Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

Just as we learned early in life that 70% of the human body is composed of water, water covers approximately the same percentage of the earth’s surface. While fishing and harvesting of algae have occurred throughout human history,¹ it has only been since the 1970s that widespread scientific interest in the great biological and chemical diversity of the vast oceans of the world has led to investigations into medical and cosmetic applications of the rich life beneath the sea.² During this period, the marine environment has been found to boast multiple organisms with unique metabolisms adapted for survival in challenging conditions, yielding secondary metabolites, some of which have become valuable in the pharmaceutical and cosmeceutical markets.^3,4 Thus, the inclusion of bioactive substances from the sea in drugs and cosmetic products is primarily a recent phenomenon.¹ In fact, marine ingredients in cosmetics are thought to confer various benefits to skin health, including antioxidant, anti-acne, anti-wrinkle, and anti-tyrosinase activity.

Chemistry and biologic activity

Several marine microbial natural products have been found to display antimicrobial, antitumor, and anti-inflammatory activity.^2,5 And seaweed extracts (green, brown, and red algal compounds that include constituents such as phlorotannins, sulfated polysaccharides, and tyrosinase inhibitors) have been incorporated into cosmeceutical products, with a long history of traditional folk uses for various health – including skin – conditions.^3,6,7 Kim and Li reviewed the beneficial health effects of marine fungi-derived terpenoids in 2012, reporting that hundreds of these compounds have been discovered in the last few decades, with many exhibiting anti-inflammatory, anticancer, antimicrobial, and antioxidant activity.^8,9 Terpenoids, or isoprenoids, are a subclass of prenyllipids, which include prenylquinones, sterols, and terpenes, the largest class of natural substances.¹⁰

The terpenes are the largest group of biologically diverse marine compounds, and include the pseudopterosins, which are structurally discrete active metabolites of the Caribbean gorgonian soft coral Pseudopterogorgia elisabethae, which is native to the waters of the Caribbean Sea, Central Bahamas, Bermuda, the West Indies, and the Florida keys.^11,12 The most common gorgonian corals are diterpenes.¹³ Twenty-six derivatives of the octocoral P. elisabethae (designated PsA-PsZ), also known as the sea whip, sea fan, or sea plume, have been isolated.^11,12,14 Pseudopterosins were first isolated in 1986.^14,15

Based on the identified biologic activities, particularly anti-inflammatory capacity, of pseudopterosins, researchers have investigated their potential for treatment of various conditions including asthma, cancer, contact dermatitis, dermatoheliosis, HIV, photodamage, psoriasis, and rheumatoid arthritis.^1,11

After decades of extensive research of pseudopterosins, these tricyclic diterpene glycosides are thought to provide superior anti-inflammatory and analgesic properties, compared to standard anti-inflammatory treatments, without inducing adverse side effects; they also offer marked antimicrobial and wound-healing effects.^{3,11,14,16-19}

Other marine diterpene glycosides include eleutherobins and fucosides, which also exhibit notable biologic activity.¹⁵ In particular, the anti-inflammatory and analgesic activities of pseudopterosins have been found to be concentration- and dose-dependently more potent than the standard-bearing indomethacin.^11,14,17

Marine ingredients in topical formulations

The first product to include pseudopterosins was the skin formulation Resilience marketed by Estée Lauder over a decade ago.^19,20 Natural marine ingredients have since been incorporated into a few more products, such as Imedeen, an oral skin care preparation that contains Marine Complex.²¹

In 2012, Rietveld et al. ascertained whether the Marine Complex from Imedeen could variously alter skin morphogenesis in female and male human skin equivalents. Cells were culled from female and male donors between the ages of 30 and 45 years for human skin equivalents that were cultured for 7 or 11 weeks with or without Marine Complex. The investigators found that the number of Ki67-positive epidermal cells was greatly augmented by Marine Complex in female human skin equivalents. The Marine Complex significantly spurred the level of secreted pro-collagen I and elevated the deposition of laminin 332 and collagen type VII in the dermis. Human skin equivalents treated with Marine Complex also exhibited more viable epidermal cell layers and a thicker dermal extracellular matrix, compared to controls, with these effects less salient in male human skin equivalents. The investigators concluded that supplementation with Marine Complex positively stimulated overall human skin equivalent tissue formation, with its effects on the basement membrane and dermal constituents suggestive of potential for use against human skin aging.²¹

