inquiry was not when the plaintiff became aware that Dr. Rhode may have committed medical negligence, but when any defendant may have committed medical negligence against the patient Kathryn. The case is currently on appeal to the Supreme Court of Illinois.

In addition to the discovery rule, other situations may toll the limitations period. One example is fraudulent concealment of a right of action, where the statute may be tolled during the period of concealment. And in all jurisdictions, the running of the time period is halted in malpractice complaints involving treatment of a minor until that minor reaches a certain age, such as age of majority, or after a stipulated number of years, for example, 6 years.

Occasionally, a health care provider may overlook an important tolling provision. California, for example, has a rule that any “payment” made to an injured party must be accompanied by a written statement regarding the applicable statute of limitations.

In the recent Coastal Surgical Institute v. Blevins case,⁷ the defendant surgeon made a payment of $4,118.23 for medical expenses incurred by an unrepresented plaintiff, but had neglected to attach a release or a written notice regarding the statute of limitations. The plaintiff subsequently decided to file a lawsuit, even though more than a year – the statutory period – had lapsed.

Under the facts, the limitation period was tolled, and the trial court allowed the case to go forward, ultimately finding liability and awarding damages of $500,000, later reduced to $285,114. The court of appeals affirmed the decision.

This case has prompted MIEC, a malpractice insurance carrier, to emphasize putting in writing the restrictions imposed by the limitations statute to any unrepresented patient. MIEC also warned that the term “payment” might be construed liberally, citing case examples that include a free counseling session and the provision of specialized care for a student injured by a school’s gym equipment.

References

1. Kaplan v. Mamelak, 162 Cal. App. 4th 637 (2008).

2. Yoshizaki v. Hilo Hospital, 433 P.2d 220 (1967).

3. Jacoby v. Kaiser Foundation Hospital, 622 P.2d 613 (1981).

4. Yamaguchi v. Queen’s Medical Center, 648 P.2d 689 (1982).

5. Buck v. Miles, 971 P.2d 717 (1999).

6. Moon v. Rhode, IL. 2015 App. 3d 130613.

7. Coastal Surgical Institute v. Blevins, 232 Cal. App. 4th 1321 (2015).

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, “Medical Malpractice: Understanding the Law, Managing the Risk” (2006). For additional information, readers may contact the author at [email protected].

Question: In July 2002, a patient in California underwent surgery for a herniated T8-9 disk, but the surgeon instead removed the T6-7 and T7-8 disks. On Sept. 11, 2002, the surgeon discussed with the patient the MRI findings showing his mistake. On Sept. 17, 2003, the patient filed a malpractice lawsuit, just 6 days beyond California’s 1-year limitations period. California subscribes to the discovery rule, that is, a cause of action accrues only when a claimant discovers or should have discovered injury was the result of negligence.

Which of the following choices is best?

A. The lawsuit filed Sept. 17, 2003, is time barred, as the negligent surgery took place in July 2002.

B. On its face, the lawsuit was filed too late, being 1 year and 6 days after the Sept. 11, 2002, discussion date.

C. The lawsuit was timely filed, so long as the claimant can prove he was out of town for more than 6 days of that year.

D. The patient should sue as an action in battery, which has a longer statute of limitations.

E. All choices except A are correct.

Answer: E. At common law, there was no time limit that barred a plaintiff from bringing a claim, although an equitable doctrine of laches existed to foreclose an action that had long lapsed. Statutory changes in the law now require that lawsuits be brought in a timely manner so that the evidence remains fresh, accurate, and reliable.

Another reason is to provide repose to the wrongdoer, that is, relief from worrying for an indefinite period of time whether a lawsuit will be brought. This time period, during which a lawsuit must be filed or it will be barred, is termed the statute of limitations. It is 2 years for the tort of negligence in most jurisdictions, with states such as California and Tennessee placing a 1-year limit on medical malpractice claims. In California, the running of the statute is tolled (temporarily halted) for the days a claimant is out of state.

The above case scenario is taken from Kaplan v. Mamelak,¹ where the plaintiff’s lawsuit was not barred to allow him to identify the number of days he was out of town. The court also permitted a cause of action in battery, which is covered under a longer statute of limitations, as well as one sounding in malpractice.

Patients who are injured from malpractice may not always be aware that a negligent act had taken place, and some injuries may remain latent for a long period. Recognizing this, statutes of limitation emphasize the date when the plaintiff first discovered that the injury resulted from negligence. This is termed the discovery rule.

Stated more formally, the limitations period commences at the time the cause of action (negligence or other wrongs) accrues, and this usually means when the claimant knew (actual knowledge) or should have known (constructive knowledge).

The rule, in the words of one court, is meant to balance the need for “prompt assertion of claims” against a policy “favoring adjudication of claims on the merits and ensuring that a party with a valid claim will be given an opportunity to present it.”

As is typical of other jurisdictions, Hawaii sought to clarify the discovery rule in a series of court cases, beginning with Yoshizaki v. Hilo Hospital,² where the court deemed a cause of action “does not begin to run until the plaintiff knew or should have known of the defendant’s negligence.”

Subsequently, Hawaii’s Intermediate Court of Appeals explained that the state’s 2-year limitations statute commences when the plaintiff discovers, or through the use of reasonable diligence should have discovered, 1) the damage; 2) the violation of the duty; and 3) the causal connection between the violation of the duty and the damage.³

The court subsequently held that the rule prevents the running of the limitations period until “the plaintiff [has] knowledge of those facts which are necessary for an actionable claim.”⁴ In 1999, the Hawaii Supreme Court clarified that it was “factual knowledge,” rather than “legal knowledge,” that starts the clock running, and that legal knowledge of a defendant’s negligence was not required.⁵

More recently, litigation over the time barring of claims was evident in Moon v. Rhode,⁶ where Dr. Clarissa Rhode and Central Illinois Radiological Associates were sued for negligently misreading a patient’s CT scans.

