Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&E,original magnification ×100).

Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&E,original magnification ×100).

Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&E,original magnification ×100).

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.

Last week, one of my patients presented with a BMI of 49 and two canes. Knee x-ray shows marked medial compartment narrowing bilaterally. We will inject her knees with steroids, but this will be temporary.

As the obesity epidemic continues to rage, native joints are rapidly being replaced with metal ones. Our pitiful homegrown joints were not designed to carry all this human weight. Joint forces in the hip and knee have been estimated to be 3 times body weight when walking on level ground and 6-10 times body weight when stooping or bending. Combine this with all the ‘screen time’ (average 8 hours a day for U.S. adults) and all the trips to the bathroom from the poorly controlled diabetes, and we are set up for needing a lot more orthopedic surgeons.

So should we push for surgery?

I am reluctant to immediately and eagerly pursue surgery based upon data from Ward et al. elucidating the increased risk for complications after joint surgery among patients with a BMI > 40 (J.Arthroplasty. 2015 Jun 3. pii: S0883-5403(15)00474-X. doi: 10.1016/j.arth.2015.03.045. [Epub ahead of print]). Data from the bariatric literature suggest that the risk of complications following joint replacement is lower if bariatric surgery is performed first. Weight loss as we look toward joint replacement is a good idea for both our orthopedic colleagues and our patients.

So we will work on weight loss first

In patients with osteoarthritis, a moderate amount of weight loss can significantly improve knee function. The short term efficacy of weight loss is comparable to joint replacement. But clinicians need to be wary of the “pain-exercise block”: patients telling us they cannot lose weight because the pain prevents them from exercising. I tell my patients that weight loss and weight maintenance can be managed effectively through dietary modification and that they do not have to run a marathon, they just need to walk if they can. But patients do not always want to hear this. Caloric restriction is psychologically painful for many. I remind them that 30 minutes of exercise can be undone in 30 seconds with a bar of chocolate, so we need to skip the chocolate bar if we do light exercise or forgo exercise altogether. Exercise is important for a million other reasons, but many of our patients can’t engage, especially when presenting with gait assist devices.

My patient and I started the discussion of bariatric surgery. In the meantime, we are going to try a trial of lorcaserin and hope the knees hold out. We are likely going to need more steroids.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter: @jonebbert.

Last week, one of my patients presented with a BMI of 49 and two canes. Knee x-ray shows marked medial compartment narrowing bilaterally. We will inject her knees with steroids, but this will be temporary.

As the obesity epidemic continues to rage, native joints are rapidly being replaced with metal ones. Our pitiful homegrown joints were not designed to carry all this human weight. Joint forces in the hip and knee have been estimated to be 3 times body weight when walking on level ground and 6-10 times body weight when stooping or bending. Combine this with all the ‘screen time’ (average 8 hours a day for U.S. adults) and all the trips to the bathroom from the poorly controlled diabetes, and we are set up for needing a lot more orthopedic surgeons.

So should we push for surgery?

I am reluctant to immediately and eagerly pursue surgery based upon data from Ward et al. elucidating the increased risk for complications after joint surgery among patients with a BMI > 40 (J.Arthroplasty. 2015 Jun 3. pii: S0883-5403(15)00474-X. doi: 10.1016/j.arth.2015.03.045. [Epub ahead of print]). Data from the bariatric literature suggest that the risk of complications following joint replacement is lower if bariatric surgery is performed first. Weight loss as we look toward joint replacement is a good idea for both our orthopedic colleagues and our patients.

So we will work on weight loss first

In patients with osteoarthritis, a moderate amount of weight loss can significantly improve knee function. The short term efficacy of weight loss is comparable to joint replacement. But clinicians need to be wary of the “pain-exercise block”: patients telling us they cannot lose weight because the pain prevents them from exercising. I tell my patients that weight loss and weight maintenance can be managed effectively through dietary modification and that they do not have to run a marathon, they just need to walk if they can. But patients do not always want to hear this. Caloric restriction is psychologically painful for many. I remind them that 30 minutes of exercise can be undone in 30 seconds with a bar of chocolate, so we need to skip the chocolate bar if we do light exercise or forgo exercise altogether. Exercise is important for a million other reasons, but many of our patients can’t engage, especially when presenting with gait assist devices.