Previously, Xhauflaire-Uhoda et al. evaluated the skin hydrating and firming dose-response effects of cosmetic preparations enriched in algae- and fish collagen–derived substances in randomized controlled double-blind medium-term (12 subjects aged 18-55 years) and short-term (3 subjects over the age of 50) trials. In the short term, serum formulations enriched in marine compounds manifested a superior moisturizing effect on the forearm compared with creams. In later stages, cream formulations were more active, especially after repeated applications. Investigators observed a sustained firming activity in association with both the lotion and cream during treatment, but such results did not persist after treatment was stopped.²²

Product development

Technological advances, including sampling strategies, nanoscale nuclear magnetic resonance for structure determination, total chemical synthesis, fermentation, exploration of genomic and metagenomic resources, combinatorial biosynthesis, synthetic biology, and biotechnology represent important ways in which novel marine natural products are being developed, according to several authors.^1,2,4

Conclusion

Marine ingredients are a relatively new and fascinating category of substances that can and are being harnessed for pharmaceutical, cosmeceutical, cosmetic, and nutritional uses. Beyond the challenges of obtaining sufficient raw materials and producing effective formulations, the continued viability of such resources may be threatened by human exploitation of the seas and climate change. That said, the oceans offer the greatest biodiversity on the planet and dermatologic preparations derived from such sources present intriguing possibilities, particularly the apparent anti-inflammatory activity of gorgonian and other terpenes. These compounds appear to have the potential to replace, or serve as desirable alternatives to, conventional therapies for inflammatory skin disorders.

References

1. Biotechnol Adv. 2011;29(5):468-82.

2. Mar Drugs. 2013;11(3):700-17.

3. Mar Drugs. 2014;12(2):1066-101.

4. Future Med Chem. 2011;3(12):1475-89.

5. Org Lett. 2000;2(4):507-10.

6. Mar Drugs. 2013;11(1):146-64.

7. J Cosmet Dermatol. 2014;13(1):56-67.

8. Adv Food Nutr Res. 2012;65:409-13.

9. Crit Rev Microbiol. 2011;37(3):245-9.

10. Nat Chem Biol. 2007;3(7):408-14.

11. J Drugs Dermatol. 2013;12(10):1177-9.

12. J Ind Microbiol Biotechnol. 2006;33(7):532-8.

13. Nat Prod Rep. 2009;26(5):681-710.

14. Proc Natl Acad Sci USA. 1986;83(17):6238-40.

15. Bioorg Med Chem. 2011;19(22):6702-19.

16. Arch Biochem Biophys. 2004;424(1):97-104.

17. Asia Pac J Clin Nutr. 2006;15(2):143-52.

18. J Nat Prod. 2004;67(10):1672-80.

19. Mar Drugs. 2004 May;2:73-82.

20. J Nat Prod. 2004;67(8):1216-38.

21. J Cosmet Dermatol. 2012;11(3):213-22.

22. Int J Cosmet Sci. 2008;30(2):131-8.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Just as we learned early in life that 70% of the human body is composed of water, water covers approximately the same percentage of the earth’s surface. While fishing and harvesting of algae have occurred throughout human history,¹ it has only been since the 1970s that widespread scientific interest in the great biological and chemical diversity of the vast oceans of the world has led to investigations into medical and cosmetic applications of the rich life beneath the sea.² During this period, the marine environment has been found to boast multiple organisms with unique metabolisms adapted for survival in challenging conditions, yielding secondary metabolites, some of which have become valuable in the pharmaceutical and cosmeceutical markets.^3,4 Thus, the inclusion of bioactive substances from the sea in drugs and cosmetic products is primarily a recent phenomenon.¹ In fact, marine ingredients in cosmetics are thought to confer various benefits to skin health, including antioxidant, anti-acne, anti-wrinkle, and anti-tyrosinase activity.