The 90-year-old patient, Kathryn Moon, was admitted to Proctor Hospital May 18, 2009, and died 11 days later following surgery and complications of fluid overload and a pneumoperitoneum. Dr. Rhode, a radiologist, interpreted two CT scans, which an independent expert in 2013 determined were negligently misread. A lawsuit was then brought against Dr. Rhode, who was not a named defendant when the plaintiff had timely filed a medical negligence action back in 2011 against the surgeon and the attending doctor.

The court of appeals held that the discovery rule can be applied to wrongful death and survival actions, and that the statute of limitations begins to run when the plaintiff knows or should have known that the death was “wrongfully caused.” However, this did not necessarily mean knowledge of a specific defendant’s negligent conduct or knowledge of the existence of a cause of action.

The court stated: “Plaintiff filed his complaint long after he became possessed with sufficient information, which put him on inquiry to determine whether actionable conduct was involved.” The court ruled that the relevant inquiry was not when the plaintiff became aware that Dr. Rhode may have committed medical negligence, but when any defendant may have committed medical negligence against the patient Kathryn. The case is currently on appeal to the Supreme Court of Illinois.

In addition to the discovery rule, other situations may toll the limitations period. One example is fraudulent concealment of a right of action, where the statute may be tolled during the period of concealment. And in all jurisdictions, the running of the time period is halted in malpractice complaints involving treatment of a minor until that minor reaches a certain age, such as age of majority, or after a stipulated number of years, for example, 6 years.

Occasionally, a health care provider may overlook an important tolling provision. California, for example, has a rule that any “payment” made to an injured party must be accompanied by a written statement regarding the applicable statute of limitations.

In the recent Coastal Surgical Institute v. Blevins case,⁷ the defendant surgeon made a payment of $4,118.23 for medical expenses incurred by an unrepresented plaintiff, but had neglected to attach a release or a written notice regarding the statute of limitations. The plaintiff subsequently decided to file a lawsuit, even though more than a year – the statutory period – had lapsed.

Under the facts, the limitation period was tolled, and the trial court allowed the case to go forward, ultimately finding liability and awarding damages of $500,000, later reduced to $285,114. The court of appeals affirmed the decision.

This case has prompted MIEC, a malpractice insurance carrier, to emphasize putting in writing the restrictions imposed by the limitations statute to any unrepresented patient. MIEC also warned that the term “payment” might be construed liberally, citing case examples that include a free counseling session and the provision of specialized care for a student injured by a school’s gym equipment.

References

1. Kaplan v. Mamelak, 162 Cal. App. 4th 637 (2008).

2. Yoshizaki v. Hilo Hospital, 433 P.2d 220 (1967).

3. Jacoby v. Kaiser Foundation Hospital, 622 P.2d 613 (1981).

4. Yamaguchi v. Queen’s Medical Center, 648 P.2d 689 (1982).

5. Buck v. Miles, 971 P.2d 717 (1999).

6. Moon v. Rhode, IL. 2015 App. 3d 130613.

7. Coastal Surgical Institute v. Blevins, 232 Cal. App. 4th 1321 (2015).

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, “Medical Malpractice: Understanding the Law, Managing the Risk” (2006). For additional information, readers may contact the author at [email protected].

The best advice Sarah Stella, MD, ever received was simple: “You can’t cure everyone, but you can help everyone.” Why has the adage stuck with her?

Because the advice came from her dad, “and he’s been right about a lot of things before,” she says with a smile.

Dr. Stella got into medicine—clearly with her father’s blessing—to satisfy her “intense curiosity about my fellow human beings and to try to ease suffering.” She has risen to be an academic hospitalist at Denver Health and is one of eight new members of Team Hospitalist, The Hospitalist’s volunteer editorial advisory board.

Question: Tell us about your training. What did you like most/dislike during the process?

Answer: I attended medical school at Michigan State College of Human Medicine. I appreciated their humanistic approach to medical education. I chose the University of Colorado for my internal medicine residency because I love the sunshine and the mountains and because I thought the large academic program would complement my community-based medical school training. I loved being able to easily access nature on my days off.

Q: What do you like most about working as a hospitalist?

A: Spending time with incredible patients and working to solve difficult problems alongside amazing colleagues. I also love the diversity of the work, being involved in direct patient care, teaching students and residents, being a part of committees, performing quality improvement research. I love the flexibility of the job, which allows me to spend time with my family and travel fairly frequently to far-flung places.

Q: Did you have a mentor during your training or early career?

A: My earliest mentor was my father, also a physician [an oncologist]. Some of my earliest medical memories are of going to the hospital with my dad, who also brought home petri dishes from the lab, which my brother and I then used to perform household science experiments. My dad taught me my first lessons about the scientific method and about the importance of a strong work ethic and mentorship. Since then, I have had many outstanding mentors and role models for various aspects of my training/career. During my time at Denver Health, Drs. Richard K. Albert and Marisha Burden have provided me with invaluable mentorship in my scholarly pursuits.

Q: Have you tried to mentor others? Why or why not?

A: I have really loved mentoring students and residents. It is among the most meaningful experiences of my career. Presently, I am a mentor for undergraduate students from underrepresented minority groups. The maturity, passion, and drive these students possess inspires me.

Q: Why is your mentoring focused on minorities? What is the appeal of that to you?

A: I mentor students and residents from all backgrounds. However, mentoring students from underrepresented minority groups is especially important to me. Ethnic minorities continue to have decreased access to healthcare and disproportionately high morbidity and mortality. In order to improve these disparities, we need to have more healthcare providers from these groups. Yet such students, while they may initially be attracted to a career in medicine, are much less likely to maintain their interest. The reasons for this are complicated but may be explained by differences in access to mentors to help guide and inspire them, write letters, etc.

Q: As a hospitalist, seeing most of your patients for the very first time, what aspect of patient care is most challenging?

A: Developing a rapport with patients. I try to use some techniques from social psychology to help me more easily. The hospital is a particularly depersonalizing place, so trying to see the person behind the patient does help.