My patient and I started the discussion of bariatric surgery. In the meantime, we are going to try a trial of lorcaserin and hope the knees hold out. We are likely going to need more steroids.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter: @jonebbert.

Last week, one of my patients presented with a BMI of 49 and two canes. Knee x-ray shows marked medial compartment narrowing bilaterally. We will inject her knees with steroids, but this will be temporary.

As the obesity epidemic continues to rage, native joints are rapidly being replaced with metal ones. Our pitiful homegrown joints were not designed to carry all this human weight. Joint forces in the hip and knee have been estimated to be 3 times body weight when walking on level ground and 6-10 times body weight when stooping or bending. Combine this with all the ‘screen time’ (average 8 hours a day for U.S. adults) and all the trips to the bathroom from the poorly controlled diabetes, and we are set up for needing a lot more orthopedic surgeons.

So should we push for surgery?

I am reluctant to immediately and eagerly pursue surgery based upon data from Ward et al. elucidating the increased risk for complications after joint surgery among patients with a BMI > 40 (J.Arthroplasty. 2015 Jun 3. pii: S0883-5403(15)00474-X. doi: 10.1016/j.arth.2015.03.045. [Epub ahead of print]). Data from the bariatric literature suggest that the risk of complications following joint replacement is lower if bariatric surgery is performed first. Weight loss as we look toward joint replacement is a good idea for both our orthopedic colleagues and our patients.

So we will work on weight loss first

In patients with osteoarthritis, a moderate amount of weight loss can significantly improve knee function. The short term efficacy of weight loss is comparable to joint replacement. But clinicians need to be wary of the “pain-exercise block”: patients telling us they cannot lose weight because the pain prevents them from exercising. I tell my patients that weight loss and weight maintenance can be managed effectively through dietary modification and that they do not have to run a marathon, they just need to walk if they can. But patients do not always want to hear this. Caloric restriction is psychologically painful for many. I remind them that 30 minutes of exercise can be undone in 30 seconds with a bar of chocolate, so we need to skip the chocolate bar if we do light exercise or forgo exercise altogether. Exercise is important for a million other reasons, but many of our patients can’t engage, especially when presenting with gait assist devices.

My patient and I started the discussion of bariatric surgery. In the meantime, we are going to try a trial of lorcaserin and hope the knees hold out. We are likely going to need more steroids.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter: @jonebbert.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

Recently, the West Virginia Supreme Court ruled that patients can sue doctors if they became addicted to a medication the doctors prescribed even if the patients have committed crimes, such as doctor shopping, to get there.

Apparently, no one can be held responsible for their own actions anymore.

-Oxford-/iStockphotos.com

This is a serious catch-22 for doctors. On the one hand, we have ethical considerations, and oaths, to help others and relieve suffering. Now, on the flip side, doing just that can open us to legal action.

I prescribe narcotics. I try to use them judiciously, and only in people for whom other options have failed or are contraindicated. I suspect most doctors are the same. Every drug has its risks and benefits, and we try to make a calculated decision for each patient. I ask for the patient’s input, too, since he or she is the one who’ll be taking it.

I also have to depend on patients’ honesty. Patients who sell drugs to others, take more than I’ve prescribed, or use other methods of getting them (doctor shopping, buying them off the street) are all committing serious offenses. The development of monitoring databases where I can check on such behaviors has helped me catch those who’ve abused the medications.

One person quoted in an article about the court decision said, “I lied to everybody. I would steal. I pawned my grandma’s wedding rings. I was breaking into houses, doing anything and everything to stay high.”

So, obviously, that was all the doctor’s fault. He was trying to help her, and apparently led her to commit theft and burglary. I suppose the next step in such insanity is that he could be charged as an accomplice in her crimes. After all, it’s not her fault that she decided to steal from others.

This opens up a gold mine. Crooks obtaining narcotics through illicit means can now sue the doctors who were originally trying to help them.

How will it affect me?

I’ll likely further decrease my writing for controlled pain meds. I really can’t give up my DEA number entirely, because I need it to write for several epilepsy medications. But the use of narcotics in my practice will decline. Other docs will probably do the same.

Sadly, this only hurts those who legitimately need pain relief. It will be harder for them to find doctors willing to prescribe narcotics, and even if they do, it’s possible those physicians won’t take their insurance.