Chemistry and biologic activity

Several marine microbial natural products have been found to display antimicrobial, antitumor, and anti-inflammatory activity.^2,5 And seaweed extracts (green, brown, and red algal compounds that include constituents such as phlorotannins, sulfated polysaccharides, and tyrosinase inhibitors) have been incorporated into cosmeceutical products, with a long history of traditional folk uses for various health – including skin – conditions.^3,6,7 Kim and Li reviewed the beneficial health effects of marine fungi-derived terpenoids in 2012, reporting that hundreds of these compounds have been discovered in the last few decades, with many exhibiting anti-inflammatory, anticancer, antimicrobial, and antioxidant activity.^8,9 Terpenoids, or isoprenoids, are a subclass of prenyllipids, which include prenylquinones, sterols, and terpenes, the largest class of natural substances.¹⁰

The terpenes are the largest group of biologically diverse marine compounds, and include the pseudopterosins, which are structurally discrete active metabolites of the Caribbean gorgonian soft coral Pseudopterogorgia elisabethae, which is native to the waters of the Caribbean Sea, Central Bahamas, Bermuda, the West Indies, and the Florida keys.^11,12 The most common gorgonian corals are diterpenes.¹³ Twenty-six derivatives of the octocoral P. elisabethae (designated PsA-PsZ), also known as the sea whip, sea fan, or sea plume, have been isolated.^11,12,14 Pseudopterosins were first isolated in 1986.^14,15

Based on the identified biologic activities, particularly anti-inflammatory capacity, of pseudopterosins, researchers have investigated their potential for treatment of various conditions including asthma, cancer, contact dermatitis, dermatoheliosis, HIV, photodamage, psoriasis, and rheumatoid arthritis.^1,11

After decades of extensive research of pseudopterosins, these tricyclic diterpene glycosides are thought to provide superior anti-inflammatory and analgesic properties, compared to standard anti-inflammatory treatments, without inducing adverse side effects; they also offer marked antimicrobial and wound-healing effects.^{3,11,14,16-19}

Other marine diterpene glycosides include eleutherobins and fucosides, which also exhibit notable biologic activity.¹⁵ In particular, the anti-inflammatory and analgesic activities of pseudopterosins have been found to be concentration- and dose-dependently more potent than the standard-bearing indomethacin.^11,14,17

Marine ingredients in topical formulations

The first product to include pseudopterosins was the skin formulation Resilience marketed by Estée Lauder over a decade ago.^19,20 Natural marine ingredients have since been incorporated into a few more products, such as Imedeen, an oral skin care preparation that contains Marine Complex.²¹

In 2012, Rietveld et al. ascertained whether the Marine Complex from Imedeen could variously alter skin morphogenesis in female and male human skin equivalents. Cells were culled from female and male donors between the ages of 30 and 45 years for human skin equivalents that were cultured for 7 or 11 weeks with or without Marine Complex. The investigators found that the number of Ki67-positive epidermal cells was greatly augmented by Marine Complex in female human skin equivalents. The Marine Complex significantly spurred the level of secreted pro-collagen I and elevated the deposition of laminin 332 and collagen type VII in the dermis. Human skin equivalents treated with Marine Complex also exhibited more viable epidermal cell layers and a thicker dermal extracellular matrix, compared to controls, with these effects less salient in male human skin equivalents. The investigators concluded that supplementation with Marine Complex positively stimulated overall human skin equivalent tissue formation, with its effects on the basement membrane and dermal constituents suggestive of potential for use against human skin aging.²¹