Q: What aspect of patient care is most rewarding?

A: Really connecting with patients and seeing them thrive. Working at a safety-net hospital, I have the privilege of caring for some of the most underserved but some of the most gracious and beautiful people.

Q: Are you on teaching service? If so, what aspect of teaching in the 21st century is most difficult? And what is most enjoyable?

A: I do enjoy supervising medical students and residents at all levels and attend frequently on the medical wards. I particularly love teaching medical students because of their enthusiasm and curiosity. I love being reminded of basic pathophysiology by a thoughtfully asked question from a medical student. I am a big advocate of bedside rounding. Finding a way to do this efficiently and while teaching to all the levels on the team is challenging. Also, I still enjoy my own direct patient care activities and feel that they challenge me in a different way and make me a better teacher.

Q: Outside of patient care, tell us about your career interests.

A: My research has focused on understanding problems experienced by patients following hospital discharge and designing systems to help ameliorate them. On an institutional level, I serve on several committees, including the Utilization Review Committee, and a group aiming to improve collaboration between hospitalists and primary care physicians and improve discharge transitions. I have participated in several LEAN events aimed at understanding and improving various systems issues.

Q: When you aren’t working, what is important to you?

A: My family and friends, sunshine, and travel. My husband grew up in Papua, New Guinea, and Australia, and both of his parents are physicians, so he is very understanding and not the least bit grossed out when I regale him with stories involving bodily fluids. We have a beautiful, inquisitive 3-year-old daughter and her furry older sister, Ginger Wasabi Ninja. As the oldest of seven, I also love hanging out with my siblings.

Q: What SHM event has made the most lasting impression on you?

A: I really enjoyed HM16, particularly the keynote address by our U.S. Surgeon General and fellow hospitalist, Vivek Murthy, MD, who discussed the role hospitalists can play in public health. His message that we hospitalists should put as much of an effort into trying to improve health outside the walls of the hospital as we do within the walls really resonated with me and has encouraged me to get more involved in the community. TH

Richard Quinn is a freelance writer in New Jersey.

The best advice Sarah Stella, MD, ever received was simple: “You can’t cure everyone, but you can help everyone.” Why has the adage stuck with her?

Because the advice came from her dad, “and he’s been right about a lot of things before,” she says with a smile.

Dr. Stella got into medicine—clearly with her father’s blessing—to satisfy her “intense curiosity about my fellow human beings and to try to ease suffering.” She has risen to be an academic hospitalist at Denver Health and is one of eight new members of Team Hospitalist, The Hospitalist’s volunteer editorial advisory board.

Question: Tell us about your training. What did you like most/dislike during the process?

Answer: I attended medical school at Michigan State College of Human Medicine. I appreciated their humanistic approach to medical education. I chose the University of Colorado for my internal medicine residency because I love the sunshine and the mountains and because I thought the large academic program would complement my community-based medical school training. I loved being able to easily access nature on my days off.

Q: What do you like most about working as a hospitalist?

A: Spending time with incredible patients and working to solve difficult problems alongside amazing colleagues. I also love the diversity of the work, being involved in direct patient care, teaching students and residents, being a part of committees, performing quality improvement research. I love the flexibility of the job, which allows me to spend time with my family and travel fairly frequently to far-flung places.

Q: Did you have a mentor during your training or early career?

A: My earliest mentor was my father, also a physician [an oncologist]. Some of my earliest medical memories are of going to the hospital with my dad, who also brought home petri dishes from the lab, which my brother and I then used to perform household science experiments. My dad taught me my first lessons about the scientific method and about the importance of a strong work ethic and mentorship. Since then, I have had many outstanding mentors and role models for various aspects of my training/career. During my time at Denver Health, Drs. Richard K. Albert and Marisha Burden have provided me with invaluable mentorship in my scholarly pursuits.

Q: Have you tried to mentor others? Why or why not?

A: I have really loved mentoring students and residents. It is among the most meaningful experiences of my career. Presently, I am a mentor for undergraduate students from underrepresented minority groups. The maturity, passion, and drive these students possess inspires me.

Q: Why is your mentoring focused on minorities? What is the appeal of that to you?

A: I mentor students and residents from all backgrounds. However, mentoring students from underrepresented minority groups is especially important to me. Ethnic minorities continue to have decreased access to healthcare and disproportionately high morbidity and mortality. In order to improve these disparities, we need to have more healthcare providers from these groups. Yet such students, while they may initially be attracted to a career in medicine, are much less likely to maintain their interest. The reasons for this are complicated but may be explained by differences in access to mentors to help guide and inspire them, write letters, etc.

Q: As a hospitalist, seeing most of your patients for the very first time, what aspect of patient care is most challenging?

A: Developing a rapport with patients. I try to use some techniques from social psychology to help me more easily. The hospital is a particularly depersonalizing place, so trying to see the person behind the patient does help.

Q: What aspect of patient care is most rewarding?

A: Really connecting with patients and seeing them thrive. Working at a safety-net hospital, I have the privilege of caring for some of the most underserved but some of the most gracious and beautiful people.

Q: Are you on teaching service? If so, what aspect of teaching in the 21st century is most difficult? And what is most enjoyable?

A: I do enjoy supervising medical students and residents at all levels and attend frequently on the medical wards. I particularly love teaching medical students because of their enthusiasm and curiosity. I love being reminded of basic pathophysiology by a thoughtfully asked question from a medical student. I am a big advocate of bedside rounding. Finding a way to do this efficiently and while teaching to all the levels on the team is challenging. Also, I still enjoy my own direct patient care activities and feel that they challenge me in a different way and make me a better teacher.

Q: Outside of patient care, tell us about your career interests.

A: My research has focused on understanding problems experienced by patients following hospital discharge and designing systems to help ameliorate them. On an institutional level, I serve on several committees, including the Utilization Review Committee, and a group aiming to improve collaboration between hospitalists and primary care physicians and improve discharge transitions. I have participated in several LEAN events aimed at understanding and improving various systems issues.