Some will say my reaction to the ruling means I don’t care, which isn’t true. I do care. I signed up for this job to help people. But I also have a family to support and protect, and have to think of them, too.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently, the West Virginia Supreme Court ruled that patients can sue doctors if they became addicted to a medication the doctors prescribed even if the patients have committed crimes, such as doctor shopping, to get there.

Apparently, no one can be held responsible for their own actions anymore.

-Oxford-/iStockphotos.com

This is a serious catch-22 for doctors. On the one hand, we have ethical considerations, and oaths, to help others and relieve suffering. Now, on the flip side, doing just that can open us to legal action.

I prescribe narcotics. I try to use them judiciously, and only in people for whom other options have failed or are contraindicated. I suspect most doctors are the same. Every drug has its risks and benefits, and we try to make a calculated decision for each patient. I ask for the patient’s input, too, since he or she is the one who’ll be taking it.

I also have to depend on patients’ honesty. Patients who sell drugs to others, take more than I’ve prescribed, or use other methods of getting them (doctor shopping, buying them off the street) are all committing serious offenses. The development of monitoring databases where I can check on such behaviors has helped me catch those who’ve abused the medications.

One person quoted in an article about the court decision said, “I lied to everybody. I would steal. I pawned my grandma’s wedding rings. I was breaking into houses, doing anything and everything to stay high.”

So, obviously, that was all the doctor’s fault. He was trying to help her, and apparently led her to commit theft and burglary. I suppose the next step in such insanity is that he could be charged as an accomplice in her crimes. After all, it’s not her fault that she decided to steal from others.

This opens up a gold mine. Crooks obtaining narcotics through illicit means can now sue the doctors who were originally trying to help them.

How will it affect me?

I’ll likely further decrease my writing for controlled pain meds. I really can’t give up my DEA number entirely, because I need it to write for several epilepsy medications. But the use of narcotics in my practice will decline. Other docs will probably do the same.

Sadly, this only hurts those who legitimately need pain relief. It will be harder for them to find doctors willing to prescribe narcotics, and even if they do, it’s possible those physicians won’t take their insurance.

Some will say my reaction to the ruling means I don’t care, which isn’t true. I do care. I signed up for this job to help people. But I also have a family to support and protect, and have to think of them, too.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently, the West Virginia Supreme Court ruled that patients can sue doctors if they became addicted to a medication the doctors prescribed even if the patients have committed crimes, such as doctor shopping, to get there.

Apparently, no one can be held responsible for their own actions anymore.

-Oxford-/iStockphotos.com

This is a serious catch-22 for doctors. On the one hand, we have ethical considerations, and oaths, to help others and relieve suffering. Now, on the flip side, doing just that can open us to legal action.

I prescribe narcotics. I try to use them judiciously, and only in people for whom other options have failed or are contraindicated. I suspect most doctors are the same. Every drug has its risks and benefits, and we try to make a calculated decision for each patient. I ask for the patient’s input, too, since he or she is the one who’ll be taking it.

I also have to depend on patients’ honesty. Patients who sell drugs to others, take more than I’ve prescribed, or use other methods of getting them (doctor shopping, buying them off the street) are all committing serious offenses. The development of monitoring databases where I can check on such behaviors has helped me catch those who’ve abused the medications.

One person quoted in an article about the court decision said, “I lied to everybody. I would steal. I pawned my grandma’s wedding rings. I was breaking into houses, doing anything and everything to stay high.”

So, obviously, that was all the doctor’s fault. He was trying to help her, and apparently led her to commit theft and burglary. I suppose the next step in such insanity is that he could be charged as an accomplice in her crimes. After all, it’s not her fault that she decided to steal from others.

This opens up a gold mine. Crooks obtaining narcotics through illicit means can now sue the doctors who were originally trying to help them.

How will it affect me?

I’ll likely further decrease my writing for controlled pain meds. I really can’t give up my DEA number entirely, because I need it to write for several epilepsy medications. But the use of narcotics in my practice will decline. Other docs will probably do the same.

Sadly, this only hurts those who legitimately need pain relief. It will be harder for them to find doctors willing to prescribe narcotics, and even if they do, it’s possible those physicians won’t take their insurance.

Some will say my reaction to the ruling means I don’t care, which isn’t true. I do care. I signed up for this job to help people. But I also have a family to support and protect, and have to think of them, too.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.