Previously, Xhauflaire-Uhoda et al. evaluated the skin hydrating and firming dose-response effects of cosmetic preparations enriched in algae- and fish collagen–derived substances in randomized controlled double-blind medium-term (12 subjects aged 18-55 years) and short-term (3 subjects over the age of 50) trials. In the short term, serum formulations enriched in marine compounds manifested a superior moisturizing effect on the forearm compared with creams. In later stages, cream formulations were more active, especially after repeated applications. Investigators observed a sustained firming activity in association with both the lotion and cream during treatment, but such results did not persist after treatment was stopped.²²

Product development

Technological advances, including sampling strategies, nanoscale nuclear magnetic resonance for structure determination, total chemical synthesis, fermentation, exploration of genomic and metagenomic resources, combinatorial biosynthesis, synthetic biology, and biotechnology represent important ways in which novel marine natural products are being developed, according to several authors.^1,2,4

Conclusion

Marine ingredients are a relatively new and fascinating category of substances that can and are being harnessed for pharmaceutical, cosmeceutical, cosmetic, and nutritional uses. Beyond the challenges of obtaining sufficient raw materials and producing effective formulations, the continued viability of such resources may be threatened by human exploitation of the seas and climate change. That said, the oceans offer the greatest biodiversity on the planet and dermatologic preparations derived from such sources present intriguing possibilities, particularly the apparent anti-inflammatory activity of gorgonian and other terpenes. These compounds appear to have the potential to replace, or serve as desirable alternatives to, conventional therapies for inflammatory skin disorders.

References

1. Biotechnol Adv. 2011;29(5):468-82.

2. Mar Drugs. 2013;11(3):700-17.

3. Mar Drugs. 2014;12(2):1066-101.

4. Future Med Chem. 2011;3(12):1475-89.

5. Org Lett. 2000;2(4):507-10.

6. Mar Drugs. 2013;11(1):146-64.

7. J Cosmet Dermatol. 2014;13(1):56-67.

8. Adv Food Nutr Res. 2012;65:409-13.

9. Crit Rev Microbiol. 2011;37(3):245-9.

10. Nat Chem Biol. 2007;3(7):408-14.

11. J Drugs Dermatol. 2013;12(10):1177-9.

12. J Ind Microbiol Biotechnol. 2006;33(7):532-8.

13. Nat Prod Rep. 2009;26(5):681-710.

14. Proc Natl Acad Sci USA. 1986;83(17):6238-40.

15. Bioorg Med Chem. 2011;19(22):6702-19.

16. Arch Biochem Biophys. 2004;424(1):97-104.

17. Asia Pac J Clin Nutr. 2006;15(2):143-52.

18. J Nat Prod. 2004;67(10):1672-80.

19. Mar Drugs. 2004 May;2:73-82.

20. J Nat Prod. 2004;67(8):1216-38.

21. J Cosmet Dermatol. 2012;11(3):213-22.

22. Int J Cosmet Sci. 2008;30(2):131-8.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Just as we learned early in life that 70% of the human body is composed of water, water covers approximately the same percentage of the earth’s surface. While fishing and harvesting of algae have occurred throughout human history,¹ it has only been since the 1970s that widespread scientific interest in the great biological and chemical diversity of the vast oceans of the world has led to investigations into medical and cosmetic applications of the rich life beneath the sea.² During this period, the marine environment has been found to boast multiple organisms with unique metabolisms adapted for survival in challenging conditions, yielding secondary metabolites, some of which have become valuable in the pharmaceutical and cosmeceutical markets.^3,4 Thus, the inclusion of bioactive substances from the sea in drugs and cosmetic products is primarily a recent phenomenon.¹ In fact, marine ingredients in cosmetics are thought to confer various benefits to skin health, including antioxidant, anti-acne, anti-wrinkle, and anti-tyrosinase activity.