Q: When you aren’t working, what is important to you?

A: My family and friends, sunshine, and travel. My husband grew up in Papua, New Guinea, and Australia, and both of his parents are physicians, so he is very understanding and not the least bit grossed out when I regale him with stories involving bodily fluids. We have a beautiful, inquisitive 3-year-old daughter and her furry older sister, Ginger Wasabi Ninja. As the oldest of seven, I also love hanging out with my siblings.

Q: What SHM event has made the most lasting impression on you?

A: I really enjoyed HM16, particularly the keynote address by our U.S. Surgeon General and fellow hospitalist, Vivek Murthy, MD, who discussed the role hospitalists can play in public health. His message that we hospitalists should put as much of an effort into trying to improve health outside the walls of the hospital as we do within the walls really resonated with me and has encouraged me to get more involved in the community. TH

Richard Quinn is a freelance writer in New Jersey.

The best advice Sarah Stella, MD, ever received was simple: “You can’t cure everyone, but you can help everyone.” Why has the adage stuck with her?

Because the advice came from her dad, “and he’s been right about a lot of things before,” she says with a smile.

Dr. Stella got into medicine—clearly with her father’s blessing—to satisfy her “intense curiosity about my fellow human beings and to try to ease suffering.” She has risen to be an academic hospitalist at Denver Health and is one of eight new members of Team Hospitalist, The Hospitalist’s volunteer editorial advisory board.

Question: Tell us about your training. What did you like most/dislike during the process?

Answer: I attended medical school at Michigan State College of Human Medicine. I appreciated their humanistic approach to medical education. I chose the University of Colorado for my internal medicine residency because I love the sunshine and the mountains and because I thought the large academic program would complement my community-based medical school training. I loved being able to easily access nature on my days off.

Q: What do you like most about working as a hospitalist?

A: Spending time with incredible patients and working to solve difficult problems alongside amazing colleagues. I also love the diversity of the work, being involved in direct patient care, teaching students and residents, being a part of committees, performing quality improvement research. I love the flexibility of the job, which allows me to spend time with my family and travel fairly frequently to far-flung places.

Q: Did you have a mentor during your training or early career?

A: My earliest mentor was my father, also a physician [an oncologist]. Some of my earliest medical memories are of going to the hospital with my dad, who also brought home petri dishes from the lab, which my brother and I then used to perform household science experiments. My dad taught me my first lessons about the scientific method and about the importance of a strong work ethic and mentorship. Since then, I have had many outstanding mentors and role models for various aspects of my training/career. During my time at Denver Health, Drs. Richard K. Albert and Marisha Burden have provided me with invaluable mentorship in my scholarly pursuits.

Q: Have you tried to mentor others? Why or why not?

A: I have really loved mentoring students and residents. It is among the most meaningful experiences of my career. Presently, I am a mentor for undergraduate students from underrepresented minority groups. The maturity, passion, and drive these students possess inspires me.

Q: Why is your mentoring focused on minorities? What is the appeal of that to you?

A: I mentor students and residents from all backgrounds. However, mentoring students from underrepresented minority groups is especially important to me. Ethnic minorities continue to have decreased access to healthcare and disproportionately high morbidity and mortality. In order to improve these disparities, we need to have more healthcare providers from these groups. Yet such students, while they may initially be attracted to a career in medicine, are much less likely to maintain their interest. The reasons for this are complicated but may be explained by differences in access to mentors to help guide and inspire them, write letters, etc.

Q: As a hospitalist, seeing most of your patients for the very first time, what aspect of patient care is most challenging?

A: Developing a rapport with patients. I try to use some techniques from social psychology to help me more easily. The hospital is a particularly depersonalizing place, so trying to see the person behind the patient does help.

Q: What aspect of patient care is most rewarding?

A: Really connecting with patients and seeing them thrive. Working at a safety-net hospital, I have the privilege of caring for some of the most underserved but some of the most gracious and beautiful people.

Q: Are you on teaching service? If so, what aspect of teaching in the 21st century is most difficult? And what is most enjoyable?

A: I do enjoy supervising medical students and residents at all levels and attend frequently on the medical wards. I particularly love teaching medical students because of their enthusiasm and curiosity. I love being reminded of basic pathophysiology by a thoughtfully asked question from a medical student. I am a big advocate of bedside rounding. Finding a way to do this efficiently and while teaching to all the levels on the team is challenging. Also, I still enjoy my own direct patient care activities and feel that they challenge me in a different way and make me a better teacher.

Q: Outside of patient care, tell us about your career interests.

A: My research has focused on understanding problems experienced by patients following hospital discharge and designing systems to help ameliorate them. On an institutional level, I serve on several committees, including the Utilization Review Committee, and a group aiming to improve collaboration between hospitalists and primary care physicians and improve discharge transitions. I have participated in several LEAN events aimed at understanding and improving various systems issues.

Q: When you aren’t working, what is important to you?

A: My family and friends, sunshine, and travel. My husband grew up in Papua, New Guinea, and Australia, and both of his parents are physicians, so he is very understanding and not the least bit grossed out when I regale him with stories involving bodily fluids. We have a beautiful, inquisitive 3-year-old daughter and her furry older sister, Ginger Wasabi Ninja. As the oldest of seven, I also love hanging out with my siblings.

Q: What SHM event has made the most lasting impression on you?

A: I really enjoyed HM16, particularly the keynote address by our U.S. Surgeon General and fellow hospitalist, Vivek Murthy, MD, who discussed the role hospitalists can play in public health. His message that we hospitalists should put as much of an effort into trying to improve health outside the walls of the hospital as we do within the walls really resonated with me and has encouraged me to get more involved in the community. TH

Richard Quinn is a freelance writer in New Jersey.