Chemistry and biologic activity

Several marine microbial natural products have been found to display antimicrobial, antitumor, and anti-inflammatory activity.^2,5 And seaweed extracts (green, brown, and red algal compounds that include constituents such as phlorotannins, sulfated polysaccharides, and tyrosinase inhibitors) have been incorporated into cosmeceutical products, with a long history of traditional folk uses for various health – including skin – conditions.^3,6,7 Kim and Li reviewed the beneficial health effects of marine fungi-derived terpenoids in 2012, reporting that hundreds of these compounds have been discovered in the last few decades, with many exhibiting anti-inflammatory, anticancer, antimicrobial, and antioxidant activity.^8,9 Terpenoids, or isoprenoids, are a subclass of prenyllipids, which include prenylquinones, sterols, and terpenes, the largest class of natural substances.¹⁰

The terpenes are the largest group of biologically diverse marine compounds, and include the pseudopterosins, which are structurally discrete active metabolites of the Caribbean gorgonian soft coral Pseudopterogorgia elisabethae, which is native to the waters of the Caribbean Sea, Central Bahamas, Bermuda, the West Indies, and the Florida keys.^11,12 The most common gorgonian corals are diterpenes.¹³ Twenty-six derivatives of the octocoral P. elisabethae (designated PsA-PsZ), also known as the sea whip, sea fan, or sea plume, have been isolated.^11,12,14 Pseudopterosins were first isolated in 1986.^14,15

Based on the identified biologic activities, particularly anti-inflammatory capacity, of pseudopterosins, researchers have investigated their potential for treatment of various conditions including asthma, cancer, contact dermatitis, dermatoheliosis, HIV, photodamage, psoriasis, and rheumatoid arthritis.^1,11

After decades of extensive research of pseudopterosins, these tricyclic diterpene glycosides are thought to provide superior anti-inflammatory and analgesic properties, compared to standard anti-inflammatory treatments, without inducing adverse side effects; they also offer marked antimicrobial and wound-healing effects.^{3,11,14,16-19}

Other marine diterpene glycosides include eleutherobins and fucosides, which also exhibit notable biologic activity.¹⁵ In particular, the anti-inflammatory and analgesic activities of pseudopterosins have been found to be concentration- and dose-dependently more potent than the standard-bearing indomethacin.^11,14,17

Marine ingredients in topical formulations

The first product to include pseudopterosins was the skin formulation Resilience marketed by Estée Lauder over a decade ago.^19,20 Natural marine ingredients have since been incorporated into a few more products, such as Imedeen, an oral skin care preparation that contains Marine Complex.²¹

In 2012, Rietveld et al. ascertained whether the Marine Complex from Imedeen could variously alter skin morphogenesis in female and male human skin equivalents. Cells were culled from female and male donors between the ages of 30 and 45 years for human skin equivalents that were cultured for 7 or 11 weeks with or without Marine Complex. The investigators found that the number of Ki67-positive epidermal cells was greatly augmented by Marine Complex in female human skin equivalents. The Marine Complex significantly spurred the level of secreted pro-collagen I and elevated the deposition of laminin 332 and collagen type VII in the dermis. Human skin equivalents treated with Marine Complex also exhibited more viable epidermal cell layers and a thicker dermal extracellular matrix, compared to controls, with these effects less salient in male human skin equivalents. The investigators concluded that supplementation with Marine Complex positively stimulated overall human skin equivalent tissue formation, with its effects on the basement membrane and dermal constituents suggestive of potential for use against human skin aging.²¹

Previously, Xhauflaire-Uhoda et al. evaluated the skin hydrating and firming dose-response effects of cosmetic preparations enriched in algae- and fish collagen–derived substances in randomized controlled double-blind medium-term (12 subjects aged 18-55 years) and short-term (3 subjects over the age of 50) trials. In the short term, serum formulations enriched in marine compounds manifested a superior moisturizing effect on the forearm compared with creams. In later stages, cream formulations were more active, especially after repeated applications. Investigators observed a sustained firming activity in association with both the lotion and cream during treatment, but such results did not persist after treatment was stopped.²²

Product development

Technological advances, including sampling strategies, nanoscale nuclear magnetic resonance for structure determination, total chemical synthesis, fermentation, exploration of genomic and metagenomic resources, combinatorial biosynthesis, synthetic biology, and biotechnology represent important ways in which novel marine natural products are being developed, according to several authors.^1,2,4

Conclusion

Marine ingredients are a relatively new and fascinating category of substances that can and are being harnessed for pharmaceutical, cosmeceutical, cosmetic, and nutritional uses. Beyond the challenges of obtaining sufficient raw materials and producing effective formulations, the continued viability of such resources may be threatened by human exploitation of the seas and climate change. That said, the oceans offer the greatest biodiversity on the planet and dermatologic preparations derived from such sources present intriguing possibilities, particularly the apparent anti-inflammatory activity of gorgonian and other terpenes. These compounds appear to have the potential to replace, or serve as desirable alternatives to, conventional therapies for inflammatory skin disorders.

References

1. Biotechnol Adv. 2011;29(5):468-82.

2. Mar Drugs. 2013;11(3):700-17.

3. Mar Drugs. 2014;12(2):1066-101.

4. Future Med Chem. 2011;3(12):1475-89.

5. Org Lett. 2000;2(4):507-10.

6. Mar Drugs. 2013;11(1):146-64.

7. J Cosmet Dermatol. 2014;13(1):56-67.

8. Adv Food Nutr Res. 2012;65:409-13.

9. Crit Rev Microbiol. 2011;37(3):245-9.

10. Nat Chem Biol. 2007;3(7):408-14.

11. J Drugs Dermatol. 2013;12(10):1177-9.

12. J Ind Microbiol Biotechnol. 2006;33(7):532-8.

13. Nat Prod Rep. 2009;26(5):681-710.

14. Proc Natl Acad Sci USA. 1986;83(17):6238-40.

15. Bioorg Med Chem. 2011;19(22):6702-19.

16. Arch Biochem Biophys. 2004;424(1):97-104.

17. Asia Pac J Clin Nutr. 2006;15(2):143-52.

18. J Nat Prod. 2004;67(10):1672-80.

19. Mar Drugs. 2004 May;2:73-82.

20. J Nat Prod. 2004;67(8):1216-38.

21. J Cosmet Dermatol. 2012;11(3):213-22.

22. Int J Cosmet Sci. 2008;30(2):131-8.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

Rigosertib failed to extend overall survival beyond that seen with best supportive care in a trial of patients who had myelodysplastic syndrome with excess blasts after failure of azacitidine or decitabine treatment.

A randomized phase III trial of rigosertib (NCT 02562443) is now underway in specific subgroups of high-risk patients, including patients with very high risk on the basis of the Revised International Prognostic Scoring System criteria, to determine whether the drug may benefit specific patient subgroups, according to Dr. Guillermo Garcia-Manero of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

MD Anderson

The ONTIME study (NCT01241500) was an open-label, randomized controlled trial at 74 medical centers in the US and Europe. Patients with refractory anemia with excess blasts ([RAEB]-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia) were enrolled based on local site assessment and treatment failure with a hypomethylating drug in the past 2 years.

Patients were randomly assigned on a 2:1 basis to receive rigosertib or best supportive care with or without low-dose cytarabine. Randomization was stratified by pretreatment bone marrow blast percentage. The 199 patients given rigosertib received 1,800 mg per 24 hours via a 72-hour continuous intravenous infusion administered every other week. Another 100 patients were assigned to best supportive care.

Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval, 6.1-10.1) in the rigosertib group and 5.9 months (95% CI, 4.1-9.3) in the best supportive care group (hazard ratio, 0.87; 95% CI, 0.67-1.14; P = 0.33), the researchers reported (Lancet Oncol. 2016;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7).

The most common grade 3 or higher adverse events were anemia (18% of 184 patients in the rigosertib group and 8% of 91 patients in the best supportive care group), thrombocytopenia (19% vs 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs 11%], and pneumonia (12% vs 11%). Adverse events led to death in 22% of 184 patients in the rigosertib group and 33% of 91 patients in the best supportive care group; three deaths were attributed to rigosertib treatment.