Monoclonal antibodies

Photo by Linda Bartlett

ORLANDO—Emicizumab, a bispecific monoclonal antibody (mAb), could potentially change the treatment paradigm of hemophilia A, according to a speaker at the World Federation of Hemophilia 2016 World Congress.

Results of a phase 1/2 study suggest that emicizumab can be safe and effective as once-weekly prophylaxis in patients with severe hemophilia A, whether or not they have factor VIII (FVIII) inhibitors.

There were no severe adverse events (AEs) or thromboembolic events associated with the mAb.

None of the patients developed neutralizing anti-drug antibodies, and the annualized bleeding rate (ABR) was low, with 8 of the 18 patients studied having no bleeds.

Keiji Nogami, MD, PhD, of Nara Medical University in Kashihara, Japan, presented these results at the congress.* This research was sponsored by Chugai Pharmaceutical Co., Ltd., which is co-developing emicizumab with Genentech.

The phase 1 part of this study included both healthy subjects and hemophilia A patients. Results in the healthy subjects were published in Blood, and early results in the patients were published in NEJM.

Patients and treatment

The 18 patients in this study had severe hemophilia A, and 11 had FVIII inhibitors. They were 12 to 58 years of age at baseline, and all were Japanese.

The patients received once-weekly subcutaneous injections of emicizumab at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3).

There were 6 patients in each cohort. Cohorts 1 and 2 each had 4 patients with inhibitors, and there were 3 patients with inhibitors in cohort 3.

For the phase 2 extension portion of the study, dose-escalation was allowed in cohorts 1 and 2. A total of 4 patients had their doses increased because of suboptimal bleeding control—3 in cohort 1 and 1 in cohort 2.

The mean follow-up was 32.6 months in cohort 1, 27.0 months in cohort 2, and 21.4 months in cohort 3.

One of the patients with inhibitors in cohort 2 discontinued emicizumab due to injection site erythema of mild intensity during the phase 1 portion of the study. And one of the patients without inhibitors in cohort 3 did not continue on to the phase 2 portion of the study because prior treatment was sufficiently effective.

Safety

The safety analysis included all 18 patients, and all of these patients experienced AEs—a total of 150 events. The most common AEs were nasopharyngitis (n=8), contusion (n=7), and injection site reactions (n=7).

The AEs were largely of mild or moderate intensity. There were 4 severe AEs, but none of them were related to emicizumab.

There were 14 treatment-related AEs in 7 patients, but all were resolved. There were no thromboembolic AEs or clinically significant abnormalities of coagulation tests.

There were no neutralizing anti-drug antibodies. Three patients developed anti-drug antibodies after starting emicizumab, but this did not affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of the mAb.

Efficacy

In cohort 1, the median ABR was 32.5 at baseline, 4.4 at 12 weeks, and 1.4 at last follow-up (median of 32.6 months).

In cohort 2, the median ABR was 18.3 at baseline, 0.0 at 12 weeks, and 0.2 at last follow-up (median of 27.0 months).

In cohort 3, the median ABR was 15.2 at baseline, 0.0 at 12 weeks, and 0.0 at last follow-up (median of 21.4 months).

Eight patients did not experience any bleeds—1 inhibitor patient in cohort 1, 3 inhibitor patients in cohort 2, 2 inhibitor patients in cohort 3, and 2 non-inhibitor patients in cohort 3.

Breakthrough bleeds were successfully treated with standard episodic treatment, FVIII products, or bypassing agents.

Based on these results, Dr Nogami said emicizumab prophylaxis has the potential to change the treatment paradigm of hemophilia A, irrespective of inhibitor status.

*Hanabusa H et al, Updated results of an ongoing long-term phase 1/2 study of emicizumab (ACE910) in hemophilia A patients with or without inhibitors, WFH 2016 World Congress, July 2016.

Monoclonal antibodies

Photo by Linda Bartlett

ORLANDO—Emicizumab, a bispecific monoclonal antibody (mAb), could potentially change the treatment paradigm of hemophilia A, according to a speaker at the World Federation of Hemophilia 2016 World Congress.

Results of a phase 1/2 study suggest that emicizumab can be safe and effective as once-weekly prophylaxis in patients with severe hemophilia A, whether or not they have factor VIII (FVIII) inhibitors.

There were no severe adverse events (AEs) or thromboembolic events associated with the mAb.

None of the patients developed neutralizing anti-drug antibodies, and the annualized bleeding rate (ABR) was low, with 8 of the 18 patients studied having no bleeds.

Keiji Nogami, MD, PhD, of Nara Medical University in Kashihara, Japan, presented these results at the congress.* This research was sponsored by Chugai Pharmaceutical Co., Ltd., which is co-developing emicizumab with Genentech.

The phase 1 part of this study included both healthy subjects and hemophilia A patients. Results in the healthy subjects were published in Blood, and early results in the patients were published in NEJM.

Patients and treatment

The 18 patients in this study had severe hemophilia A, and 11 had FVIII inhibitors. They were 12 to 58 years of age at baseline, and all were Japanese.

The patients received once-weekly subcutaneous injections of emicizumab at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3).

There were 6 patients in each cohort. Cohorts 1 and 2 each had 4 patients with inhibitors, and there were 3 patients with inhibitors in cohort 3.

For the phase 2 extension portion of the study, dose-escalation was allowed in cohorts 1 and 2. A total of 4 patients had their doses increased because of suboptimal bleeding control—3 in cohort 1 and 1 in cohort 2.

The mean follow-up was 32.6 months in cohort 1, 27.0 months in cohort 2, and 21.4 months in cohort 3.

One of the patients with inhibitors in cohort 2 discontinued emicizumab due to injection site erythema of mild intensity during the phase 1 portion of the study. And one of the patients without inhibitors in cohort 3 did not continue on to the phase 2 portion of the study because prior treatment was sufficiently effective.

Safety

The safety analysis included all 18 patients, and all of these patients experienced AEs—a total of 150 events. The most common AEs were nasopharyngitis (n=8), contusion (n=7), and injection site reactions (n=7).