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society.

[email protected]

On Twitter @maryjodales

(Reuters) - Patients with hypertension and moderate risk of heart disease slashed their long-term risk of heart attack and stroke 40 percent by taking a blood pressure medication as well as a statin cholesterol fighter, according to a large global study that could change medical practice.

Results from the trial, called HOPE-3, could prod far more doctors to add a statin to antihypertensive therapy for such patients who have no prior history of heart attack or stroke, researchers said.

The data was presented on Saturday at the annual scientific session of the American College of Cardiology in Chicago.

To enroll in the trial, patients had to have at least one risk factor for heart disease such as obesity or smoking, in addition to being over 60 for women and over 55 for men.

"Intermediate-risk people with hypertension had a clear benefit when taking both a statin and an agent that lowers blood pressure," Dr. Salim Yusuf, a professor of cardiology at McMaster University in Ontario, Canada who headed the 12,000-patient global study, said in an interview.

Patients with systolic blood pressure of 140 and higher were deemed in the study to have high blood pressure. They experienced a 40 percent reduced risk of heart attack and stroke over a six-year period when taking AstraZeneca Plc's statin Crestor (rosuvastatin) as well as a combination tablet containing blood pressure treatment candesartan and the diuretic hydrochlorothiazide.

Patients with normal or low systolic pressure had the same approximate 25 percent reduction in cardiovascular events as seen among patients in one arm of the study who took only statins.

Yusuf said the trial underscores that if a patient at moderate heart risk has high blood pressure, defined as 140 or higher, "give them both a statin and a blood pressure medication as a matter of course." He said statins are not automatically given now to patients with hypertension that are at only moderate risk of heart attack or stroke.

Yusuf's trial included research centers in China, India, Latin America, Africa and Canada, but not the United States because of far greater research costs there. The trial was funded by the Canadian Institutes of Health Research and AstraZeneca.

A separate study published in November found that lowering blood pressure to below 120 dramatically reduced heart failure and risk of death in adults aged 50 and older. But the five-year U.S. government-sponsored study of more than 9,300 patients showed a higher rate of adverse side effects, including kidney damage, in the aggressively treated patients.

(Reuters) - Patients with hypertension and moderate risk of heart disease slashed their long-term risk of heart attack and stroke 40 percent by taking a blood pressure medication as well as a statin cholesterol fighter, according to a large global study that could change medical practice.

Results from the trial, called HOPE-3, could prod far more doctors to add a statin to antihypertensive therapy for such patients who have no prior history of heart attack or stroke, researchers said.

The data was presented on Saturday at the annual scientific session of the American College of Cardiology in Chicago.

To enroll in the trial, patients had to have at least one risk factor for heart disease such as obesity or smoking, in addition to being over 60 for women and over 55 for men.

"Intermediate-risk people with hypertension had a clear benefit when taking both a statin and an agent that lowers blood pressure," Dr. Salim Yusuf, a professor of cardiology at McMaster University in Ontario, Canada who headed the 12,000-patient global study, said in an interview.

Patients with systolic blood pressure of 140 and higher were deemed in the study to have high blood pressure. They experienced a 40 percent reduced risk of heart attack and stroke over a six-year period when taking AstraZeneca Plc's statin Crestor (rosuvastatin) as well as a combination tablet containing blood pressure treatment candesartan and the diuretic hydrochlorothiazide.

Patients with normal or low systolic pressure had the same approximate 25 percent reduction in cardiovascular events as seen among patients in one arm of the study who took only statins.

Yusuf said the trial underscores that if a patient at moderate heart risk has high blood pressure, defined as 140 or higher, "give them both a statin and a blood pressure medication as a matter of course." He said statins are not automatically given now to patients with hypertension that are at only moderate risk of heart attack or stroke.

Yusuf's trial included research centers in China, India, Latin America, Africa and Canada, but not the United States because of far greater research costs there. The trial was funded by the Canadian Institutes of Health Research and AstraZeneca.