The AEs were largely of mild or moderate intensity. There were 4 severe AEs, but none of them were related to emicizumab.

There were 14 treatment-related AEs in 7 patients, but all were resolved. There were no thromboembolic AEs or clinically significant abnormalities of coagulation tests.

There were no neutralizing anti-drug antibodies. Three patients developed anti-drug antibodies after starting emicizumab, but this did not affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of the mAb.

Efficacy

In cohort 1, the median ABR was 32.5 at baseline, 4.4 at 12 weeks, and 1.4 at last follow-up (median of 32.6 months).

In cohort 2, the median ABR was 18.3 at baseline, 0.0 at 12 weeks, and 0.2 at last follow-up (median of 27.0 months).

In cohort 3, the median ABR was 15.2 at baseline, 0.0 at 12 weeks, and 0.0 at last follow-up (median of 21.4 months).

Eight patients did not experience any bleeds—1 inhibitor patient in cohort 1, 3 inhibitor patients in cohort 2, 2 inhibitor patients in cohort 3, and 2 non-inhibitor patients in cohort 3.

Breakthrough bleeds were successfully treated with standard episodic treatment, FVIII products, or bypassing agents.

Based on these results, Dr Nogami said emicizumab prophylaxis has the potential to change the treatment paradigm of hemophilia A, irrespective of inhibitor status.

*Hanabusa H et al, Updated results of an ongoing long-term phase 1/2 study of emicizumab (ACE910) in hemophilia A patients with or without inhibitors, WFH 2016 World Congress, July 2016.

Monoclonal antibodies

Photo by Linda Bartlett

ORLANDO—Emicizumab, a bispecific monoclonal antibody (mAb), could potentially change the treatment paradigm of hemophilia A, according to a speaker at the World Federation of Hemophilia 2016 World Congress.

Results of a phase 1/2 study suggest that emicizumab can be safe and effective as once-weekly prophylaxis in patients with severe hemophilia A, whether or not they have factor VIII (FVIII) inhibitors.

There were no severe adverse events (AEs) or thromboembolic events associated with the mAb.

None of the patients developed neutralizing anti-drug antibodies, and the annualized bleeding rate (ABR) was low, with 8 of the 18 patients studied having no bleeds.

Keiji Nogami, MD, PhD, of Nara Medical University in Kashihara, Japan, presented these results at the congress.* This research was sponsored by Chugai Pharmaceutical Co., Ltd., which is co-developing emicizumab with Genentech.

The phase 1 part of this study included both healthy subjects and hemophilia A patients. Results in the healthy subjects were published in Blood, and early results in the patients were published in NEJM.

Patients and treatment

The 18 patients in this study had severe hemophilia A, and 11 had FVIII inhibitors. They were 12 to 58 years of age at baseline, and all were Japanese.

The patients received once-weekly subcutaneous injections of emicizumab at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3).

There were 6 patients in each cohort. Cohorts 1 and 2 each had 4 patients with inhibitors, and there were 3 patients with inhibitors in cohort 3.

For the phase 2 extension portion of the study, dose-escalation was allowed in cohorts 1 and 2. A total of 4 patients had their doses increased because of suboptimal bleeding control—3 in cohort 1 and 1 in cohort 2.

The mean follow-up was 32.6 months in cohort 1, 27.0 months in cohort 2, and 21.4 months in cohort 3.

One of the patients with inhibitors in cohort 2 discontinued emicizumab due to injection site erythema of mild intensity during the phase 1 portion of the study. And one of the patients without inhibitors in cohort 3 did not continue on to the phase 2 portion of the study because prior treatment was sufficiently effective.

Safety

The safety analysis included all 18 patients, and all of these patients experienced AEs—a total of 150 events. The most common AEs were nasopharyngitis (n=8), contusion (n=7), and injection site reactions (n=7).

The AEs were largely of mild or moderate intensity. There were 4 severe AEs, but none of them were related to emicizumab.

There were 14 treatment-related AEs in 7 patients, but all were resolved. There were no thromboembolic AEs or clinically significant abnormalities of coagulation tests.

There were no neutralizing anti-drug antibodies. Three patients developed anti-drug antibodies after starting emicizumab, but this did not affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of the mAb.

Efficacy

In cohort 1, the median ABR was 32.5 at baseline, 4.4 at 12 weeks, and 1.4 at last follow-up (median of 32.6 months).

In cohort 2, the median ABR was 18.3 at baseline, 0.0 at 12 weeks, and 0.2 at last follow-up (median of 27.0 months).

In cohort 3, the median ABR was 15.2 at baseline, 0.0 at 12 weeks, and 0.0 at last follow-up (median of 21.4 months).

Eight patients did not experience any bleeds—1 inhibitor patient in cohort 1, 3 inhibitor patients in cohort 2, 2 inhibitor patients in cohort 3, and 2 non-inhibitor patients in cohort 3.

Breakthrough bleeds were successfully treated with standard episodic treatment, FVIII products, or bypassing agents.

Based on these results, Dr Nogami said emicizumab prophylaxis has the potential to change the treatment paradigm of hemophilia A, irrespective of inhibitor status.

*Hanabusa H et al, Updated results of an ongoing long-term phase 1/2 study of emicizumab (ACE910) in hemophilia A patients with or without inhibitors, WFH 2016 World Congress, July 2016.

Woman at work

ORLANDO—Even mild or moderate hemophilia B can have a negative impact on the education and careers of patients, according to the B-HERO-S study.

Ninety-four percent of the patients studied said their disease had a negative impact on their education, and 95% said hemophilia had a negative impact on their work.

More than half of patients who had stopped working said they stopped due to hemophilia-related financial issues and/or complications.

These findings were presented in a poster at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Novo Nordisk.

The previous HERO study revealed career challenges for patients with hemophilia A or B, but it covered mostly males with moderate or severe disease.

The B-HERO-S study, on the other hand, included only patients with hemophilia B, some of whom were female and most of whom had moderate or mild disease. (This study also included caregivers of children with hemophilia, but data on those subjects will not be discussed here.)

In all, there were 299 patients, 86 of whom were women. The patients had a median age of 29 (range, 18-70). Twenty-five percent had mild hemophilia, 63% had moderate disease, and 11% had severe hemophilia.

Education

Most of the patients (71%) had at least some college education, and 17% had graduated from college.

A majority of patients (94%) said their disease had a negative impact on their education. Seventy-five percent of the patients, including those with mild or moderate disease, said hemophilia had a moderate or large impact on their education.

Patients reported difficulty concentrating at school due to bleeds or pain (69%), difficulty attending school or participating in activities due to mobility issues (44%), and hemophilia-related absences (32%).

Career

Most of the patients (81%) were working full- or part-time when surveyed. Fifty-eight percent had office-based jobs, and 39% had jobs involving manual labor. Only 10% of patients said their disease affected their career choice.

Of the 58 patients (19%) who were not working at the time of the study, 62% had never worked. Of those who worked previously, 59% said they stopped due to hemophilia-related financial issues, and 55% said they stopped due to the disease itself and/or its complications.

Nearly all patients (95%) said their disease had a negative impact on their work. Seventy percent said the impact was moderate, 20% said it was small, and 5% said it was large.

Having moderate disease, comorbidities, a higher education, and/or receiving routine infusions were all associated with a higher impact.

Thirty percent of patients said that treatment allowed them to work in most situations. This was more likely in patients with mild hemophilia (41%) and those treated on-demand (48%).

Twenty-seven percent of patients with moderate hemophilia and 28% with severe disease said they could work in most situations. Twenty-seven percent of patients receiving routine infusions said they were able to work in most situations.

“The B-HERO-S study brought to light many challenges faced by some patients with mild/moderate hemophilia B, including affected women and girls,” said Michelle Witkop, of Northern Regional Bleeding Disorder Center in Traverse City, Michigan.

“With hemophilia treatment centers (HTCs) and local hemophilia chapters focused on proactive education in people with severe hemophilia and their families, B-HERO-S data tells us we need to make sure that those with mild/moderate hemophilia B come to the HTC for routine visits so that we can proactively address issues that might come up in school, activities, and career choice.”

*Cutter S et al, Impact of mild to severe hemophilia on education and work by US adult men and women and caregivers of children with hemophilia B: the bridging hemophilia B experiences results and opportunities into solutions (B-HERO-S) study, WFH 2016 World Congress, July 2016.

Woman at work

ORLANDO—Even mild or moderate hemophilia B can have a negative impact on the education and careers of patients, according to the B-HERO-S study.

Ninety-four percent of the patients studied said their disease had a negative impact on their education, and 95% said hemophilia had a negative impact on their work.

More than half of patients who had stopped working said they stopped due to hemophilia-related financial issues and/or complications.

These findings were presented in a poster at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Novo Nordisk.

The previous HERO study revealed career challenges for patients with hemophilia A or B, but it covered mostly males with moderate or severe disease.

The B-HERO-S study, on the other hand, included only patients with hemophilia B, some of whom were female and most of whom had moderate or mild disease. (This study also included caregivers of children with hemophilia, but data on those subjects will not be discussed here.)

In all, there were 299 patients, 86 of whom were women. The patients had a median age of 29 (range, 18-70). Twenty-five percent had mild hemophilia, 63% had moderate disease, and 11% had severe hemophilia.

Education

Most of the patients (71%) had at least some college education, and 17% had graduated from college.

A majority of patients (94%) said their disease had a negative impact on their education. Seventy-five percent of the patients, including those with mild or moderate disease, said hemophilia had a moderate or large impact on their education.

Patients reported difficulty concentrating at school due to bleeds or pain (69%), difficulty attending school or participating in activities due to mobility issues (44%), and hemophilia-related absences (32%).

Career

Most of the patients (81%) were working full- or part-time when surveyed. Fifty-eight percent had office-based jobs, and 39% had jobs involving manual labor. Only 10% of patients said their disease affected their career choice.

Of the 58 patients (19%) who were not working at the time of the study, 62% had never worked. Of those who worked previously, 59% said they stopped due to hemophilia-related financial issues, and 55% said they stopped due to the disease itself and/or its complications.

Nearly all patients (95%) said their disease had a negative impact on their work. Seventy percent said the impact was moderate, 20% said it was small, and 5% said it was large.

Having moderate disease, comorbidities, a higher education, and/or receiving routine infusions were all associated with a higher impact.

Thirty percent of patients said that treatment allowed them to work in most situations. This was more likely in patients with mild hemophilia (41%) and those treated on-demand (48%).

Twenty-seven percent of patients with moderate hemophilia and 28% with severe disease said they could work in most situations. Twenty-seven percent of patients receiving routine infusions said they were able to work in most situations.

“The B-HERO-S study brought to light many challenges faced by some patients with mild/moderate hemophilia B, including affected women and girls,” said Michelle Witkop, of Northern Regional Bleeding Disorder Center in Traverse City, Michigan.

“With hemophilia treatment centers (HTCs) and local hemophilia chapters focused on proactive education in people with severe hemophilia and their families, B-HERO-S data tells us we need to make sure that those with mild/moderate hemophilia B come to the HTC for routine visits so that we can proactively address issues that might come up in school, activities, and career choice.”

*Cutter S et al, Impact of mild to severe hemophilia on education and work by US adult men and women and caregivers of children with hemophilia B: the bridging hemophilia B experiences results and opportunities into solutions (B-HERO-S) study, WFH 2016 World Congress, July 2016.

Woman at work

ORLANDO—Even mild or moderate hemophilia B can have a negative impact on the education and careers of patients, according to the B-HERO-S study.

Ninety-four percent of the patients studied said their disease had a negative impact on their education, and 95% said hemophilia had a negative impact on their work.