A separate study published in November found that lowering blood pressure to below 120 dramatically reduced heart failure and risk of death in adults aged 50 and older. But the five-year U.S. government-sponsored study of more than 9,300 patients showed a higher rate of adverse side effects, including kidney damage, in the aggressively treated patients.

(Reuters) - Patients with hypertension and moderate risk of heart disease slashed their long-term risk of heart attack and stroke 40 percent by taking a blood pressure medication as well as a statin cholesterol fighter, according to a large global study that could change medical practice.

Results from the trial, called HOPE-3, could prod far more doctors to add a statin to antihypertensive therapy for such patients who have no prior history of heart attack or stroke, researchers said.

The data was presented on Saturday at the annual scientific session of the American College of Cardiology in Chicago.

To enroll in the trial, patients had to have at least one risk factor for heart disease such as obesity or smoking, in addition to being over 60 for women and over 55 for men.

"Intermediate-risk people with hypertension had a clear benefit when taking both a statin and an agent that lowers blood pressure," Dr. Salim Yusuf, a professor of cardiology at McMaster University in Ontario, Canada who headed the 12,000-patient global study, said in an interview.

Patients with systolic blood pressure of 140 and higher were deemed in the study to have high blood pressure. They experienced a 40 percent reduced risk of heart attack and stroke over a six-year period when taking AstraZeneca Plc's statin Crestor (rosuvastatin) as well as a combination tablet containing blood pressure treatment candesartan and the diuretic hydrochlorothiazide.

Patients with normal or low systolic pressure had the same approximate 25 percent reduction in cardiovascular events as seen among patients in one arm of the study who took only statins.

Yusuf said the trial underscores that if a patient at moderate heart risk has high blood pressure, defined as 140 or higher, "give them both a statin and a blood pressure medication as a matter of course." He said statins are not automatically given now to patients with hypertension that are at only moderate risk of heart attack or stroke.

Yusuf's trial included research centers in China, India, Latin America, Africa and Canada, but not the United States because of far greater research costs there. The trial was funded by the Canadian Institutes of Health Research and AstraZeneca.

A separate study published in November found that lowering blood pressure to below 120 dramatically reduced heart failure and risk of death in adults aged 50 and older. But the five-year U.S. government-sponsored study of more than 9,300 patients showed a higher rate of adverse side effects, including kidney damage, in the aggressively treated patients.

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Guardian II hemostasis valve

Photo courtesy of

Vascular Solutions, Inc.

Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.

Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.

This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.

No injuries have been reported in association with this issue to date.

Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.

The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.

The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.

A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.

Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.

The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”

Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at [email protected].

Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Guardian II hemostasis valve

Photo courtesy of

Vascular Solutions, Inc.

Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.

Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.

This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.

No injuries have been reported in association with this issue to date.

Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.

The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.

The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.

A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.

Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.

The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”

Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at [email protected].

Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Guardian II hemostasis valve

Photo courtesy of

Vascular Solutions, Inc.

Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.

Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.

This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.

No injuries have been reported in association with this issue to date.

Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.

The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.

The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.

A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.

Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.

The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”

Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at [email protected].

Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Doctor with a clipboard

A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and

Drug Administration (FDA).

The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.

Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage

over existing options.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.

So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.

Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.

FDA approval

Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.

However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.

Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.

Only 6% of respondents knew the correct answer—that neither is required.

Breakthrough designation

Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”

Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”

Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.

However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.

Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.

But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.

Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.

Doctor with a clipboard

A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and

Drug Administration (FDA).

The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.

Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage

over existing options.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.

So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.

Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.

FDA approval

Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.

However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.

Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.

Only 6% of respondents knew the correct answer—that neither is required.

Breakthrough designation

Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”

Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”

Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.

However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.

Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.

But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.

Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.

Doctor with a clipboard

A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and

Drug Administration (FDA).

The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.

Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage

over existing options.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.

So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.

Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.

FDA approval

Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.

However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.

Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.

Only 6% of respondents knew the correct answer—that neither is required.

Breakthrough designation

Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”

Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”

Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.

However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.

Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.

But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.

Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”