More than half of patients who had stopped working said they stopped due to hemophilia-related financial issues and/or complications.

These findings were presented in a poster at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Novo Nordisk.

The previous HERO study revealed career challenges for patients with hemophilia A or B, but it covered mostly males with moderate or severe disease.

The B-HERO-S study, on the other hand, included only patients with hemophilia B, some of whom were female and most of whom had moderate or mild disease. (This study also included caregivers of children with hemophilia, but data on those subjects will not be discussed here.)

In all, there were 299 patients, 86 of whom were women. The patients had a median age of 29 (range, 18-70). Twenty-five percent had mild hemophilia, 63% had moderate disease, and 11% had severe hemophilia.

Education

Most of the patients (71%) had at least some college education, and 17% had graduated from college.

A majority of patients (94%) said their disease had a negative impact on their education. Seventy-five percent of the patients, including those with mild or moderate disease, said hemophilia had a moderate or large impact on their education.

Patients reported difficulty concentrating at school due to bleeds or pain (69%), difficulty attending school or participating in activities due to mobility issues (44%), and hemophilia-related absences (32%).

Career

Most of the patients (81%) were working full- or part-time when surveyed. Fifty-eight percent had office-based jobs, and 39% had jobs involving manual labor. Only 10% of patients said their disease affected their career choice.

Of the 58 patients (19%) who were not working at the time of the study, 62% had never worked. Of those who worked previously, 59% said they stopped due to hemophilia-related financial issues, and 55% said they stopped due to the disease itself and/or its complications.

Nearly all patients (95%) said their disease had a negative impact on their work. Seventy percent said the impact was moderate, 20% said it was small, and 5% said it was large.

Having moderate disease, comorbidities, a higher education, and/or receiving routine infusions were all associated with a higher impact.

Thirty percent of patients said that treatment allowed them to work in most situations. This was more likely in patients with mild hemophilia (41%) and those treated on-demand (48%).

Twenty-seven percent of patients with moderate hemophilia and 28% with severe disease said they could work in most situations. Twenty-seven percent of patients receiving routine infusions said they were able to work in most situations.

“The B-HERO-S study brought to light many challenges faced by some patients with mild/moderate hemophilia B, including affected women and girls,” said Michelle Witkop, of Northern Regional Bleeding Disorder Center in Traverse City, Michigan.

“With hemophilia treatment centers (HTCs) and local hemophilia chapters focused on proactive education in people with severe hemophilia and their families, B-HERO-S data tells us we need to make sure that those with mild/moderate hemophilia B come to the HTC for routine visits so that we can proactively address issues that might come up in school, activities, and career choice.”

*Cutter S et al, Impact of mild to severe hemophilia on education and work by US adult men and women and caregivers of children with hemophilia B: the bridging hemophilia B experiences results and opportunities into solutions (B-HERO-S) study, WFH 2016 World Congress, July 2016.

Megakaryocytes

in the bone marrow

A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.

Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.

The team also identified the probable mechanism underlying this effect.

“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.

“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”

LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.

Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.

The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.

Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.

One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.

LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.

Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.

Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.

LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.

In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.

Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.

“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”

“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”

Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.

She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.

Megakaryocytes

in the bone marrow

A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.

Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.

The team also identified the probable mechanism underlying this effect.

“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.

“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”

LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.

Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.

The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.

Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.

One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.

LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.

Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.

Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.

LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.

In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.

Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.

“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”

“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”

Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.

She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.

Megakaryocytes

in the bone marrow

A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.

Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.

The team also identified the probable mechanism underlying this effect.

“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.

“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”

LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.

Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.

The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.

Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.

One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.

LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.

Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.

Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.

LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.

In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.

Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.

“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”

“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”

Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.

She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.

Burkitt lymphoma

Image by Ed Uthman

Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.

The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.

The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.

The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.

Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.

The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.

“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”

The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.

In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.

Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.

The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.

“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.

“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”

“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”

Burkitt lymphoma

Image by Ed Uthman

Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.

The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.

The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.

The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.

Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.

The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.

“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”

The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.

In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.

Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.

The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.

“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.

“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”

“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”

Burkitt lymphoma

Image by Ed Uthman

Preclinical research suggests a novel class of compounds are effective against pediatric and adult cancers, including lymphoma.

The compounds are amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length.

The RCn compounds proved cytotoxic in a range of cancer cell lines, including the Burkitt lymphoma cell line Ramos.

The lead compound, RC16, exhibited antitumor effects in vivo and enhanced the in vitro activity of 3 other anticancer agents.

Timothy Cripe, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues reported these results in Pharmaceutical Research.

The investigators first evaluated the RCn compounds for cytotoxicity and mechanism of cell death in several adult and pediatric cancer cell lines.

“We tested RCn’s tumor killing efficacy in cell lines of numerous cancers, including sarcomas, lymphoma, and neuroblastoma,” Dr Cripe said. “We observed anticancer activity of the RCn amines in all the cancer cell lines analyzed.”

The investigators also found that RC16 was 10 times more effective in harming tumor cells than normal cells, including keratinocytes, fibroblasts, and umbilical vein endothelial cells.

In addition, RC16 demonstrated “significant antitumor effects” in several mouse models of malignancy, both when given intravenously and orally.

Because of the amphiphilic molecular structure of RC16, it self-assembled into micelles in water. This chemical structure allowed complexation of the anticancer drugs doxorubicin, etoposide, and paclitaxel.

The micelles significantly improved the in vitro antitumor activity of these drugs by enhancing their solubility in water.

“The antitumor activity of lipophilic amines was interesting because of its action on the mitochondria and lysosomes of cells,” said study author Isabella Orienti, PhD, of the University of Bologna in Italy.

“Moreover, their amphiphilic character improves their bioavailability. We correctly hypothesized these amphiphilic amines would have high antitumor activity and high bioavailability.”

“We are in the process of determining our next steps with testing this new drug,” Dr Cripe added. “This is a promising new therapy for adult and pediatric cancers, and we look forward to further testing its merits.”